|
1
|
Lim ST, Zhao X, Liu S, Zhang W, Tan Y, Mullappilly N, Swain SM, Leong ML, Rajarethinam R, Wan KF, Ruedl C, Liddle RA, Li L, Wang X. LRG1 inhibition promotes acute pancreatitis recovery by inducing cholecystokinin Type 1 receptor expression via Akt. Theranostics 2025; 15:4247-4269. [PMID: 40225588 PMCID: PMC11984386 DOI: 10.7150/thno.110116] [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: 01/08/2025] [Accepted: 03/09/2025] [Indexed: 04/15/2025] Open
Abstract
Rationale: Acute pancreatitis (AP) is a common gastrointestinal disease affecting nearly 3 million people annually worldwide. Although AP is typically self-limiting, up to 20% of patients may develop life-threatening complications. Individuals who suffer from AP also have an increased likelihood of developing other exocrine and endocrine pancreatic disorders. However, to date, there are no specific, targeted treatment modalities that can effectively improve the clinical outcomes of AP. Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a multifunctional protein with established roles in inflammation and cell mitosis. This study aims to investigate the functional role of LRG1 in AP progression and develop LRG1-targeted AP therapeutics. Methods: Levels of circulating and tissue LRG1 were determined in human patient samples and mouse models of caerulein-induced AP and pancreatic duct ligation-induced AP. Histopathological grading, amylase assay, real-time polymerase chain reaction analysis and Western blotting were used to evaluate the extent of pancreatic damage and recovery following caerulein-induced AP in both wild-type and Lrg1-/- mice. Primary acinar cells were also isolated from mice for in-vitro mechanistic studies. LRG1 neutralizing antibody was administered post-AP induction to evaluate its therapeutic potential in improving AP outcomes. Results: LRG1 is markedly increased in serum and acinar cells of AP patients and C57BL/6 mice subjected to caerulein-induced AP or pancreatic duct ligation-induced AP. Despite demonstrating no obvious pancreatic dysfunction, Lrg1-/- mice exhibited more severe pancreatic damage and inflammation during the early stages of caerulein-induced AP. However, the resolution of AP was accelerated in the absence of Lrg1, which is at least partially due to LRG1's role in regulating the expression of trophic cholecystokinin (CCK) Type 1 receptor (CCK1R) via the TGFβ/ALK5/AKT pathway in acinar cells. Importantly, the administration of an LRG1-blocking antibody promoted AP recovery, evidenced by reduced overall inflammation and increased acinar cell proliferation. Conclusions: Our data provide compelling evidence for targeting LRG1 as a potential innovative therapy for promoting AP recovery.
Collapse
Affiliation(s)
- Seok Ting Lim
- Centre for Vision Research, Duke-NUS Medical School, Singapore
- Singapore Eye Research Institute, Singapore
| | - Xinmei Zhao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Avenue, Guangzhou, China
| | - Shuqing Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Avenue, Guangzhou, China
| | - Wenjuan Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Avenue, Guangzhou, China
| | - Yuanyang Tan
- School of Medical Technology, Beijing Institute of Technology, 100081, Beijing, China
| | | | - Sandip M Swain
- Department of Medicine, Duke University, Durham, NC, 27710, U.S.A
| | - Mei Ling Leong
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Ravisankar Rajarethinam
- Advanced Molecular Pathology Laboratory (AMPL), Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Kah Fei Wan
- Antibody Technology Division, Experimental Drug Development Centre, A*STAR, Singapore
| | - Christiane Ruedl
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Rodger A. Liddle
- Department of Medicine, Duke University, Durham, NC, 27710, U.S.A
| | - Liang Li
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology
| | - Xiaomeng Wang
- Centre for Vision Research, Duke-NUS Medical School, Singapore
- Singapore Eye Research Institute, Singapore
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| |
Collapse
|
|
2
|
Alverdy J. Unpacking the sepsis controversy. Trauma Surg Acute Care Open 2025; 10:e001733. [PMID: 40047013 PMCID: PMC11881180 DOI: 10.1136/tsaco-2024-001733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 02/08/2025] [Indexed: 03/09/2025] Open
Abstract
Despite its many definitions and revisions, consensus statements and clinical guidelines, the term 'sepsis' continues to be referred to as a discrete clinical entity that is often claimed to be a direct cause of mortality. The assertion that sepsis can be defined as a 'life-threatening organ dysfunction caused by a dysregulated host response to infection,' has led to a field dominated by failed clinical trials informed by host-centered, pathogen-agnostic, animal experiments in which animal models do not recapitulate the clinical condition. The observations from the National Health Service from England that claim that 77.5% of sepsis deaths occur in those aged 75 years or older and those from the USA indicating that most patients dying of sepsis have also been diagnosed with 'hospice qualifying conditions,' seem to refute the assertion that sepsis is caused by, rather than associated with, a 'dysregulated host response.' This piece challenges the current conceptual framework that forms the basis of the sepsis definition. Here we posit that as a result of both its definition and the use of inappropriate animal models, ineffective clinical treatments continue to be pursued in this field.
