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Almutary KH, Zaghloul MS, Nader MA, Elsheakh AR. Mechanistic insights into the protective potential of ambrisentan against L-arginine induced acute pancreatitis and multiorgan damage (role of NRF2/HO-1 and TXNIP/NLRP3 pathways). Biomed Pharmacother 2025; 187:118119. [PMID: 40319659 DOI: 10.1016/j.biopha.2025.118119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025] Open
Abstract
Acute pancreatitis (AP) is an abrupt inflammation of the pancreatic tissue. The severity of AP varies from mild and self-limiting to severe, potentially fatal, and can affect several organ systems. The most severe type of AP causes multiple organ damage (MOD) due to systemic inflammation. In this study, ambrisentan (AMB), an endothelin A receptor antagonist (ETA), was investigated for its potential to ameliorate L-arginine (L-Arg) induced AP and MOD in rats. AP was induced using L-Arg (100 mg/100 g). Two doses of AMB were tested and compared to N-acetylcystiene (NAC) effect. AMB restored the normal structure of the pancreatic, hepatic, pulmonary, and renal tissues. In addition, it normalized the levels of pancreatic enzymes, lactate dehydrogenase (LDH), serum liver enzymes, and kidney biomarkers. Furthermore, AMB corrected the imbalance in the levels of oxidants/antioxidants caused by L-Arg. In contrast, AMB (5 mg/kg) significantly upregulated the protein levels of adenosine monophosphate protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxidase-1(HO-1) and thioredoxin reductase 1 (TXNRD1) by approximately 69.59 %, 85.14 %, 688 % and 96 % respectively, compared with those in rats treated with L-Arg. Furthermore, AMB (5 mg/kg) significantly lowered the thioredoxin-interacting protein (TXNIP), nod-like Receptor Protein 3 (NLRP3), glycogen synthase kinase-3β (GSK-3β), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), CD68, autophagic markers (P62 and LC3) and apoptotic marker caspase 3 by around 62.43 %, 73.56 %, 62.5 %,70 %, 80.3 %, 93 %, 96.7 %, 95 %, 39.6 % respectively, compared to the group treated with L-Arg. AMB effectively improved the AP and MOD produced by L-Arg through its anti-inflammatory and antioxidant properties. NRF2/HO-1 and TXNIP/NLRP3 pathways play major roles in these protective effects.
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Affiliation(s)
- Khaled H Almutary
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Majmaah University, P.O.Box 66, Majmaah 11952, Saudi Arabia
| | - Marwa S Zaghloul
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt.
| | - Manar A Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt
| | - Ahmed R Elsheakh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt; Future Studies and Risks Management & National Committee of Drugs, Academy of Scientific Research, Ministry of Higher Education, Elsayeda Zeinab, Egypt
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Nista EC, Parello S, Brigida M, Amadei G, Saviano A, De Lucia SS, Petruzziello C, Migneco A, Ojetti V. Exploring the Role of Gut Microbiota and Probiotics in Acute Pancreatitis: A Comprehensive Review. Int J Mol Sci 2025; 26:3433. [PMID: 40244415 PMCID: PMC11989318 DOI: 10.3390/ijms26073433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/02/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025] Open
Abstract
Acute pancreatitis (AP) is a common and potentially severe gastrointestinal condition characterized by acute inflammation of the pancreas. The pathophysiology of AP is multifactorial and intricate, involving a cascade of events that lead to pancreatic injury and systemic inflammation. The progression of AP is influenced by many factors, including genetic predispositions, environmental triggers, and immune dysregulation. Recent studies showed a critical involvement of the gut microbiota in shaping the immune response and modulating inflammatory processes during AP. This review aims to provide a comprehensive overview of the emerging role of gut microbiota and probiotics in AP. We analyzed the implication of gut microbiota in pathogenesis of AP and the modification during an acute attack. The primary goals of microbiome-based therapies, which include probiotics, prebiotics, antibiotics, fecal microbiota transplantation, and enteral nutrition, are to alter the composition of the gut microbial community and the amount of metabolites derived from the microbiota. By resetting the entire flora or supplementing it with certain beneficial organisms and their byproducts, these therapeutic approaches aim to eradicate harmful microorganisms, reducing inflammation and avoiding bacterial translocation and the potential microbiota-based therapeutic target for AP from nutrition to pre- and probiotic supplementation to fecal transplantation.
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Affiliation(s)
- Enrico Celestino Nista
- Fondazione Policlinico Gemelli, Istituiti di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy; (E.C.N.); (S.P.); (G.A.); (A.S.); (S.S.D.L.); (A.M.)
| | - Simone Parello
- Fondazione Policlinico Gemelli, Istituiti di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy; (E.C.N.); (S.P.); (G.A.); (A.S.); (S.S.D.L.); (A.M.)
| | - Mattia Brigida
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, 00133 Rome, Italy;
| | - Giulio Amadei
- Fondazione Policlinico Gemelli, Istituiti di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy; (E.C.N.); (S.P.); (G.A.); (A.S.); (S.S.D.L.); (A.M.)
| | - Angela Saviano
- Fondazione Policlinico Gemelli, Istituiti di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy; (E.C.N.); (S.P.); (G.A.); (A.S.); (S.S.D.L.); (A.M.)
| | - Sara Sofia De Lucia
- Fondazione Policlinico Gemelli, Istituiti di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy; (E.C.N.); (S.P.); (G.A.); (A.S.); (S.S.D.L.); (A.M.)
| | | | - Alessio Migneco
- Fondazione Policlinico Gemelli, Istituiti di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168 Rome, Italy; (E.C.N.); (S.P.); (G.A.); (A.S.); (S.S.D.L.); (A.M.)
| | - Veronica Ojetti
- Ospedale San Carlo di Nancy, GVM Research, 00165 Rome, Italy
- Department of Internal Medicine, UniCamillus International Medical University of Rome, 00131 Rome, Italy
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3
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Vargas A, Dutta P, Hawa F, Quingalahua E, Marin R, Vilela A, Nix T, Mendoza-Ladd A, Wilcox CM, Chalhoub JM, Machicado JD. Effect of selective COX-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs on severity of acute pancreatitis: A systematic review and meta-analysis. Pancreatology 2025:S1424-3903(25)00061-4. [PMID: 40155261 DOI: 10.1016/j.pan.2025.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND It's been suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the inflammatory response and severity of acute pancreatitis (AP). In this systematic review and meta-analysis, we aimed to explore the impact of selective COX-2 and non-selective NSAIDs compared to non-NSAID options on the severity of AP. METHODS We searched MEDLINE, EMBASE, and Cochrane Central, from database inception through September 2023. We included RCTs and observational studies comparing NSAIDs with non-NSAID controls. The primary outcome was the development of severe acute pancreatitis (SAP) characterized by persistent organ failure lasting >48 h. Secondary outcomes included mortality, pancreatic necrosis, length of stay (LOS), pain relief, and requirement for rescue analgesia. Meta-analysis was conducted separately for selective COX-2 inhibitors and non-selective NSAIDs. RESULTS Eleven studies met eligibility criteria including 1830 patients with AP. Of 3 studies that used selective NSAIDs (1 RCT and 2 observational), COX-2 inhibitors significantly reduced SAP (OR = 0.38; 95 %CI 0.27-0.52; p < 0.001; I2 = 0 %), pancreatic necrosis (OR = 0.48; 95 %CI 0.29-0.78; p = 0.003; I2 = 0 %), LOS by 5.51 days (95 %CI -10.80 to -0.22; p = 0.04; I2 = 97 %), and rescue opioids (OR = 0.32; 95 %CI 0.24-0.45; p < 0.001; I2 = 0 %). However, the certainty of the evidence was graded as low to very low using GRADE methodology. There was no significant effect of COX-2 inhibitors on mortality. Of 8 studies (all RCTs) that compared non-selective NSAIDs and non-NSAIDs, there was no difference in clinical outcomes, pain relief, and need for rescue analgesia. CONCLUSIONS Selective COX-2 inhibitors potentially mitigate disease severity and shorten hospitalization in patients with AP, while non-selective NSAIDs lack this benefit. Confirmatory large-scale RCTs are warranted to validate these findings.
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Affiliation(s)
- Alejandra Vargas
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Priyata Dutta
- Department of Internal Medicine, Trinity Health, Ann Arbor, MI, USA
| | - Fadi Hawa
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| | - Elit Quingalahua
- Department of Pediatrics, Central Michigan University, Saginaw, MI, USA
| | - Ricardo Marin
- Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ana Vilela
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Tyler Nix
- Division of Research and Informatics, Taubman Health Sciences Library, University of Michigan, Ann Arbor, MI, USA
| | - Antonio Mendoza-Ladd
- Division of Gastroenterology and Hepatology, University of California Davis Health, Sacramento, CA, USA
| | - C Mel Wilcox
- Digestive Health Institute, Orlando Health, Orlando, FL, USA
| | - Jean M Chalhoub
- Division of Gastroenterology and Hepatology, Staten Island University Hospital, Staten Island, NY, USA
| | - Jorge D Machicado
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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Park J, Eun Y, Han K, Jung J, Kang S, Kim S, Hyun JJ, Kim H, Shin DW. Rheumatoid arthritis and risk of pancreatitis: a nationwide cohort study. Sci Rep 2025; 15:7607. [PMID: 40038384 PMCID: PMC11880365 DOI: 10.1038/s41598-025-91898-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 02/24/2025] [Indexed: 03/06/2025] Open
Abstract
We aimed to assess whether patients with rheumatoid arthritis (RA) have a higher risk of developing acute and chronic pancreatitis compared to individuals without RA. We identified 54,910 individuals with RA between 2010 and 2017. After exclusion, they were matched in a 1:3 ratio based on age and gender to control population without RA. Cox regression analyses were performed to estimate hazard ratio. During a median follow-up of 5.5 years, 0.18% of the patients with RA and 0.14% of the matched control developed acute pancreatitis. The risk acute pancreatitis was higher in the RA cohort compared to matched control (adjusted hazard ratio [aHR] 1.33; 95% confidence interval [CI] 1.02-1.74). In the case of chronic pancreatitis, 0.11% of patients with RA and 0.09% of the matched control developed chronic pancreatitis. Patients with RA appear to have a marginally elevated risk of chronic pancreatitis compared to matched controls (aHR 1.25, 95% CI 0.90-1.74), though this increase did not achieve statistical significance. The risk of acute pancreatitis is slightly higher in individuals with RA than in matched controls. The risk of chronic pancreatitis did not show statistical significance, but it tended to increase marginally in patients with RA.
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Affiliation(s)
- Jiho Park
- Division of Infectious Disease, Department of Internal Medicine, Konkuk University of Medicine, Seoul, Republic of Korea
| | - Yeonghee Eun
- Division of Rheumatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - JinHyung Jung
- Samsung Biomedical Research Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Seonyoung Kang
- Division of Rheumatology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seonghye Kim
- International Healthcare Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jong Jin Hyun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hyungjin Kim
- Department of Medical Humanities, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Dong Wook Shin
- Department of Family Medicine & Supportive Care Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
- Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Science and Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea.
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Mahapatra SJ, Garg PK. Organ Failure and Prediction of Severity in Acute Pancreatitis. Gastroenterol Clin North Am 2025; 54:1-19. [PMID: 39880521 DOI: 10.1016/j.gtc.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
Organ failure (OF) is a sinister development in the clinical course of acute pancreatitis, and its prediction is crucial for triaging the patient. Persistent systemic inflammatory response syndrome and raised interleukin-6 levels have a good predictive accuracy. Pathophysiology involves the release of damage-associated molecular patterns as a consequence of pancreatic injury, recruitment of inflammatory cells, and the release of proinflammatory cytokines and chemokines causing cytokine storm. Respiratory system is the most common and earliest to fail. Although a few therapeutic options are in the pipeline, renewed efforts are required to develop targeted therapies to mitigate systemic inflammation and OF.
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Affiliation(s)
| | - Pramod Kumar Garg
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India.