Collapse
Affiliation(s)
- John Alverdy
- The University of Chicago Division of the Biological Sciences, Chicago, Illinois, USA
| |
Collapse
|
|
3
|
Sutar P, Pethe A, Kumar P, Tripathi D, Maity D. Hydrogel Innovations in Biosensing: A New Frontier for Pancreatitis Diagnostics. Bioengineering (Basel) 2025; 12:254. [PMID: 40150718 PMCID: PMC11939681 DOI: 10.3390/bioengineering12030254] [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: 12/18/2024] [Revised: 02/24/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Pancreatitis is a prominent and severe type of inflammatory disorder that has grabbed a lot of scientific and clinical interest to prevent its onset. It should be detected early to avoid the development of serious complications, which occur due to long-term damage to the pancreas. The accurate measurement of biomarkers that are released from the pancreas during inflammation is essential for the detection and early treatment of patients with severe acute and chronic pancreatitis, but this is sub-optimally performed in clinically relevant practices, mainly due to the complexity of the procedure and the cost of the treatment. Clinically available tests for the early detection of pancreatitis are often time-consuming. The early detection of pancreatitis also relates to disorders of the exocrine pancreas, such as cystic fibrosis in the hereditary form and cystic fibrosis-like syndrome in the acquired form of pancreatitis, which are genetic disorders with symptoms that can be correlated with the overexpression of specific markers such as creatinine in biological fluids like urine. In this review, we studied how to develop a minimally invasive system using hydrogel-based biosensors, which are highly absorbent and biocompatible polymers that can respond to specific stimuli such as enzymes, pH, temperature, or the presence of biomarkers. These biosensors are helpful for real-time health monitoring and medical diagnostics since they translate biological reactions into quantifiable data. This paper also sheds light on the possible use of Ayurvedic formulations along with hydrogels as a treatment strategy. These analytical devices can be used to enhance the early detection of severe pancreatitis in real time.
Collapse
Affiliation(s)
- Prerna Sutar
- School of Health Sciences and Technology, UPES, Bidholi Campus, Dehradun 248007, Uttarakhand, India
| | - Atharv Pethe
- School of Health Sciences and Technology, UPES, Bidholi Campus, Dehradun 248007, Uttarakhand, India
| | - Piyush Kumar
- School of Health Sciences and Technology, UPES, Bidholi Campus, Dehradun 248007, Uttarakhand, India
| | - Divya Tripathi
- School of Health Sciences and Technology, UPES, Bidholi Campus, Dehradun 248007, Uttarakhand, India
| | - Dipak Maity
- Integrated Nanosystems Development Institute, Indiana University Indianapolis, Indianapolis, IN 46202, USA
- Department of Chemistry and Chemical Biology, Indiana University Indianapolis, Indianapolis, IN 46202, USA
| |
Collapse
|
|
4
|
Wen E, Tian Y, Fang M, Zhang Y, Zhao H, Wang Z, Zhang L, Li X. The P2X7-Mediated Mitochondrial ROS as an Emerging Core Target of Tuftsin Nanoparticles in Severe Acute Pancreatitis Therapy via Regulating Mitophagy. ACS APPLIED MATERIALS & INTERFACES 2025; 17:7521-7538. [PMID: 39854589 DOI: 10.1021/acsami.4c21010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
20% acute pancreatitis (AP) develops into severe AP (SAP), a global health crisis, with an increased mortality rate to 30%-50%. Mitochondrial damage and immune disorders are direct factors, which exacerbate the occurrence and progression of AP. So far, mitochondrial and immunity injury in SAP remains largely elusive, with no established treatment options available. Immunomodulation is a promising approach to treat pancreatitis. Herein, we proved that Tuftsin (TN), a vital endogenous immunomodulator, can inhibit SAP, while it is limited by extremely short biological half-life, low bioavailability, and the inconvenience of administration. Nano platform is the positive choice. Interestingly, we found that the activated P2X7 signaling was closely associated with the enhanced pancreatic inflammation via damaging mitochondrial function in SAP. Herein, we engineered a nanoplatform containing a Se-Se bond responsive for ROS to deliver TN, namely, DSPE-Se-Se-MPEG@TN (DSSM@TN), contributing to increases in TN's half-life and bioavailability. We synthesized TN-loaded ROS-responsive DSPE-Se-Se- MPEG@TN liposomes (DSSM@TN NPs) via a one-step emulsification method, which exhibited good biosecurity, high stability, suitable size, favorable ROS responsiveness and biocompatibility, as well as excellent capability for releasing TN during oxidative stress and inflammation environment. Moreover, the Se-Se bond with ROS-responsive ability was first proved to play a vital role for TN-loaded liposomes to enhance its anti-inflammation and antioxidant abilities via targeting damaged mitochondria during SAP progression. Mechanistically, DSSM@TN targeting damaged pancreas simultaneously inhibits mitochondrial dysfunction and inflammation in vivo and vitro via mitochondrial P2X7 signaling-impaired Nrf2/HO-1 signaling-inhibited PINK1/PARKIN pathway. Consequently, such a ROS-responsive immunotherapy nanomedicine targeted mitochondria holds great potential in facilitating substantial clinical progress in SAP treatment.
Collapse
Affiliation(s)
- E Wen
- Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Yu Tian
- Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Mingxiao Fang
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Yuezhou Zhang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Hongyun Zhao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Zhigang Wang
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Liang Zhang
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
- Ultrasound Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| | - Xingsheng Li
- Department of Gerontology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China
| |
Collapse
|
|
5
|
Wen B, Huang Y, Deng G, Yan Q, Jia L. Gut microbiota analysis and LC-MS-based metabolomics to investigate AMPK/NF-κB regulated by Clostridium butyricum in the treatment of acute pancreatitis. J Transl Med 2024; 22:1072. [PMID: 39604956 PMCID: PMC11600808 DOI: 10.1186/s12967-024-05764-w] [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: 05/27/2024] [Accepted: 10/14/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is an inflammatory condition with potentially life-threatening complications. This study investigates the therapeutic potential of Clostridium butyricum for modulating the inflammatory cascade through the AMPK/NF-κB signaling pathway, focusing on inflammation induced by AP. LC-MS analysis of serum samples from AP patients highlighted the regulation of lipid metabolism and inflammation, and found that metabolites involved in the inhibition of NF-κB phosphorylation and the AMPK activation pathway were downregulated. We hypothesized that pre-administration of Clostridium butyricum and its culture supernatant could mitigate AP-induced damage by modulating the AMPK/NF-κB pathway. METHODS Lipopolysaccharide (LPS)-induced cell inflammation models. LPS combined with CAE induced acute pancreatitis in mice. We divided mice into four groups: Con, AP, AP + C.Buty (AP with Clostridium butyricum treatment), and AP + CFS (AP with culture supernatant treatment). Analyses were performed using WB, RT-qPCR, Elisa, flow cytometry, IHC, and HE, respectively. RESULTS Our study shows that CFS can reduce the apoptosis of LPS-induced cellular inflammation and reduce the release of LPS-induced cytoinflammatory factors through the AMPK/NF-κB pathway in vitro. In vivo, Clostridium butyricum and its supernatant significantly reduced inflammatory markers, and corrected histopathological alterations in AP mice. Gut microbiota analysis further supported these results, showing that Clostridium butyricum and its supernatant could restore the balance of intestinal flora disrupted by AP. CONCLUSIONS Mechanistically, our results indicated that the therapeutic effects of Clostridium butyricum are mediated through the activation of AMPK, leading to the inhibition of the NF-κB pathway, thereby reducing the production of pro-inflammatory cytokines. Clostridium butyricum and its culture supernatant exert a protective effect against AP-induced damage by modulating the AMPK/NF-κB signaling pathway. Future studies will further elucidate the molecular mechanisms underlying the beneficial effects of Clostridium butyricum in AP and explore its clinical applicability in human subjects.
Collapse
Affiliation(s)
- Biyan Wen
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510013, China
- Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China
| | - Yaoxing Huang
- Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China
| | - Guiqing Deng
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510013, China
| | - Qingqing Yan
- Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China
| | - Lin Jia
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510013, China.
- Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China.