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Swetha K, Indumathi MC, Kishan R, Siddappa S, Chen CH, Marathe GK. Selenium Mitigates Caerulein and LPS-induced Severe Acute Pancreatitis by Inhibiting MAPK, NF-κB, and STAT3 Signaling via the Nrf2/HO-1 Pathway. Biol Trace Elem Res 2025:10.1007/s12011-025-04531-2. [PMID: 39907886 DOI: 10.1007/s12011-025-04531-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025]
Abstract
Severe acute pancreatitis (SAP) leads to systemic inflammation, resulting in multiorgan damage. Acute lung injury and acute respiratory distress syndrome develop in one-third of SAP patients, with a high mortality rate of 60% due to secondary complications. Patients with pancreatitis often have selenium deficiency, and selenium supplements may provide beneficial effects. This study examined the protective role of selenium in a model of SAP induced by caerulein + lipopolysaccharide (cae + LPS). Mice were administered selenium (1 mg/kg) before being challenged with caerulein (6 injections of 50 μg/kg) and LPS (10 mg/kg). At 3 h after the last caerulein injection, blood was collected for estimating pancreatic enzymes and cytokine levels, and the mice were euthanized. We performed morphological and histological studies, measured levels of protease and oxidative stress markers and conducted western blot, ELISA, and RT-qPCR analyses. We examined lung tissue histologically and estimated myeloperoxidase levels. Selenium pretreatment significantly reduced pancreatic enzyme levels such as amylase, lipase, and proteases (specifically MMPs) and reversed tissue injury in the pancreas and lungs caused by cae + LPS. In addition, selenium-treated mice showed decreased levels of inflammatory markers and chemokines. Examination of the downstream inflammatory pathways confirmed the protective effect of selenium, which mediates its anti-inflammatory and antioxidant action by inhibiting the major inflammatory signaling pathways (MAPKs, NF-κB, and STAT3) and activating the phosphorylation of Nrf2 via Nrf2/HO-1 pathways. These findings suggest that selenium may be a potential therapeutic option for treating SAP-associated secondary complications.
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Affiliation(s)
- Kamatam Swetha
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri Mysore, 570006, India
| | | | - Raju Kishan
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri Mysore, 570006, India
| | - Shiva Siddappa
- Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education and Research, Mysore, 570015, India
| | - Chu-Huang Chen
- Vascular and Medicinal Research, The Texas Heart Institute, Houston, TX, 77030, USA
| | - Gopal K Marathe
- Department of Studies in Biochemistry, University of Mysore, Manasagangotri Mysore, 570006, India.
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri Mysore, 570006, India.
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Hamo-Giladi DB, Fokra A, Sabo E, Kabala A, Minkov I, Hamoud S, Hadad S, Abassi Z, Khamaysi I. Involvement of heparanase in the pathogenesis of acute pancreatitis: Implication of novel therapeutic approaches. J Cell Mol Med 2024; 28:e18512. [PMID: 39248454 PMCID: PMC11382361 DOI: 10.1111/jcmm.18512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 06/07/2024] [Accepted: 06/18/2024] [Indexed: 09/10/2024] Open
Abstract
Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully understood and causal treatment options are not available. Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato-protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato-protective effect better than each drug alone. Thus, the current study examines the pancreato-protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild-type (WT) and Hpa over-expressing (Hpa-Tg) mice. Cerulein-induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa-Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti-Hpa drug combinations constitute a novel therapy for this common orphan disease.
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Affiliation(s)
- Dalit B Hamo-Giladi
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | - Ahmad Fokra
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | - Edmond Sabo
- Department of Pathology, Carmel Hospital, Haifa, Israel
| | - Aviva Kabala
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | - Irena Minkov
- Department of Pathology, Rambam Health Care Center, Haifa, Israel
| | - Shadi Hamoud
- Department of Internal Medicine E, Rambam Health Care Center, Haifa, Israel
| | - Salim Hadad
- Department of Pharmacy, Rambam Health Care Center, Haifa, Israel
| | - Zaid Abassi
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Haifa, Israel
- Department of Laboratory Medicine, Rambam Health Care Center, Haifa, Israel
| | - Iyad Khamaysi
- Department of Gastroenterology, Rambam Health Care Center, Haifa, Israel
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Mititelu A, Grama A, Colceriu MC, Benţa G, Popoviciu MS, Pop TL. Role of Interleukin 6 in Acute Pancreatitis: A Possible Marker for Disease Prognosis. Int J Mol Sci 2024; 25:8283. [PMID: 39125854 PMCID: PMC11311934 DOI: 10.3390/ijms25158283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/24/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Acute pancreatitis (AP) is a significant cause of morbidity, even in children, and is frequently associated with systemic manifestations. There are many cytokines involved in the inflammatory response characteristic of this disease. Interleukin 6 (IL-6) is one of the most important cytokines involved in AP, beginning from cellular injury and continuing to the systemic inflammatory response and distant organ involvement. IL-6 is a multifunctional cytokine that regulates acute-phase response and inflammation. It is produced by various cells and exerts its biological role on many cells through its high-affinity complex receptor. IL-6 has been investigated as a predicting maker for severe forms of AP. Many studies have validated the use of IL-6 serum levels in the first 48 h as a reliable marker for severe evolution and multisystemic involvement. Still, it has not been used in daily practice until now. This review discusses the main binding mechanisms by which IL-6 triggers cellular response and the AP pathogenetic mechanisms in which IL-6 is involved. We then emphasize the promising role of IL-6 as a prognostic marker, which could be added as a routine marker at admission in children with AP.
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Affiliation(s)
- Alexandra Mititelu
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Marius-Cosmin Colceriu
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
| | - Gabriel Benţa
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
| | | | - Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.M.); (M.-C.C.); (G.B.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
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9
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Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
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Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
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10
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Han Z, Li J, Yi X, Zhang T, Liao D, You J, Ai J. Diagnostic accuracy of interleukin-6 in multiple diseases: An umbrella review of meta-analyses. Heliyon 2024; 10:e27769. [PMID: 38515672 PMCID: PMC10955306 DOI: 10.1016/j.heliyon.2024.e27769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/23/2024] Open
Abstract
Objective This review aims to conduct a comprehensive study of the diagnostic accuracy of interleukin-6 (IL-6) for multiple diseases by utilizing existing systematic reviews and meta-analyses. Methods We performed a thorough search of Embase, Web of Science, PubMed, and Cochrane Database of Systematic Reviews up to April 2023 to gather meta-analyses that investigate the diagnostic accuracy of IL-6. To assess the methodological quality of the studies, we employed the Assessing the Methodological Quality of Systematic Reviews-2 and Grading of Recommendations, Assessment, Development and Evaluation criteria. Results We included 34 meta-analyses out of the 3024 articles retrieved from the search. These meta-analyses covered 9 categories of diseases of the International Classification of Diseases-11. Studies rated as "Critically Low" or "Very Low" in the quality assessment process were excluded, resulting in a total of 6 meta-analyses that encompassed sepsis, colorectal cancer, tuberculous pleural effusion (TPE), endometriosis, among others. Among these diseases, IL-6 demonstrated a relatively high diagnostic potential in accurately identifying TPE and endometriosis. Conclusions IL-6 exhibited favorable diagnostic accuracy across multiple diseases, suggesting its potential as a reliable diagnostic biomarker in the near future. Substantial evidence supported its high diagnostic accuracy, particularly in the cases of TPE and endometriosis.
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Affiliation(s)
| | | | | | - Tianyi Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 88 South Keyuan Road, Chengdu, 610041, PR China
| | - Dazhou Liao
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 88 South Keyuan Road, Chengdu, 610041, PR China
| | - Jia You
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 88 South Keyuan Road, Chengdu, 610041, PR China
| | - Jianzhong Ai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 88 South Keyuan Road, Chengdu, 610041, PR China
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Mattke J, Darden CM, Lawrence MC, Kuncha J, Shah YA, Kane RR, Naziruddin B. Toll-like receptor 4 in pancreatic damage and immune infiltration in acute pancreatitis. Front Immunol 2024; 15:1362727. [PMID: 38585277 PMCID: PMC10995222 DOI: 10.3389/fimmu.2024.1362727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 03/11/2024] [Indexed: 04/09/2024] Open
Abstract
Acute pancreatitis is a complex inflammatory disease resulting in extreme pain and can result in significant morbidity and mortality. It can be caused by several factors ranging from genetics, alcohol use, gall stones, and ductal obstruction caused by calcification or neutrophil extracellular traps. Acute pancreatitis is also characterized by immune cell infiltration of neutrophils and M1 macrophages. Toll-like receptor 4 (TLR4) is a pattern recognition receptor that has been noted to respond to endogenous ligands such as high mobility group box 1 (HMGB1) protein and or exogenous ligands such as lipopolysaccharide both of which can be present during the progression of acute pancreatitis. This receptor can be found on a variety of cell types from endothelial cells to resident and infiltrating immune cells leading to production of pro-inflammatory cytokines as well as immune cell activation and maturation resulting in the furthering of pancreatic damage during acute pancreatitis. In this review we will address the various mechanisms mediated by TLR4 in the advancement of acute pancreatitis and how targeting this receptor could lead to improved outcomes for patients suffering from this condition.
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Affiliation(s)
- Jordan Mattke
- Baylor University, Institute of Biomedical Studies, Waco, TX, United States
| | - Carly M. Darden
- Baylor University Medical Center, Annette C. and Harold C. Simmons Transplant Institute, Dallas, TX, United States
| | - Michael C. Lawrence
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, TX, United States
| | - Jayachandra Kuncha
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, TX, United States
| | - Yumna Ali Shah
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, TX, United States
| | - Robert R. Kane
- Baylor University, Institute of Biomedical Studies, Waco, TX, United States
| | - Bashoo Naziruddin
- Baylor University Medical Center, Annette C. and Harold C. Simmons Transplant Institute, Dallas, TX, United States
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12
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Wang H, Lü M, Li W, Shi J, Peng L. Early Predictive Value of Different Indicators for Persistent Organ Failure in Acute Pancreatitis: A Systematic Review and Network Meta-Analysis. J Clin Gastroenterol 2024; 58:307-314. [PMID: 36930726 PMCID: PMC10855994 DOI: 10.1097/mcg.0000000000001843] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/11/2023] [Indexed: 03/19/2023]
Abstract
GOALS In this study, we conducted this network meta-analysis (based on the ANOVA model) to evaluate the predictive efficacy of each early predictor. BACKGROUND Persistent organ failure (POF) is one of the determining factors in patients with acute pancreatitis (AP); however, the diagnosis of POF has a long-time lag (>48 h). It is of great clinical significance for the early noninvasive prediction of POF. STUDY We conducted a comprehensive and systematic search in PubMed, Cochrane library, Embase, and Web of Science to identify relevant clinical trials, case-control studies, or cohort studies, extracted the early indicators of POF in studies, and summarized the predictive efficacy of each indicator through network meta-analysis. The diagnostic odds ratio (DOR) was used to rank the prediction efficiency of each indicator. RESULTS We identified 23 studies in this network meta-analysis, including 10,393 patients with AP, of which 2014 patients had POF. A total of 10 early prediction indicators were extracted. The mean and 95% CI lower limit of each predictive indicator were greater than 1.0. Albumin had the largest diagnostic odds ratio, followed by high-density lipoprotein-cholesterol (HDL-C), Ranson Score, beside index for severity in acute pancreatitis Score, acute physiology and chronic health evaluation II, C-reactive protein (CRP), Interleukin 6 (IL-6), Interleukin 8 (IL-8), Systemic Inflammatory Response Syndrome (SIRS) and blood urea nitrogen. CONCLUSIONS Albumin, high-density lipoprotein-cholesterol, Ranson Score, and beside index for severity in acute pancreatitis Score are effective in the early prediction of POF in patients with AP, which can provide evidence for developing effective prediction systems. However, due to the limitations of the extraction method of predictive indicators in this study, some effective indicators may not be included in this meta-analysis.
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Affiliation(s)
- Huan Wang
- Department of Gastroenterology, Wenjiang District People’s Hospital of Chengdu
| | - Muhan Lü
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University
- Human Microecology and Precision Diagnosis and Treatment of Luzhou Key Laboratory
- Cardiovascular and Metabolic Diseases of Sichuan Key Laboratory, Luzhou, China
| | - Wei Li
- Department of Gastroenterology, Wenjiang District People’s Hospital of Chengdu
| | - Jingfen Shi
- Institute for Health Policy and Hospital Management, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Lan Peng
- Department of Gastroenterology, Wenjiang District People’s Hospital of Chengdu
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13
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Idiz UO, Aru B, Kaya C, Peker KD, Tatar C, Guler M, Tunay A, Demirel GY, Gurol AO. Could we use PD-1 and PD-L1 expression on lymphocytes and monocytes as predictive markers for prognosis of acute biliary pancreatitis? Immunol Lett 2024; 265:37-43. [PMID: 38199503 DOI: 10.1016/j.imlet.2024.106836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 01/03/2024] [Accepted: 01/07/2024] [Indexed: 01/12/2024]
Abstract
PURPOSE This study aimed to assess the significance of immunophenotyping and serum cytokines in predicting the clinical progression of acute biliary pancreatitis (ABP). MATERIALS AND METHODS Cytokine levels, T-helper, cytotoxic T, natural killer (NK) cells, monocytes, HLA-DR, and PD-1, as well as PDL-1 immune checkpoints, were measured in ABP patients at the time of diagnosis and compared with results from healthy volunteers. The study also compared leukocyte counts, hematocrit, immunophenotyping results, cytokine statuses, and PD-1, PDL-1 expression between healthy volunteers and ABP subgroups categorized by pancreatitis severity. RESULTS The study included 65 ABP patients and 20 healthy volunteers. Significant differences were observed between groups in hematocrit, leukocyte counts, total monocytes, lymphocytes, CD3+ total T cells, CD4+ Th cells, PD-1 expression on CD4+ and CD8+T lymphocytes, HLA-DR expression on CD14+ monocytes, NK cells, PD-L1 expression on CD14+ monocytes, classical and intermediate monocytes, as well as levels of IL-6, IL-8, IL-10, IL-18, and IL-33 cytokines. Moderate correlations were found with lymphocyte counts, PD-1+CD4+ cells, PD-L1+CD14+ cells, and strong correlations with HLA-DR+CD14+ cells. Hematocrit, CD3+ total T cells, NK cells, CD4+PD-1 + T cells, and CD8+PD-1 + T cells showed independent associations with the severity of ABP. Lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, CD4+PD-1 + T cells, classical, and intermediate monocytes exhibited the highest Area Under the Curve rates in determining organ failure. CONCLUSIONS Hematocrit, lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, and intermediate monocytes emerged as parameters most closely associated with the severity and these parameters could be useful in predicting the severity of ABP.
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Affiliation(s)
- Ufuk Oguz Idiz
- Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey; Institute of Health Sciences, Istanbul University, Istanbul, Turkey; Department of Immunology, Istanbul University, DETAE, Istanbul, Turkey.
| | - Basak Aru
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Turkey
| | - Cemal Kaya
- Department of General Surgery, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey
| | - Kivanc Derya Peker
- Department of General Surgery, Hisar Hospital Intercontinental, Istanbul, Turkey
| | - Cihad Tatar
- Department of General Surgery, Acibadem University, Istanbul, Turkey
| | - Mert Guler
- Department of General Surgery, Istanbul Training and Research Hospital, Istanbul, Turkey
| | - Abdurrahman Tunay
- Department of Anesthesia and Reanimation, Istanbul Training and Research Hospital, Istanbul, Turkey
| | | | - Ali Osman Gurol
- Department of Immunology, Istanbul University, DETAE, Istanbul, Turkey
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14
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Pellegrini J, Sodoma AM, Munshi R, Russe-Russe JR, Arias J, Farraj KL, Pellegrini RG, Singh J. Impact of Obesity on Outcomes Associated With Acute Alcoholic Pancreatitis. Cureus 2024; 16:e51653. [PMID: 38313969 PMCID: PMC10838057 DOI: 10.7759/cureus.51653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 02/06/2024] Open
Abstract
The incidence and prevalence of obesity have been rising in the United States, negatively impacting the population's overall health. This study seeks to better understand the impact of obesity on patients presenting with acute alcoholic pancreatitis (AAP). Data collected using the National Inpatient Sample (NIS) from the fourth quarter of 2015 to 2019 with a principal diagnosis of AAP and secondary obesity were analyzed. Confounders were adjusted for multivariate regression analysis using a multitude of factors. A total of 229,510 patients were identified with a diagnosis of AAP, among which 14,150 were also identified as obese. A majority of the sample, both obese and non-obese patients with AAP, were middle-aged white females. The average comorbidity index (CCI) was lower in the non-obese cohort compared to the obese cohort. Compared to non-obese patients, patients with AAP who were obese had higher hospital charges and a longer LOS (p<0.05. Additionally, compared to non-obese patients, obese patients with AAP had higher odds of mortality and adverse events, such as acute renal failure and respiratory failure (p<0.05). Current research supports these complications, which have shown an association with increased visceral fat in or around the pancreas that can ultimately worsen acute pancreatitis outcomes and aggravate AAP by damaging the intestinal mucosal barrier. These findings should be considered when treating obese patients who develop AAP. Strategies to increase surveillance of such patients should be implemented to reduce complications and mortality in this population.
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Affiliation(s)
- James Pellegrini
- Gastroenterology, Nassau University Medical Center, East Meadow, USA
| | - Andrej M Sodoma
- Internal Medicine, South Shore University Hospital, Bay Shore, USA
| | - Rezwan Munshi
- Internal Medicine, Nassau University Medical Center, East Meadow, USA
| | | | - Jonathan Arias
- Internal Medicine, Nassau University Medical Center, East Meadow, USA
| | - Kristen L Farraj
- Internal Medicine, Nassau University Medical Center, East Meadow, USA
| | | | - Jaspreet Singh
- Gastroenterology, South Shore University Hospital, Bay Shore, USA
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15
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Oikonomou P, Nikolaou C, Papachristou F, Sovatzidis A, Lambropoulou M, Giouleka C, Kontaxis V, Linardoutsos D, Papalois A, Pitiakoudis M, Tsaroucha A. Eugenol Reduced ΜPO, CD45 and HMGB1 Expression and Attenuated the Expression of Leukocyte Infiltration Markers in the Intestinal Tissue in Biliopancreatic Duct Ligation-Induced Pancreatitis in Rats. MEDICINA (KAUNAS, LITHUANIA) 2023; 60:74. [PMID: 38256335 PMCID: PMC10820626 DOI: 10.3390/medicina60010074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/30/2023] [Accepted: 12/26/2023] [Indexed: 01/24/2024]
Abstract
Background and Objectives: Inflammation and dysregulation in the intestinal barrier function in acute pancreatitis (AP) trigger pancreatic lesions, systemic inflammatory response, and multiple organ dysfunction. Eugenol, as the main component of clove (Syzygium aromaticum), is known for its antioxidant and anti-inflammatory properties. We studied the potentially beneficial effect of eugenol in a rodent model of biliopancreatic duct ligation-induced AP. Materials and Methods: Rats were randomly divided into three groups: Sham, AP, and AP + eugenol (15 mg/kg/day). Serum TNFα, IL-6, IL-18, and resistin levels, as well as IL-6, TNFα, MPO, HMGB1, and CD45 tissue expression, were determined at various timepoints after the induction of AP. Results: Eugenol attenuated hyperemia and inflammatory cell infiltration in the intestinal mucosal, submucosal, and muscular layers. IL-6 and resistin serum levels were significantly reduced in the AP + eugenol group, while serum TNFα and IL-18 levels remained unaffected overall. TNFα pancreatic and intestinal expression was attenuated by eugenol at 72 h, while IL-6 expression was affected only in the pancreas. MPO, CD45, and HMGB1 intestinal expression was significantly reduced in eugenol-treated rats. Conclusions: Eugenol managed to attenuate the inflammatory response in the intestine in duct ligation-induced AP in rats.
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Affiliation(s)
- Panagoula Oikonomou
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Christina Nikolaou
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Fotini Papachristou
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
| | - Apostolos Sovatzidis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Maria Lambropoulou
- Laboratory of Histology-Embryology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Charikleia Giouleka
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Vasileios Kontaxis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Dimitrios Linardoutsos
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Apostolos Papalois
- Experimental Research Center, ELPEN Pharmaceuticals, Pikermi, 19009 Athens, Greece;
| | - Michael Pitiakoudis
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
| | - Alexandra Tsaroucha
- Postgraduate Program in Hepatobiliary and Pancreatic Surgery, 2nd Department of Surgery, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (A.S.); (C.G.); (V.K.); (D.L.); (M.P.); (A.T.)
- Laboratory of Experimental Surgery and Surgical Research, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (C.N.); (F.P.)
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16
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Dhar Chowdhury S, Thomas A, Kurien RT, Gupta P, John A, Rajeeb J, David VG, Nair SC, Simon EG, Dutta AK, Joseph AJ, Eapen CE. Secondary thrombotic microangiopathy (TMA) precipitated by acute pancreatitis: A case series. Pancreatology 2023; 23:1045-1047. [PMID: 38487925 DOI: 10.1016/j.pan.2023.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 08/05/2023] [Accepted: 10/09/2023] [Indexed: 03/19/2024]
Affiliation(s)
| | - Ajith Thomas
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | | | - Piyush Gupta
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | - Anoop John
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | - Jaleel Rajeeb
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | | | - Sukesh Chandran Nair
- Department of Transfusion Medicine and Immunohaematology, Christian Medical College, Vellore, India
| | - Ebby George Simon
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | - Amit Kumar Dutta
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | | | - C E Eapen
- Department of Gastroenterology, Christian Medical College, Vellore, India
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17
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Chen B, Moin A, Virk HUH, Jneid H, Virani SS, Krittanawong C. Association of Cardiovascular Disease and Pancreatitis: What Came First, the Chicken or the Egg? J Clin Med 2023; 12:7101. [PMID: 38002718 PMCID: PMC10672425 DOI: 10.3390/jcm12227101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/04/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
(1) Background: Recent studies suggest an association between pancreatitis and cardiovascular disease. This article aims to review the available evidence linking cardiovascular disease with acute and chronic pancreatitis. (2) Methods: A comprehensive search was conducted on the PubMed/MEDLINE database from inception to April 2022 using Medical Subject Heading and keywords related to pancreatitis and cardiovascular disease. The search was limited to English-language literature involving human subjects, and various study types, including observational studies, case-control studies, cohort studies, and clinical trials, were screened for eligibility. Following data extraction, the authors conducted a narrative synthesis of the studies. (3) Results: Longitudinal studies indicate that a history of acute pancreatitis is associated with an increased risk of acute atherosclerotic cardiovascular disease and acute coronary syndrome. Elevated triglyceride levels (>2000 mg/dL) have a temporal relationship with acute pancreatitis. Cross-sectional studies have shown that acute pancreatitis is associated with cardiac injury during the acute phase. Based on longitudinal studies, chronic pancreatitis is associated with an increased risk of cerebrovascular diseases. However, data regarding the relationship between chronic pancreatitis and myocardial infarction are conflicting. (4) Conclusions: Based on the available evidence, having a history of acute pancreatitis appears to increase the risk of acute atherosclerotic cardiovascular disease. However, there is insufficient evidence to conclude whether chronic pancreatitis is associated with cardiovascular disease, and no definitive studies have yielded conflicting results.
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Affiliation(s)
- Bing Chen
- Department of Gastroenterology and Hepatology, Geisinger Medical Center, Danville, PA 17822, USA
| | - Aleena Moin
- Department of Internal Medicine-Pediatrics, Geisinger Medical Center, Danville, PA 17822, USA
| | - Hafeez Ul Hassan Virk
- Harrington Heart & Vascular Institute, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Hani Jneid
- John Sealy Distinguished Centennial Chair in Cardiology, Division of Cardiology, University of Texas Medical Branch, Houston, TX 77058, USA
| | - Salim S. Virani
- Section of Cardiology and Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Office of the Vice Provost (Research), The Aga Khan University, Karachi 74800, Pakistan
| | - Chayakrit Krittanawong
- Cardiology Division, NYU Langone Health and NYU School of Medicine, New York, NY 10016, USA
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18
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Skipper MT, Albertsen BK, Schmiegelow K, Andrés-Jensen L. Long-term effects of asparaginase-associated pancreatitis. Pediatr Blood Cancer 2023:e30528. [PMID: 37376950 DOI: 10.1002/pbc.30528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 05/19/2023] [Indexed: 06/29/2023]
Abstract
Pancreatitis is a common and severe toxicity that occurs during asparaginase treatment for acute lymphoblastic leukemia, and has received increasing attention during the last decades. However, no consensus regarding follow-up exists. In this commentary, we highlight potential long-term health-related effects following asparaginase-associated pancreatitis, thereby providing clinicians with a framework when following these patients during and after cessation of therapy.
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Affiliation(s)
- Mette Tiedemann Skipper
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Birgitte Klug Albertsen
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Kjeld Schmiegelow
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Liv Andrés-Jensen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
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19
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Kilic G, Kilic GE, Ozkahraman A, Konur S, Dertli R, Kayar Y. Course of Acute Pancreatitis Patients with Renal Failure According to Balthazar Classification. Niger J Clin Pract 2023; 26:680-685. [PMID: 37470639 DOI: 10.4103/njcp.njcp_728_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
Background and Aim There are criteria that include many organ systems to predict the prognosis in acute pancreatitis (AP) patients. In this study, we aimed to show how the course of the disease changes according to the Balthazar classification in AP patients presenting with renal failure. Methods and Materials Our study included 352 patients who were admitted to the Emergency Service of our hospital and were diagnosed and hospitalized with AP. According to the Balthazar score, patients with scores of 0-2, 4-6, and 8-10 were evaluated as mild, moderate, and severe AP, respectively. Demographic data (age, gender) of all patients were documented. The etiology of AP was determined in all patients. Biliary, drug/toxic, alcohol, infections, hyperlipidemia, post-endoscopic retrograde cholangiopancreatography (ERCP), genetics, hypercalcemia, structural anomalies, and malignancy were evaluated as the etiology. Those without any underlying pathology were evaluated as idiopathic AP. The patients were divided into two groups as those with and without renal insufficiency. All patients underwent helical computed tomography (section 64, Aquilion; Toshiba Medical Systems, Tokyo) within the first 12 hours and between days 3 and 7. Pancreas, peripancreatic and extrapancreatic findings, and complications were examined. "The Statistical Package for the Social Sciences 19.0 (SPSS Armonk, NY: IBM Corp.)" was used for all analyses. Kolmogorov-Smirnov test and histograms were used to determine whether there was a normal distribution. The non-parametric data of the groups were compared using the Mann-Whitney U test and the parametric data using the ındependent t test. Chi-square test was used to test categorical data. Cases with P < 0.05 were considered statistically significant. Results : While 22 (6.2%) patients had renal insufficiency, 332 (95.8%) patients did not have renal insufficiency. In the evaluation made in terms of AP severity; according to Balthazar classification at admission, there was no difference in mild and moderate pancreatitis for kidney insufficiency in both groups, but it was significantly higher in the group with severe pancreatitis [2 (9.1%) versus 1 (0.3%), P < 0.001]. In the evaluation made after 72 hours; renal failure was significantly lower in the group with mild pancreatitis [11 (50.0%) versus 245 (73.8%), P: 0.016] and severe renal failure was significantly higher in severe pancreatitis [7 (31.8%) versus 13 (%) 3.9), P < 0.001]. Conclusions Early intensive care unit admission and close follow-up and early treatment in AP patients change the course of the disease. In our study, we showed that serum creatinine level is an important parameter in the course of AP and has a predictive value for the course of the disease.
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Affiliation(s)
- G Kilic
- Department of Internal Medicine, Van Education and Research Hospital, Division of Gastroenterology, Van, Turkey
| | - G E Kilic
- Department of Internal Medicine, Van Education and Research Hospital, Van, Turkey
| | - A Ozkahraman
- Department of Internal Medicine, Van Education and Research Hospital, Van, Turkey
| | - S Konur
- Department of Internal Medicine, Van Education and Research Hospital, Van, Turkey
| | - R Dertli
- Department of Internal Medicine, Van Education and Research Hospital, Division of Gastroenterology, Van, Turkey
| | - Y Kayar
- Department of Internal Medicine, Van Education and Research Hospital, Division of Gastroenterology, Van, Turkey
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20
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Tomaszewska E, Świątkiewicz M, Muszyński S, Donaldson J, Ropka-Molik K, Arciszewski MB, Murawski M, Schwarz T, Dobrowolski P, Szymańczyk S, Dresler S, Bonior J. Repetitive Cerulein-Induced Chronic Pancreatitis in Growing Pigs-A Pilot Study. Int J Mol Sci 2023; 24:ijms24097715. [PMID: 37175426 PMCID: PMC10177971 DOI: 10.3390/ijms24097715] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Chronic pancreatitis (CP) is an irreversible and progressive inflammatory disease. Knowledge on the development and progression of CP is limited. The goal of the study was to define the serum profile of pro-inflammatory cytokines and the cell antioxidant defense system (superoxidase dismutase-SOD, and reduced glutathione-GSH) over time in a cerulein-induced CP model and explore the impact of these changes on selected cytokines in the intestinal mucosa and pancreatic tissue, as well as on selected serum biochemical parameters. The mRNA expression of CLDN1 and CDH1 genes, and levels of Claudin-1 and E-cadherin, proteins of gut barrier, in the intestinal mucosa were determined via western blot analysis. The study showed moderate pathomorphological changes in the pigs' pancreas 43 days after the last cerulein injection. Blood serum levels of interleukin (IL)-1-beta, IL-6, tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGTP), SOD and GSH were increased following cerulein injections. IL-1-beta, IL-6, TNF-alpha and GSH were also increased in jejunal mucosa and pancreatic tissue. In duodenum, decreased mRNA expression of CDH1 and level of E-cadherin and increased D-lactate, an indicator of leaky gut, indicating an inflammatory state, were observed. Based on the current results, we can conclude that repetitive cerulein injections in growing pigs not only led to CP over time, but also induced inflammation in the intestine. As a result of the inflammation, the intestinal barrier was impaired.
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Affiliation(s)
- Ewa Tomaszewska
- Department of Animal Physiology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Małgorzata Świątkiewicz
- Department of Animal Nutrition and Feed Science, National Research Institute of Animal Production, 32-083 Balice, Poland
| | - Siemowit Muszyński
- Department of Biophysics, Faculty of Environmental Biology, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Janine Donaldson
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg 2193, South Africa
| | - Katarzyna Ropka-Molik
- Department of Animal Molecular Biology, National Research Institute of Animal Production, 32-083 Balice, Poland
| | - Marcin B Arciszewski
- Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Maciej Murawski
- Department of Animal Nutrition, Biotechnology and Fisheries, Faculty of Animal Science, University of Agriculture in Kraków, 30-059 Kraków, Poland
| | - Tomasz Schwarz
- Department of Animal Genetics, Breeding and Ethology, Faculty of Animal Science, University of Agriculture in Kraków, 30-059 Kraków, Poland
| | - Piotr Dobrowolski
- Department of Functional Anatomy and Cytobiology, Faculty of Biology and Biotechnology, Maria Curie-Sklodowska University, 20-033 Lublin, Poland
| | - Sylwia Szymańczyk
- Department of Animal Physiology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland
| | - Sławomir Dresler
- Department of Analytical Chemistry, Medical University of Lublin, 20-059 Lublin, Poland
- Department of Plant Physiology and Biophysics, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, 20-033 Lublin, Poland
| | - Joanna Bonior
- Department of Medical Physiology, Chair of Biomedical Sciences, Institute of Physiotherapy, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland
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21
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Podda M, Pellino G, Di Saverio S, Coccolini F, Pacella D, Cioffi SPB, Virdis F, Balla A, Ielpo B, Pata F, Poillucci G, Ortenzi M, Damaskos D, De Simone B, Sartelli M, Leppaniemi A, Jayant K, Catena F, Giuliani A, Di Martino M, Pisanu A. Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study. Updates Surg 2023; 75:493-522. [PMID: 36899292 PMCID: PMC10005914 DOI: 10.1007/s13304-023-01488-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 02/24/2023] [Indexed: 03/12/2023]
Abstract
The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990).
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Affiliation(s)
- Mauro Podda
- Emergency Surgery Unit, Department of Surgical Science, Policlinico Universitario "D. Casula", Azienda Ospedaliero-Universitaria di Cagliari, University of Cagliari, SS 554, Km 4,500, Monserrato, 09042, Cagliari, Italy.
| | - Gianluca Pellino
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
- Colorectal Surgery Unit, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Salomone Di Saverio
- Department of Surgery, "Madonna del Soccorso" Hospital, San Benedetto del Tronto, Italy
| | - Federico Coccolini
- General, Emergency and Trauma Surgery Unit, Pisa University Hospital, Pisa, Italy
| | - Daniela Pacella
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | | | - Francesco Virdis
- Trauma and Acute Care Surgery Unit, "Niguarda Ca Granda" Hospital, Milan, Italy
| | - Andrea Balla
- General and Minimally-Invasive Surgery Unit, "San Paolo" Hospital, Civitavecchia, Rome, Italy
| | | | - Francesco Pata
- General Surgery Unit, "Nicola Giannettasio" Hospital, Corigliano-Rossano, Italy
| | - Gaetano Poillucci
- Department of General Surgery, Policlinico Umberto I, La Sapienza University of Rome, Rome, Italy
| | - Monica Ortenzi
- Department of General and Emergency Surgery, Marche Polytechnic University, Ancona, Italy
| | - Dimitrios Damaskos
- Department of Upper G.I. Surgery, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK
| | - Belinda De Simone
- Department of Emergency and Metabolic Minimally Invasive Surgery, Centre Hospitalier Intercommunal de Poissy/Saint Germain en Laye, Poissy Cedex, France
| | | | - Ari Leppaniemi
- Department of Abdominal Surgery, Abdominal Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Kumar Jayant
- Department of Surgery & Cancer, Imperial College London, Du Cane Road, London, UK
| | - Fausto Catena
- Department of Emergency and Trauma Surgery, "Bufalini" Hospital, Cesena, Italy
| | - Antonio Giuliani
- General and Emergency Surgery Unit, San Carlo Hospital, Potenza, Italy
| | - Marcello Di Martino
- Division of Hepatobiliary and Liver Transplantation Surgery, "A.O.R.N. Cardarelli", Naples, Italy
| | - Adolfo Pisanu
- Emergency Surgery Unit, Department of Surgical Science, Policlinico Universitario "D. Casula", Azienda Ospedaliero-Universitaria di Cagliari, University of Cagliari, SS 554, Km 4,500, Monserrato, 09042, Cagliari, Italy
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22
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Shin IS, Park CH, Moon JH, Lee JK, Lee DH, Yang MJ. Human Bone Marrow-derived Clonal Mesenchymal Stem Cells Decrease the Initial C-Reactive Protein Level in Patients With Moderately Severe to Severe Acute Pancreatitis. Gastroenterology 2023; 164:1317-1320.e2. [PMID: 36801388 DOI: 10.1053/j.gastro.2023.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/04/2023] [Accepted: 02/12/2023] [Indexed: 02/23/2023]
Affiliation(s)
- Il Sang Shin
- Department of Internal Medicine, SoonChunHyang University School of Medicine, Bucheon, Korea
| | - Chang-Hwan Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Jong Ho Moon
- Department of Internal Medicine, SoonChunHyang University School of Medicine, Bucheon, Korea.
| | - Jun Kyu Lee
- Department of Internal Medicine, Dongguk University School of Medicine, Ilsan, Korea
| | - Don Haeng Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Min Jae Yang
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, Korea
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23
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Venkatesh K, Glenn H, Delaney A, Andersen CR, Sasson SC. Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis. Front Immunol 2023; 13:1077414. [PMID: 36713404 PMCID: PMC9874226 DOI: 10.3389/fimmu.2022.1077414] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Introduction Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities. Methods A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention. Results 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease. Conclusions AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.
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Affiliation(s)
- Karthik Venkatesh
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
| | - Hannah Glenn
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Anthony Delaney
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Christopher R. Andersen
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Sarah C. Sasson
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia
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24
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Song Q, Gao H, Wu W, Gao Y, Yang J, Jiao Z, Luo Y. Gabexate Mesylate-Poloxamer 407 Conjugate Alleviates Sodium Taurocholate-Induced Severe Acute Pancreatitis in an Optimized Rat Model. Dig Dis Sci 2023; 68:138-146. [PMID: 35451710 DOI: 10.1007/s10620-022-07497-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/16/2021] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND AIMS We have previously shown that gabexate mesylate-poloxamer 407 conjugate (GMTI) alleviates traumatic pancreatitis in rats. In this study, we evaluated the therapeutic effect of GMTI on sodium taurocholate-induced severe acute pancreatitis (SAP) in an optimized rat model. METHODS An SAP rat model was established via microinjection of 3.5% sodium taurocholate and retention in the bile duct for 1 min. SAP rats were administered GMTI via tail vein injection (i.v.) or tail vein injection + intraperitoneal injection (i.v. + i.p.). All rats were sacrificed at 12 h after treatment. Biochemical approach and enzyme-linked immunosorbent assay were performed to measure the serum levels of amylase (AMY), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Hematoxylin and eosin staining and TUNEL assay were conducted to examine histopathology and acinar cell apoptosis in the rat pancreas. RESULTS SAP was successfully induced in all model rats, as evidenced by progressively aggravating SAP symptoms and signs, pancreatic histopathological abnormalities, as well as elevated serum levels of TNF-α, IL-6, and AMY. The mortality rates at 1 h, 6 h, and 12 h were 0%, 0%, and 25%, respectively. GMTI therapy via i.v. or i.v. + i.p. significantly reduced pancreatic wet weights, ascites amounts, pathological scores, and circulating levels of TNF-α and IL-6 while promoting acinar cell apoptosis in SAP rats. GMTI therapy via i.v. + i.p. outperformed i.v. in improving pancreatic histology and reducing TNF-α and IL-6 serum levels in SAP rats. CONCLUSIONS Our optimized SAP rat model is reliable and reproducible. GMTI therapy is a promising approach against SAP.
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Affiliation(s)
- Qing Song
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Hanjing Gao
- Department of Ultrasound, Second Medical Center, General Hospital of Chinese PLA, Beijing, 100853, China
| | - Wen Wu
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Yu Gao
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Jihua Yang
- Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Ziyu Jiao
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China
| | - Yukun Luo
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China.
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25
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Shao Y, Li C, Jiang Y, Li H, Tang X, Gao Z, Zhang D. Inhibition of Caspase-11-Mediated Pyroptosis Alleviates Acute Kidney Injury Associated with Severe Acute Pancreatitis in Rats. J INVEST SURG 2023; 36:1-7. [DOI: 10.1080/08941939.2022.2142868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Yang Shao
- Qingdao Medical College, Qingdao University, Qingdao, Shandong Province, China
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Chang Li
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Yingjian Jiang
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Hongbo Li
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Xuefei Tang
- Qingdao Medical College, Qingdao University, Qingdao, Shandong Province, China
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Zhaoyu Gao
- Qingdao Medical College, Qingdao University, Qingdao, Shandong Province, China
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
| | - Dianliang Zhang
- Department of The First General Surgery, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong Province, China
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Abstract
AIM Acute lung injury (ALI) is a common complication of severe acute pancreatitis (SAP) with a high mortality. Early prediction of patients at risk in initial stage can improve the long-term survival. METHODS A total of 91 patients with SAP out of 1647 acute pancreatitis patients from January 2015 to December 2020 were considered. A predictive model for SAP-associated ALI was constructed based on the valuable risk factors identified from routine clinical characteristics and plasma biomarkers. The value of the model was evaluated and compared with Lung Injury Prediction Score (LIPS). A nomogram was built to visualize the model. RESULTS Diabetes, oxygen supplementation, neutrophil count and D-dimer were found to be associated with ALI in SAP. The predictive model based on these factors had an area under the receiver operating characteristic curve [AUC: 0.88, 95% confidence interval (CI): 0.81-0.95], which was superior to LIPS (AUC: 0.71, 95% CI: 0.60-0.83), also with the higher sensitivity (65%) and specificity (96%) than LIPS (62%, 74%, respectively). Decision curve analysis of the model showed a higher net benefit than LIPS. Visualization by a nomogram facilitated the application of the model. CONCLUSION Diabetes, oxygen supplementation, neutrophil count and D-dimer were risk factors for SAP-associated ALI. The combination of these routine clinical data and the model visualization by a nomogram provided a simple and effective way in predicting ALI in the early phase of SAP.
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27
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Nazerian Y, Ghasemi M, Yassaghi Y, Nazerian A, Mahmoud Hashemi S. Role of SARS-CoV-2-induced Cytokine Storm in Multi-Organ Failure: Molecular Pathways and Potential Therapeutic Options. Int Immunopharmacol 2022; 113:109428. [PMID: 36379152 PMCID: PMC9637536 DOI: 10.1016/j.intimp.2022.109428] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/19/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022]
Abstract
Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called “cytokine storm” is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19.
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Affiliation(s)
- Yasaman Nazerian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Ghasemi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Younes Yassaghi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Mahmoud Hashemi
- Medical nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Corresponding author at: Medical nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran / Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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28
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Ni W, Ma YF, Chen T, Chen X. Toll-Like Receptor 9 Signaling Pathway Contributes to Intestinal Mucosal Barrier Injury in Mice With Severe Acute Pancreatitis. Pancreas 2022; 51:1194-1200. [PMID: 37078945 DOI: 10.1097/mpa.0000000000002169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
OBJECTIVES The purpose of this study was to investigate the role and mechanism of toll-like receptor 9 (TLR9) in intestinal mucosal barrier injury in mice with severe acute pancreatitis (SAP). METHODS The mice were randomly divided into 3 groups: control group, SAP group, and TLR9 antagonist-treated group. The expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, diamine oxidase, and endotoxin core antibodies were detected by enzyme-linked immunosorbent assay. The protein expression of zonula occluden-1 (ZO)-1, occludin, TLR9, myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6), p-nuclear factor (NF)-κB p65, and NF-κB p65 were detected by Western blot. TdT-mediated dUTP nick-end labeling staining was used for detecting intestinal epithelial cell apoptosis. RESULTS The expression of TLR9 and its related pathway proteins MyD88, TRAF6, and p-NF-κB p65 in the intestinal tract of SAP mice were significantly increased compared with that of control mice. Inhibition of the TLR9 expression could reduce the level of serum proinflammatory cytokines, reduce the apoptosis of intestinal epithelial cells, improve intestinal permeability, and ultimately reduce the damage of intestinal mucosal barrier function in SAP. CONCLUSIONS Toll-like receptor 9/MyD88/TRAF6/NF-κB signaling pathway plays an important role in intestinal mucosal barrier injury of SAP.
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Affiliation(s)
- Wei Ni
- From the Intensive Care Unit,The First People's Hospital of Shuangliu District, Chengdu City, China
| | - Yu-Feng Ma
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou City, China
| | - Tao Chen
- Department of Digestive Endoscopy, Suining Central Hospital, Suining City, China
| | - Xia Chen
- Department of Gastroenterology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu City, China
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The retroelement Lx9 puts a brake on the immune response to virus infection. Nature 2022; 608:757-765. [PMID: 35948641 DOI: 10.1038/s41586-022-05054-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 06/30/2022] [Indexed: 11/08/2022]
Abstract
The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago1,2. However, it was not until the advancement of genomic sequencing technologies that the abundance and repertoire of transposable elements were revealed, and they are now known to constitute up to two-thirds of mammalian genomes3,4. The presence of DNA regulatory regions including promoters, enhancers and transcription-factor-binding sites within transposable elements5-8 has led to the hypothesis that transposable elements have been co-opted to regulate mammalian gene expression and cell phenotype8-14. Mammalian transposable elements include recent acquisitions and ancient transposable elements that have been maintained in the genome over evolutionary time. The presence of ancient conserved transposable elements correlates positively with the likelihood of a regulatory function, but functional validation remains an essential step to identify transposable element insertions that have a positive effect on fitness. Here we show that CRISPR-Cas9-mediated deletion of a transposable element-namely the LINE-1 retrotransposon Lx9c11-in mice results in an exaggerated and lethal immune response to virus infection. Lx9c11 is critical for the neogenesis of a non-coding RNA (Lx9c11-RegoS) that regulates genes of the Schlafen family, reduces the hyperinflammatory phenotype and rescues lethality in virus-infected Lx9c11-/- mice. These findings provide evidence that a transposable element can control the immune system to favour host survival during virus infection.
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30
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Hong XX, Wang HY, Yang JM, Lin BF, Min QQ, Liang YZ, Huang PD, Zhong ZY, Guo SJ, Huang B, Xu YF. Systemic injury caused by taurocholate-induced severe acute pancreatitis in rats. Exp Ther Med 2022; 24:468. [PMID: 35747153 PMCID: PMC9204573 DOI: 10.3892/etm.2022.11395] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/13/2022] [Indexed: 11/06/2022] Open
Abstract
Systemic injury plays a central role in severe acute pancreatitis (SAP). Retrograde biliopancreatic duct infusion of sodium taurocholate (NaT) is commonly used to establish SAP animal models. To better characterize the systemic injury in this model, SAP was induced in Sprague-Dawley rats by NaT administration (3.5 or 5%), followed by sacrifice at 3, 6, 9, 12, 24, 48 and 72 h. Normal saline was used as a control in Sham-operated rats. The mortality rate, ascites volume, and serum and ascitic fluid amylase and lipase activities were assessed. Multiple organ dysfunction, including dysfunction of the pancreas, lung, ileum, liver, and kidney, was investigated using hematoxylin and eosin staining. The interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels in the ascitic fluid, serum, and ileum tissues were evaluated using an enzyme-linked immunosorbent assay (ELISA). Tight junction proteins, zonula occludens-1 (ZO-1) and occludin, in ileum tissues were studied using immunofluorescence. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (CRE) and urea levels were measured using an automatic biochemical analyzer. The results of the present study indicated that both 3.5 and 5% NaT could induce a stable elevation of pancreatitis indices, with histopathological injury of the pancreas, lungs and ileum (5% NaT). The ascitic fluid levels of IL-6 and IL-1β were increased in the 5% NaT group. ALT and AST levels increased temporarily and recovered in 72 h, without a significant increase in CRE and urea levels or apparent hepatic and renal pathological injury. In conclusion, rats with NaT-induced SAP have characteristics of necrotizing hemorrhagic pancreatitis with multiple organ injuries, including inflammatory lung injury, ischemic intestinal injury and slight liver and kidney injuries.
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Affiliation(s)
- Xin-Xin Hong
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Hong-Yan Wang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Jiong-Ming Yang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Bao-Fu Lin
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Qin-Qin Min
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Yi-Zhong Liang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Pei-Di Huang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Zi-You Zhong
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Shao-Ju Guo
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Bin Huang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
| | - Yi-Fei Xu
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China
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Gao Y, Gao Y, Niu Z, Liu J, Feng H, Sun J, Wang L, Pan L. CCCTC-binding factor-mediated microRNA-340-5p suppression aggravates myocardial injury in rats with severe acute pancreatitis through activation of the HMGB1/TLR4 axis. Immunopharmacol Immunotoxicol 2022; 44:306-315. [PMID: 35238277 DOI: 10.1080/08923973.2022.2043898] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 02/13/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND Severe acute pancreatitis (SAP) is a life-threatening disorder associated with multisystem organ failure. This study aimed to investigate the function of high mobility group box 1 (HMGB1) in SAP-induced myocardial injury. METHODS A rat model with SAP was induced. The pathological changes in rat pancreatic and cardiac tissues were examined by HE staining. Cardiomyocyte apoptosis in rat cardiac tissues, and the serum levels of myocardial injury markers and pro-inflammatory cytokines were examined. Rat primary cardiomyocytes were treated with H2O2 for in vitro experiments. The regulatory molecules of HMGB1 were predicted by bioinformatics analysis. Altered expression of HMGB1, microRNA (miR)-340-5p and CCCTC-binding factor (CTCF) was introduced in rats or cells to investigate their roles in myocardial injury. RESULTS CTCF and HMGB1 were highly expressed but miR-340-5p was poorly expressed in cardiac tissues of rats with SAP. HMGB1 silencing reduced toll-like receptor 4 (TLR4) expression to promote proliferation and reduce apoptosis of H2O2-treated cardiomyocytes. miR-340-5p targeted HMGB1 mRNA, while CTCF suppressed miR-340-5p transcription. CTCF upregulation or miR-340-5p downregulation blocked the effects of HMGB1 silencing on cardiomyocytes. In vivo, CTCF silencing alleviated injury in rat pancreatic and cardiac tissues and reduced the expression of creatine kinase-MB (CK-MB), lactic dehydrogenase, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in rat serum. But further overexpression of HMGB1 or inhibition of miR-340-5p aggravated the symptoms in rats. CONCLUSION This study demonstrated that CTCF reduces transcription of miR-340-5p to promote HMGB1 expression, which activates TLR4 expression and promotes myocardial injury in rats with SAP.
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Affiliation(s)
- Yazhou Gao
- Department of Emergency Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Yanxia Gao
- Department of Emergency Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Zequn Niu
- Department of Emergency Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Jie Liu
- Department of Emergency Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Hui Feng
- Department of Emergency Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Jiangli Sun
- Department of Emergency Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Liming Wang
- Department of Emergency Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Longfei Pan
- Department of Emergency Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
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Rasch S, Sancak S, Erber J, Wießner J, Schulz D, Huberle C, Algül H, Schmid RM, Lahmer T. Influence of extracorporeal cytokine adsorption on hemodynamics in severe acute pancreatitis: Results of the matched cohort pancreatitis cytosorbents inflammatory cytokine removal (PACIFIC) study. Artif Organs 2022; 46:1019-1026. [PMID: 35182395 DOI: 10.1111/aor.14195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/02/2022] [Accepted: 01/24/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Outcome of severe acute pancreatitis (SAP) highly depends on the degree of systemic inflammation and organ failure. Although treatment approaches targeting the inflammatory cascade have failed in pancreatitis, recent studies suggest that extracorporeal cytokine adsorption effectively reduces concentrations of pro-inflammatory cytokines and potentially improves the outcome of sepsis. METHODS Sixteen patients with SAP, presenting within 7 days upon onset of pain, an APACHE-II score of ≥10 and ≥1 marker of poor prognosis, received 2 consecutive 24-h treatments with CytoSorb® extracorporeal cytokine adsorption (intervention group). Hemodynamics, organ failure, and mortality were compared with an APACHE-II score-matched retrospective control group of 32 patients. RESULTS The primary objective (20% decrease in the vasopressor dependency index or 20% increase in the cardiac index) was reached in 68.8% of the intervention and 28.1% of the control patients (p = 0.007), respectively. The cytokine adsorption significantly reduced IL-6 (-1998 pg/ml, p = 0.005) serum levels and resulted in stable CRP (p = 0.101) and decreased PCT (p = 0.003) levels in contrast to increased CRP (p = 0.014) and stable PCT levels (p = 0.695) in the control group. While mortality and improvement of respiratory failure were similar in both groups, renal failure significantly improved (change of KDIGO classification 72 h postcytokine adsorption [-1 vs. 0, p = 0.005]) and the SOFA score significantly decreased (day 5: -1.8 ± 2.0 vs. 1 ± 3.8, p = 0.013) in the intervention group. CONCLUSION Cytokine adsorption might be an effective treatment option to stabilize hemodynamics in SAP. It decreases levels of the pro-inflammatory marker IL-6 and stabilizes organ function according to serial SOFA score assessments.
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Affiliation(s)
- Sebastian Rasch
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
| | - Sengül Sancak
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
| | - Johanna Erber
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
| | - Johannes Wießner
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
| | - Dominik Schulz
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
| | - Christina Huberle
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
| | - Hana Algül
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany.,Comprehensive Cancer Center Munich CCCM (TUM), Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
| | - Roland M Schmid
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
| | - Tobias Lahmer
- Department of Internal Medicine II, Technical University of Munich, School of Medicine, University Hospital rechts der Isar, Munich, Germany
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Moran RA, Halloran C, Guo Q, Umapathy C, Jalaly NY, Jain S, Cowzer D, Cuadrado Robles EP, Quesada-Vázquez N, Szentesi A, Papp M, Chua T, Márta K, Sampath K, Jin DX, Sahebally SM, Kuschnereit TP, Khashab MA, Rock C, Darvasi E, Saunders R, García-Rayado G, Torrijos YS, Coady L, Papachristou GI, Mayerle J, Geoghegan J, Banks PA, Gardner TB, Szabó AN, Stevens T, Tornai T, Tóth E, McEntee G, Enrique de-Madaria, Garg PK, Hegyi P, Yadav D, Hu W, Neoptolemos J, Singh VK. Early infection is an independent risk factor for increased mortality in patients with culture-confirmed infected pancreatic necrosis. Pancreatology 2022; 22:67-73. [PMID: 34774414 DOI: 10.1016/j.pan.2021.11.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 11/01/2021] [Accepted: 11/03/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Mortality in infected pancreatic necrosis (IPN) is dynamic over the course of the disease, with type and timing of interventions as well as persistent organ failure being key determinants. The timing of infection onset and how it pertains to mortality is not well defined. OBJECTIVES To determine the association between mortality and the development of early IPN. METHODS International multicenter retrospective cohort study of patients with IPN, confirmed by a positive microbial culture from (peri) pancreatic collections. The association between timing of infection onset, timing of interventions and mortality were assessed using Cox regression analyses. RESULTS A total of 743 patients from 19 centers across 3 continents with culture-confirmed IPN from 2000 to 2016 were evaluated, mortality rate was 20.9% (155/734). Early infection was associated with a higher mortality, when early infection occurred within the first 4 weeks from presentation with acute pancreatitis. After adjusting for comorbidity, advanced age, organ failure, enteral nutrition and parenteral nutrition, early infection (≤4 weeks) and early open surgery (≤4 weeks) were associated with increased mortality [HR: 2.45 (95% CI: 1.63-3.67), p < 0.001 and HR: 4.88 (95% CI: 1.70-13.98), p = 0.003, respectively]. There was no association between late open surgery, early or late minimally invasive surgery, early or late percutaneous drainage with mortality (p > 0.05). CONCLUSION Early infection was associated with increased mortality, independent of interventions. Early surgery remains a strong predictor of excess mortality.
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Affiliation(s)
- Robert A Moran
- Department of Gastroenterology, Medical University of South Carolina, Charleston, SC, United States; Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | | | - Qiang Guo
- Department of Vascular Surgery, West China Hospital Chengdu, Chengdu, China
| | - Chandra Umapathy
- University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Niloofar Y Jalaly
- Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Saransh Jain
- All Indian Institute of Medical Sciences, New Delhi, India
| | - Darren Cowzer
- Department of Surgery, Mater Misericordiae University Hospital, Dublin, Ireland
| | | | | | - Andrea Szentesi
- First Department of Medicine, University of Szeged, Szeged, Hungary; Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
| | - Mária Papp
- Institute of Medicine, Department of Gastroenterology, University of Debrecen, Debrecen, Hungary
| | | | - Katalin Márta
- Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
| | - Kartik Sampath
- Weill Cornell Medical College, New York City, NY, United States
| | - David X Jin
- Brigham and Women's Hospital, Boston, MA, United States
| | | | | | - Mouen A Khashab
- Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Clare Rock
- Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Erika Darvasi
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | | | | | | | - Laoise Coady
- Department of Surgery, St Vincents University Hospital, Dublin, Ireland
| | | | - Julia Mayerle
- Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Justin Geoghegan
- Department of Surgery, St Vincents University Hospital, Dublin, Ireland
| | - Peter A Banks
- Brigham and Women's Hospital, Boston, MA, United States
| | | | - Anikó Nóra Szabó
- Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary
| | | | - Tamás Tornai
- Institute of Medicine, Department of Gastroenterology, University of Debrecen, Debrecen, Hungary
| | - Emese Tóth
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Gerry McEntee
- Department of Surgery, Mater Misericordiae University Hospital, Dublin, Ireland
| | | | - Pramod K Garg
- All Indian Institute of Medical Sciences, New Delhi, India
| | - Péter Hegyi
- MTA-SZTE Translational Gastroenterology Research Group, Szeged, Hungary
| | - Dhiraj Yadav
- University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Weiming Hu
- Department of Pancreatic Surgery, West China Hospital, Chengdu, China
| | - John Neoptolemos
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
| | - Vikesh K Singh
- Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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Wang G, Shang D, Zhang G, Zhang S, Jiang N, Liu H, Chen H. Effects of QingYi decoction on inflammatory markers in patients with acute pancreatitis: A meta-analysis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 95:153738. [PMID: 34544631 DOI: 10.1016/j.phymed.2021.153738] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/08/2021] [Accepted: 09/05/2021] [Indexed: 06/13/2023]
Abstract
INTRODUCTION It is widely accepted that inflammatory responses play a key role in acute pancreatitis (AP). We conducted a systematic review and meta-analysis to determine the effect of QingYi decoction on inflammatory markers. METHODS The PubMed, EMBASE, Cochrane, CNKI, CBM, and WANFGANG databases were searched for randomized controlled trials published before December 2019. Thirty-nine eligible studies were included in the meta-analysis. The quality of the included studies was assessed using the Cochrane Collaboration risk of bias tool. The standardized mean differences (SMDs) with corresponding 95% CIs were examined for inflammatory markers. The chi-square test and I2 statistic were used to assess heterogeneity. We assessed publication bias by Begg's test, Egger's test, and the trim and fill method. In addition, a meta-regression, sensitivity analysis, subgroup analysis, and cumulative meta-analysis were performed to assess the effects of confounding factors. The quality of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS The pooled effect estimate indicated that QingYi decoction treatment significantly reduced the levels of pro-inflammatory IL-6 (SMD = -3.33; 95% CI, -4.17, -2.50; p < 0.001; I2: 97.9%), IL-8 (SMD = -1.55; 95% CI, -2.03, -1.07; p < 0.001; I2: 96.1%), TNF-α (SMD = -1.04; 95% CI, -1.37, -0.72; p < 0.001; I2: 93.9%), IL-1 (SMD = -2.05; 95% CI, -3.21, -0.90; p < 0.001; I2: 93.4%), and IL-1β (SMD = -1.31; 95% CI, -2.42, -0.21; p < 0.001; I2: 89.8%) and elevated the levels of anti-inflammatory IL-10 (SMD = 0.99; 95% CI, 0.60, 1.38; p < 0.001; I2: 91.1%) among patients with AP. CONCLUSION The current review and meta-analysis suggest that the therapeutic effect of QingYi decoction may be related to its anti-inflammatory properties. Due to the high heterogeneity across the included studies, additional large-scale and rigorously designed studies are needed to confirm the conclusions of this study.
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Affiliation(s)
- Guanyu Wang
- General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Institute of Integrative Medicine of Dalian Medical University, Dalian, China
| | - Dong Shang
- General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Institute of Integrative Medicine of Dalian Medical University, Dalian, China
| | - Guixin Zhang
- General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Institute of Integrative Medicine of Dalian Medical University, Dalian, China
| | - Shenglin Zhang
- General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Institute of Integrative Medicine of Dalian Medical University, Dalian, China
| | - Nan Jiang
- Institute of Integrative Medicine of Dalian Medical University, Dalian, China; Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Huanhuan Liu
- Institute of Integrative Medicine of Dalian Medical University, Dalian, China
| | - Hailong Chen
- General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Institute of Integrative Medicine of Dalian Medical University, Dalian, China.
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Batcioglu K, Dogan T, Kustepe E, Uyumlu A, Yilmaztekin Y. Protective effect of Lycium barbarum on renal injury induced by acute pancreatitis in rats. Pharmacogn Mag 2022. [DOI: 10.4103/pm.pm_516_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Thavamani A, Umapathi KK, Sankararaman S. Prevalence and impact of acute kidney injury in hospitalized pediatric patients with acute pancreatitis. Pediatr Nephrol 2021; 36:3785-3788. [PMID: 34028603 DOI: 10.1007/s00467-021-05106-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/16/2021] [Accepted: 04/28/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND The incidence of acute pancreatitis (AP) in pediatric patients is rising with accompanying increased hospitalizations. Acute kidney injury (AKI) is associated with worse clinical outcomes in adults, and similar data in the pediatric age group is limited. METHODS We analyzed non-overlapping years of National Inpatient Sample (NIS) and Kids Inpatient Database (KID) to include all patients less than 21 years old with primary diagnosis of AP between 2003 and 2016. Patients with concomitant diagnosis of AKI were compared with patients without AKI for demographics, comorbid/etiologic conditions, procedures, complications, and mortality. Length of stay and inflation-adjusted hospitalization charges were used to compare health care resource utilization. RESULTS In total, 123,185 AP-related hospitalizations were analyzed. Overall prevalence of AKI among AP patients was 1.5% during the study period. The prevalence rate of AKI increased almost five-fold from 0.6% (2003) to a peak rate of 2.9% (2016), P < 0.001. Patients with AKI were older, more often male and had either more systemic diseases or chronic comorbid conditions such as malignancies, systemic lupus erythematosus, solid organ transplantation, hypertriglyceridemia, and hypercalcemia. Multivariate analysis demonstrated AP-related hospitalizations with AKI were 1.97 (CI 1.27-3.08, P < 0.001) times more likely to be associated with in-hospital mortality and contributed to 4.3 additional days of hospitalization (CI 4.02-4.6, P < 0.001), also incurring an additional $51,830 (CI 48571-55088, P < 0.001) in hospital charges. CONCLUSION The prevalence of AKI is increasing steadily among pediatric patients with AP and is associated with increased risk of mortality and higher health care resource expenditure.
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Affiliation(s)
- Aravind Thavamani
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, UH Rainbow Babies and Children's Hospital/Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | | | - Senthilkumar Sankararaman
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, UH Rainbow Babies and Children's Hospital/Case Western Reserve University School of Medicine, Cleveland, OH, USA.
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Machicado JD, Mounzer R, Paragomi P, Pothoulakis I, Hart PA, Conwell DL, de-Madaria E, Greer P, Yadav D, Whitcomb DC, Lee PJ, Hinton A, Papachristou GI. Rectal Indomethacin Does Not Mitigate the Systemic Inflammatory Response Syndrome in Acute Pancreatitis: A Randomized Trial. Clin Transl Gastroenterol 2021; 12:e00415. [PMID: 34704970 PMCID: PMC8553238 DOI: 10.14309/ctg.0000000000000415] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Experimental data suggest that nonsteroidal antiinflammatory drugs may prevent disease severity and mortality in acute pancreatitis (AP). The aim of this study was to compare the efficacy of rectal indomethacin vs placebo in reducing the systemic inflammatory response syndrome (SIRS) score in a high-risk AP population for clinical progression. METHODS We conducted a single-center, quadruple-blinded, randomized, placebo-controlled trial. Eligible criteria were subjects with AP and SIRS within 72 hours of presentation and those without organ failure. Subjects were allocated in a 1:1 ratio to indomethacin or placebo using simple randomization. Both interventions were administered rectally every 8 hours for 6 doses and compared using both intention-to-treat and per-protocol analyses. RESULTS A total of 42 subjects (mean age 52 years, 55% men) were randomized to indomethacin (n = 18) or placebo (n = 24). There was no significant difference between the indomethacin and placebo groups in the change of SIRS score, proportion of subjects with SIRS, and distribution of SIRS scores at 24, 48, and 72 hours from randomization. There were no significant differences in the change of C-reactive protein levels at 48 hours or clinical outcomes between both treatment groups. Indomethacin was as safe as placebo, with 2 adverse events occurring in the placebo and none in the indomethacin arm. DISCUSSION Rectal indomethacin can be safely administered over 48 hours; however, it is not superior to placebo in reducing the SIRS or clinical progression in a high-risk population with AP (ClinicalTrials.gov: NCT02692391).
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Affiliation(s)
- Jorge D. Machicado
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA;
| | - Rawad Mounzer
- Interventional Endoscopy Associates, Scottsdale, Arizona, USA;
| | - Pedram Paragomi
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Ioannis Pothoulakis
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;
| | - Darwin L. Conwell
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;
| | - Enrique de-Madaria
- Gastroenterology Department, Alicante University General Hospital, ISABIAL, Alicante, Spain;
| | - Phil Greer
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - David C. Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Peter J. Lee
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;
| | - Alice Hinton
- Division of Biostatistics, College of Public Health, the Ohio State University, Columbus, Ohio, USA.
| | - Georgios I. Papachristou
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;
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Qiu Z, Xu F, Wang Z, Yang P, Bu Z, Cheng F, Jiang H, Li L, Zhang F. Blockade of JAK2 signaling produces immunomodulatory effect to preserve pancreatic homeostasis in severe acute pancreatitis. Biochem Biophys Rep 2021; 28:101133. [PMID: 34584986 PMCID: PMC8453217 DOI: 10.1016/j.bbrep.2021.101133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 09/11/2021] [Accepted: 09/13/2021] [Indexed: 12/31/2022] Open
Abstract
JAK/STAT plays an important role in cytokine signal transduction and it is potentially involved in the proinflammatory response during the early phase of severe acute pancreatitis (SAP). However, whether JAK2 activity is upregulated and whether JAK2 inhibition plays a role in the maintenance of pancreatic homeostasis during SAP is incompletely understood. Here we show that JAK2/STAT3 activity is highly elevated in SAP and blockade of JAK2 by AG-490 protects against SAP-induced pancreatic inflammation and injury. Gene expression and ELISA studies showed that JAK2 inhibition altered the cytokine profiles in both the circulation and pancreases. Further analysis revealed that JAK2 inhibition restored the level of cytokines critical for macrophage polarization towards M2 macrophage. Our findings suggest that pharmacological targeting at JAK2/STAT signalling may be an effective choice of therapeutic interventions against SAP.
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Affiliation(s)
- Zhaolei Qiu
- Emergency Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Feng Xu
- Emergency Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhenjie Wang
- Emergency Department, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Peng Yang
- Emergency Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhang Bu
- Emergency Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Feng Cheng
- Emergency Department, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Hai Jiang
- Emergency Department, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Lei Li
- Emergency Department, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Fulong Zhang
- Emergency Department, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
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Development an Inflammation-Related Factor-Based Model for Predicting Organ Failure in Acute Pancreatitis: A Retrospective Cohort Study. Mediators Inflamm 2021; 2021:4906768. [PMID: 34545276 PMCID: PMC8449737 DOI: 10.1155/2021/4906768] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 11/18/2022] Open
Abstract
Several inflammation-related factors (IRFs) have been reported to predict organ failure of acute pancreatitis (AP) in previous clinical studies. However, there are a few shortcomings in these models. The aim of this study was to develop a new prediction model based on IRFs that could accurately identify the risk for organ failure in AP. Methods. 100 patients with their clinical information and IRF data (levels of 10 cytokines, percentages of different immune cells, and data obtained from white blood cell count) were retrospectively enrolled in this study, and 94 patients were finally selected for further analysis. Univariate and multivariate analysis were applied to evaluate the potential risk factors for the organ failure of AP. The area under the ROC curve (AUCs), sensitivity, and specificity of the relevant model were assessed to evaluate the prediction ability of IRFs. A new scoring system to predict the organ failure of AP was created based on the regression coefficient of a multivariate logistic regression model. Results. The incidence of OF in AP patients was nearly 16% (15/94) in our derivation cohort. Univariate analytic data revealed that IL6, IL8, IL10, MCP1, CD3+ CD4+ T lymphocytes, CD19+ B lymphocytes, PCT, APACHE II score, and RANSON score were potential predictors for AP organ failure, and IL6 (P = 0.038), IL8 (P = 0.043), and CD19+B lymphocytes (P = 0.045) were independent predictors according to further multivariate analysis. In addition, a preoperative scoring system (0-11 points) was constructed to predict the organ failure of AP using these three factors. The AUC of the new score system was 0.86. The optimal cut-off value of the new scoring system was 6 points. Conclusions. Our prediction model (based on IL6, IL8, and CD19+ B Lymphocyte) has satisfactory working efficiency to identify AP patients with high risk of organ failure.
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Lee PJ, Papachristou GI. Early Prediction of Severity in Acute Pancreatitis. CLINICAL PANCREATOLOGY FOR PRACTISING GASTROENTEROLOGISTS AND SURGEONS 2021:31-39. [DOI: 10.1002/9781119570097.ch4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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The challenge of prognostic markers in acute pancreatitis: internist's point of view. J Genet Eng Biotechnol 2021; 19:77. [PMID: 34036463 PMCID: PMC8149536 DOI: 10.1186/s43141-021-00178-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 05/10/2021] [Indexed: 12/12/2022]
Abstract
Acute pancreatitis, the most frequent hospitalization reason in internal medicine ward among gastrointestinal diseases, is burdened by high mortality rate. The disease manifests mainly in a mild form, but about 20-30% patients have a severe progress that requires intensive care. Patients presenting with acute pancreatitis should be clinically evaluated for organ failure signs and symptoms. Stratifying patients in the first days from symptoms onset is essential to determine therapy and care setting. The aim of our study is to evaluate prognostic factors for acute pancreatitis patients, hospitalized in internal medicine wards, and moreover, understanding the role of various prognostic scores validated in intensive care setting in predicting in-hospital mortality and/or admission to intensive care unit. We conducted a retrospective study enrolling all patients with diagnosis of acute pancreatitis admitted took an internal medicine ward between January 2013 and May 2019. Adverse outcome was considered in-hospital mortality and/or admission to intensive care unit. In total, 146 patients (137 with positive outcome and 9 with adverse outcome) were enrolled. The median age was (67.89 ± 16.44), with a slight prevalence of male (55.1%) compared to female (44.9%). C protein reactive (p = 0.02), creatinine (p = 0.01), sodium (p = 0.05), and troponin I (p = 0.013) after 48 h were significantly increased in patients with adverse outcome. In our study, progression in SOFA score independently increases the probability of adverse outcome in patients hospitalized with acute pancreatitis. SOFA score > 5 is highly predictive of in-hospital mortality (O.R. 32.00; C.I. 6.73-152.5; p = 0.001) compared to other scores. The use of an easy tool, validated in intensive care setting such as SOFA score, might help to better stratify the risk of in-hospital mortality and/or clinical worsening in patients hospitalized with acute pancreatitis in internal medicine ward.
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Langmead C, Lee PJ, Paragomi P, Greer P, Stello K, Hart PA, Whitcomb DC, Papachristou GI. A Novel 5-Cytokine Panel Outperforms Conventional Predictive Markers of Persistent Organ Failure in Acute Pancreatitis. Clin Transl Gastroenterol 2021; 12:e00351. [PMID: 33955376 PMCID: PMC8104185 DOI: 10.14309/ctg.0000000000000351] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Existing laboratory markers and clinical scoring systems have shown suboptimal accuracies for early prediction of persistent organ failure (POF) in acute pancreatitis (AP). We used information theory and machine learning to select the best-performing panel of circulating cytokines for predicting POF early in the disease course and performed verification of the cytokine panel's prognostic accuracy in an independent AP cohort. METHODS The derivation cohort included 60 subjects with AP with early serum samples collected between 2007 and 2010. Twenty-five cytokines associated with an acute inflammatory response were ranked by computing the mutual information between their levels and the outcome of POF; 5 high-ranking cytokines were selected. These cytokines were subsequently measured in early serum samples of an independent prospective verification cohort of 133 patients (2012-2016), and the results were trained in a Random Forest classifier. Cross-validated performance metrics were compared with the predictive accuracies of conventional laboratory tests and clinical scores. RESULTS Angiopoietin 2, hepatocyte growth factor, interleukin 8, resistin, and soluble tumor necrosis factor receptor 1A were the highest-ranking cytokines in the derivation cohort; each reflects a pathologic process relevant to POF. A Random Forest classifier trained the cytokine panel in the verification cohort and achieved a 10-fold cross-validated accuracy of 0.89 (area under the curve 0.91, positive predictive value 0.89, and negative predictive value 0.90), which outperformed individual cytokines, laboratory tests, and clinical scores (all P ≤ 0.006). DISCUSSION We developed a 5-cytokine panel, which accurately predicts POF early in the disease process and significantly outperforms the prognostic accuracy of existing laboratory tests and clinical scores.
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Affiliation(s)
- Christopher Langmead
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
| | - Peter J. Lee
- Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Pedram Paragomi
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Phil Greer
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Kim Stello
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - David C. Whitcomb
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Departments of Physiology & Molecular Physiology, and Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Georgios I. Papachristou
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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IL-10-1082G>A polymorphism, use of opioids and age affect the course of acute pancreatitis. Eur J Gastroenterol Hepatol 2021; 32:178-185. [PMID: 32804849 DOI: 10.1097/meg.0000000000001875] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE We aimed to determine the association of two of the most important functional polymorphisms of IL-8 and IL-10 with the clinical course and outcome of acute pancreatitis. METHOD Ninety-three patients with acute pancreatitis were genotyped for IL-8-251T>A and IL-10-1082G>A using PCR-RFLP. The severity of the disease was determined based on the Atlanta Classification system. RESULTS In patients treated with opioids, the odds for severe form of acute pancreatitis, its complications, and death were increased. Advanced age was associated with higher odds of organ/multiple organ failure and other systemic complications. Multivariate logistic regression analyses confirmed the observed effect of age and use of opioids, and revealed higher odds for the development of severe form of acute pancreatitis [P = 0.017, odds ratio (OR): 4.324, 95% confidence interval (CI): 1.305-14.323], its complications in general (P = 0.011, OR: 4.936, 95% CI: 1.442-16.897), pancreatic necrosis (P = 0.032, OR: 3.922, 95% CI: 1.122-13.707) and systemic inflammatory response syndrome (P = 0.037, OR: 3.838, 95% CI: 1.085-13.583) in the absence of IL-10-1082G>A variant allele. The effect of IL-8 -251T>A on acute pancreatitis severity or mortality was not detected. CONCLUSION Our study suggests the IL-10 -1082A allele as a protective factor in acute pancreatitis. Opioid analgesics treatment in acute pancreatitis is associated with severity, complications and mortality, while advanced age increases the risk of systemic complications.
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Anandam KY, Srinivasan P, Yasujima T, Al-Juburi S, Said HM. Proinflammatory cytokines inhibit thiamin uptake by human and mouse pancreatic acinar cells: involvement of transcriptional mechanism(s). Am J Physiol Gastrointest Liver Physiol 2021; 320:G108-G116. [PMID: 33146542 PMCID: PMC8112188 DOI: 10.1152/ajpgi.00361.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/22/2020] [Accepted: 10/27/2020] [Indexed: 01/31/2023]
Abstract
Thiamin (vitamin B1) plays critical roles in normal metabolism and function of all mammalian cells. Pancreatic acinar cells (PACs) import thiamin from circulation via specific carrier-mediated uptake that involves thiamin transporter-1 and -2 (THTR-1 and -2; products of SLC19A2 and SLC19A3, respectively). Our aim in this study was to investigate the effect(s) of proinflammatory cytokines on thiamin uptake by PACs. We used human primary (h)PACs, PAC 266-6 cells, and mice in vivo as models in the investigations. First, we examined the level of expression of THTR-1 and -2 mRNA in pancreatic tissues of patients with chronic pancreatitis and observed severe reduction in their expression compared with normal control subjects. Exposing hPACs and PAC 266-6 to proinflammatory cytokines (hyper IL-6, TNF-α, and IL-1β) was found to lead to a significant inhibition in thiamin uptake. Focusing on hyper-IL-6 (which also inhibited thiamin uptake by primary mouse PACs), the inhibition in thiamin uptake was found to be associated with significant reduction in THTR-1 and -2 proteins and mRNA expression as well as in activity of the SLC19A2 and SLC19A3 promoters; it was also associated with reduction in level of expression of the transcription factor Sp1 (which is required for activity of these promoters). Finally, blocking the intracellular Stat3 signaling pathway was found to lead to a significant reversal in the inhibitory effect of hyper IL-6 on thiamin uptake by PAC 266-6. These results show that exposure of PACs to proinflammatory cytokines negatively impacts thiamin uptake via (at least in part) transcriptional mechanism(s).NEW & NOTEWORTHY Findings of the current study demonstrate, for the first time, that exposure of pancreatic acinar cells to proinflammatory cytokines (including hyper IL-6) cause significant inhibition in vitamin B1 (thiamin; a micronutrient that is essential for normal cellular energy metabolism) and that this effect is mediated at the level of transcription of the thiamin transporter genes SLC19A2 and SLC19A3.
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Affiliation(s)
- Kasin Yadunandam Anandam
- Departments of Physiology/Biophysics, School of Medicine, University of California, Irvine, California
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
| | - Padmanabhan Srinivasan
- Departments of Physiology/Biophysics, School of Medicine, University of California, Irvine, California
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
| | - Tomoya Yasujima
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan
| | - Saleh Al-Juburi
- Departments of Physiology/Biophysics, School of Medicine, University of California, Irvine, California
| | - Hamid M Said
- Departments of Physiology/Biophysics, School of Medicine, University of California, Irvine, California
- Department of Medicine, School of Medicine, University of California, Irvine, California
- Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
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Scurt FG, Bose K, Canbay A, Mertens PR, Chatzikyrkou C. [Acute kidney injury following acute pancreatitis (AP-AKI): Definition, Pathophysiology, Diagnosis and Therapy]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2020; 58:1241-1266. [PMID: 33291178 DOI: 10.1055/a-1255-3413] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis (AP) is the most frequent gastrointestinal cause for hospitalization and one of the leading causes of in-hospital deaths. Severe acute pancreatitis is often associated with multiorgan failure and especially with acute kidney injury (AKI). AKI can develop early or late in the course of the disease and is a strong determinator of outcome. The mortality in the case of dialysis-dependent AKI and acute pancreatitis raises exponentially in the affected patients. AP-induced AKI (AP-AKI) shows many similarities but also distinct differences to other causes of AKI occurring in the intensive care unit setting. The knowledge of the exact pathophysiology can help to adjust, control and improve therapeutic approaches to the disease. Unfortunately, there are only a few studies dealing with AP and AKI.In this review, we discuss recent data about pathogenesis, causes and management of AP-AKI in patients with severe acute pancreatitis and exploit in this regard the diagnostic and prognostic potential of respective newer serum and urine markers.
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Affiliation(s)
- Florian Gunnar Scurt
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
| | - Katrin Bose
- Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany.,Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Otto-von-Guericke-Universität, Magdeburg, Deutschland
| | - Ali Canbay
- Ruhr-Universität Bochum, Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Deutschland
| | - Peter R Mertens
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
| | - Christos Chatzikyrkou
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
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Cheng Z, Liu Z, Yuan Y, Liu Z, He Y, Jiang P. Predictive value of serum soluble B7-H4 in acute pancreatitis. Eur J Clin Invest 2020; 50:e13346. [PMID: 32648937 DOI: 10.1111/eci.13346] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/06/2020] [Accepted: 06/23/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Studies reported that soluble B7-H4 (sB7-H4) was significantly related to the progression and prognosis of inflammatory diseases, and whether sB7-H4 is related to the severity and prognosis of acute pancreatitis (AP) timely has not been reported. MATERIALS AND METHODS Clinical database data of 446 AP patients were retrospectively collected, and the correlation between the expression serum levels of sB7-H4 with inflammatory factors and prognostic scores was analysed in AP patients. RESULTS Soluble B7-H4 was significantly correlated with IL-6, IL-8, TNF-α, PCT, CRP levels and WBC count (P < .01), with correlation coefficients of R = .61, .53, .46, .60, .57 and .47, respectively, and AUCs were 0.905, 0.837, 0.797, 0.858, 0.890, 0.841 and 0.855, respectively. In addition, sB7-H4 was significantly correlated with the Ranson score, APACHE II score and BISAP score (P < .001), with correlation coefficients of R = .58, .63 and .59, respectively. The AUCs of assessing local complications of AP were 0.908, 0.863, 0.785 and 0.844, respectively; assessing organ failure were 0.872, 0.790, 0.796 and 0.857, respectively; and assessing in-hospital mortality were 0.839, 0.821, 0.796 and 0.823, respectively. CONCLUSIONS Soluble B7-H4 could be used as a marker for the diagnosis, severity assessment and poor prognosis assessment of AP patients, which may have potential clinical applications.
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Affiliation(s)
- Zhixiang Cheng
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Zhengfang Liu
- Department Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yufeng Yuan
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Zhisu Liu
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yueming He
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Ping Jiang
- Department Hepatobiliary & Pancreat Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
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Glaubitz J, Wilden A, van den Brandt C, Weiss FU, Bröker BM, Mayerle J, Lerch MM, Sendler M. Experimental pancreatitis is characterized by rapid T cell activation, Th2 differentiation that parallels disease severity, and improvement after CD4 + T cell depletion. Pancreatology 2020; 20:1637-1647. [PMID: 33097430 DOI: 10.1016/j.pan.2020.10.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/14/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Acute pancreatitis is a gastrointestinal disorder of high incidence resulting in life threatening complications in up to 20% of patients. Its severe form is characterized by an extensive and systemic immune response. We investigated the role of the adaptive immune response in two experimental models of pancreatitis. METHODS In C57BI/6-mice mild pancreatitis was induced by 8-hourly injections of caerulein and severe pancreatitis by additional, partial pancreatic duct ligation. T-cell-activation was determined by flow-cytometry of CD25/CD69, T-cell-differentiation by nuclear staining of the transcription-factors Tbet, Gata3 and Foxp3. In vivo CD4+ T-cells were depleted using anti-CD4 antibody. Disease severity was determined by histology, serum amylase and lipase activities, lung MPO and serum cytokine levels (IL-6, TNFα, IL-10). RESULTS In both models T-cells were activated. Th1-differentiation (Tbet) was absent during pancreatitis but we detected a pronounced Th2/Treg (Gata3/Foxp3) response which paralleled disease severity in both models. The complete depletion of CD4+ T-cells via anti-CD4 antibody, surprisingly, reduced disease severity significantly, as well as granulocyte infiltration and pro- and anti-inflammatory cytokine levels. Co-incubation of acini and T-cells did not lead to T-cell-activation by acinar cells but to acinar damage by T-cells. During pancreatitis no significant T-cell-infiltration into the pancreas was observed. CONCLUSION T cells orchestrate the early local as well as the systemic immune responses in pancreatitis and are directly involved in organ damage. The Th2 response appears to increase disease severity, rather than conferring an immunological protection.
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Affiliation(s)
- Juliane Glaubitz
- Department of Medicine A, University Medicine, University of Greifswald, Germany
| | - Anika Wilden
- Department of Medicine A, University Medicine, University of Greifswald, Germany
| | - Cindy van den Brandt
- Department of Medicine A, University Medicine, University of Greifswald, Germany
| | - Frank U Weiss
- Department of Medicine A, University Medicine, University of Greifswald, Germany
| | - Barbara M Bröker
- Department of Immunology, Institute of Immunology and Transfusion Medicine, University Medicine, Greifswald, Germany
| | - Julia Mayerle
- Department of Medicine A, University Medicine, University of Greifswald, Germany; Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, München, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine, University of Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine, University of Greifswald, Germany.
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Prasada R, Muktesh G, Samanta J, Sarma P, Singh S, Arora SK, Dhaka N, Ramachandran R, Gupta V, Kant Sinha S, Kochhar R. Natural history and profile of selective cytokines in patients of acute pancreatitis with acute kidney injury. Cytokine 2020; 133:155177. [PMID: 32593952 DOI: 10.1016/j.cyto.2020.155177] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 06/12/2020] [Accepted: 06/13/2020] [Indexed: 12/26/2022]
Abstract
OBJECTIVES To study the natural course of patients with acute pancreatitis (AP) with acute kidney injury (AKI) and their cytokine profile. METHODS Natural course of patients with AP and AKI was studied in 97 individuals. Levels of TNFα, IL-6, IL-10, IL-8 and IL-1β were measured at presentation and at 72 h in patients who developed AKI. RESULTS Amongst the entire cohort, 16.4% patients developed AKI (persistent AKI - 11 patients, transient AKI - 5 patients). Mortality rate was 25% amongst patients with AKI. Levels of IL-6 (p = 0.035) and IL-8 (p = 0.002) were found to be significantly higher in the AKI group. On multivariate analysis, IL-8 levels at baseline were found to be an independent predictor of AKI. AKI group had significant rise of TNF-α (P < 0.001), IL-6 (P < 0.001) and IL- 1β (P < 0.001) on day 3 whereas persistent-AKI group had significant rise of TNF-α (p = 0.031), IL-6 (p = 0.001) and IL-1β on day 3 and significant decline of IL-10 (p = 0.015). Using a cut-off of 105 pg/ml, IL-8 levels at baseline could predict AKI with a sensitivity of 87.5% and specificity of 59.2%, with area under the curve being 0.744 (p = 0.002). CONCLUSION AP patients developing AKI have poor prognosis. IL-8 levels can predict AKI in patients with AP.
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Affiliation(s)
- Raghavendra Prasada
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Gaurav Muktesh
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jayanta Samanta
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Phulen Sarma
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sukhvinder Singh
- Department of Immunology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sunil K Arora
- Department of Immunology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Narendra Dhaka
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Raja Ramachandran
- Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vikas Gupta
- Department of Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Saroj Kant Sinha
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rakesh Kochhar
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Ferrero-Andrés A, Panisello-Roselló A, Roselló-Catafau J, Folch-Puy E. NLRP3 Inflammasome-Mediated Inflammation in Acute Pancreatitis. Int J Mol Sci 2020; 21:5386. [PMID: 32751171 PMCID: PMC7432368 DOI: 10.3390/ijms21155386] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/17/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022] Open
Abstract
The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.
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Affiliation(s)
- Ana Ferrero-Andrés
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
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Wang C, Zhang Y, Tan J, Chen B, Sun L. Improved Integrated Whole Proteomic and Phosphoproteomic Profiles of Severe Acute Pancreatitis. J Proteome Res 2020; 19:2471-2482. [PMID: 32283030 DOI: 10.1021/acs.jproteome.0c00229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Severe acute pancreatitis (SAP) is caused by complicated biological factors, and revealing its complex pathogenesis by single-target analysis is difficult. Systematic studies have developed slowly because extraction of degradable pancreatic proteins exposed to multiple proteases is challenging. We present integrated whole proteomic and phosphoproteomic profiles of SAP rats based on a modified protein extraction strategy with less protein degradation. Data-dependent acquisition (DDA) and data-independent acquisition (DIA) strategies were applied to select an appropriate method. Total 275 differentially expressed proteins and 757 differentially expressed phosphorylated proteins were identified by DIA-based quantitative proteomics. Several signal transduction pathways, including the AMPK, MAPK, and PI3K-Akt pathways, were enriched in SAP. Up-regulation of phosphorylated proteins involved in the process of TNFA signaling and inflammatory response was also detected in SAP. Our results improve the understanding of SAP development and progression.
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Affiliation(s)
- Cheng Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang 325000, China
| | - Yanlei Zhang
- Neurology Department, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang 325000, China
| | - Jinjuan Tan
- Institute of Virology and Biotechnology, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang 325000, China
| | - Linxiao Sun
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang 325000, China
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