| |
Collapse
|
|
6
|
Fedoruk A, Shadyro O, Edimecheva I, Fedoruk D, Khrutskin V, Kirkovsky L, Sorokin V, Talkachova H. Free radical fragmentation and oxidation in the polar part of lysophospholipids: Results of the study of blood serum of healthy donors and patients with acute surgical pathology. Redox Biol 2024; 76:103309. [PMID: 39178730 PMCID: PMC11388268 DOI: 10.1016/j.redox.2024.103309] [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: 07/12/2024] [Revised: 08/03/2024] [Accepted: 08/11/2024] [Indexed: 08/26/2024] Open
Abstract
The interaction of reactive oxygen species with cell membrane lipids is usually considered in the context of lipid peroxidation in the nonpolar component of the membrane. In this work, for the first time, data were obtained indicating that damage to human cell membranes can occur in the polar part of lysophospholipids at the interface with the aqueous environment due to free radical fragmentation (FRF) processes. FRF products, namely 1-hexadecanoyloxyacetone (PAc) and 1-octadecanoyloxyacetone (SAc), were identified in human serum, and a GC-MS method was developed to quantify PAc and SAc. The content of FRF products in serum samples of 52 healthy donors was found to be in the range of 1.98-4.75 μmol/L. A linear regression equation, CPAc&SAc (μmol/L) = 0.51 + 0.064 × years, was derived to describe the relationship between age and content of FRF products. In 70 patients with acute surgical pathology in comparison with the control group of healthy donors, two distinct clusters with different concentration levels of FRF products were revealed. The first cluster: groups of 43 patients with various localized inflammatory-destructive lesions of hollow organ walls and bacterial translocation (septic inflammation) of abdominal cavity organs. These patients showed a 1.5-1.9-fold (p = 0.012) decrease in the total concentration of PAc and SAc in serum. In the second cluster: groups of 27 patients with ischemia-reperfusion tissue damage (aseptic inflammation), - a statistically significant increase in the concentration of FRF products was observed: in 2.2-4.0 times (p = 0.0001). The obtained data allow us to further understand the role of free-radical processes in the damage of lipid molecules. FRF products can potentially be used as markers of the degree of free-radical damage of hydroxyl containing phospholipids.
Collapse
Affiliation(s)
- Alexey Fedoruk
- Department of Hepatology and Minimally Invasive Surgery, Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology, 220087, Semashko st., 8, Minsk, Belarus; Department of Transplantology, Institute of Advanced Studies and retraining of Healthcare Personnel in Educational Institutions «Belarusian State Medical University», 220083, Dzerzhinsky Ave., 83, Minsk, Belarus.
| | - Oleg Shadyro
- Laboratory of Chemistry of Free Radical Processes, Research Institute for Physical Chemical Problems of the Belarusian State University, 220006, Leningradskaya st., 14, Minsk, Belarus; Department of Radiation Chemistry and Chemical Pharmaceutical Technologies, Belarusian State University, 220030, Nezavisimosti av., 4, Minsk, Belarus
| | - Irina Edimecheva
- Laboratory of Chemistry of Free Radical Processes, Research Institute for Physical Chemical Problems of the Belarusian State University, 220006, Leningradskaya st., 14, Minsk, Belarus.
| | - Dmitry Fedoruk
- Department of Hepatology and Minimally Invasive Surgery, Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology, 220087, Semashko st., 8, Minsk, Belarus.
| | - Valery Khrutskin
- Laboratory of Chemistry of Free Radical Processes, Research Institute for Physical Chemical Problems of the Belarusian State University, 220006, Leningradskaya st., 14, Minsk, Belarus; Department of Radiation Chemistry and Chemical Pharmaceutical Technologies, Belarusian State University, 220030, Nezavisimosti av., 4, Minsk, Belarus.
| | - Leanid Kirkovsky
- Department of Hepatology and Minimally Invasive Surgery, Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology, 220087, Semashko st., 8, Minsk, Belarus.
| | - Viktor Sorokin
- Laboratory of Chemistry of Free Radical Processes, Research Institute for Physical Chemical Problems of the Belarusian State University, 220006, Leningradskaya st., 14, Minsk, Belarus; Department of Radiation Chemistry and Chemical Pharmaceutical Technologies, Belarusian State University, 220030, Nezavisimosti av., 4, Minsk, Belarus.
| | - Halina Talkachova
- Department of Hepatology and Minimally Invasive Surgery, Minsk Scientific and Practical Center for Surgery, Transplantology and Hematology, 220087, Semashko st., 8, Minsk, Belarus.
| |
Collapse
|
|
7
|
Wu HC, Chien KL, Chen CC, Fang YJ, Hu WH, Tsai MH, Liao WC. Impact of glucose-containing fluid on acute pancreatitis outcomes: A multicenter retrospective analysis. J Formos Med Assoc 2024; 123:1037-1044. [PMID: 38910095 DOI: 10.1016/j.jfma.2024.05.022] [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: 11/24/2023] [Revised: 02/11/2024] [Accepted: 05/31/2024] [Indexed: 06/25/2024] Open
Abstract
INTRODUCTION Fluid resuscitation reduces mortality and morbidity in acute pancreatitis (AP); however, whether glucose-containing fluids negatively impact AP remains uncertain. We aimed to examine the association between glucose-containing fluids and AP outcomes. METHODS This multicenter retrospective cohort study included patients diagnosed with AP between January 2015 and December 2018. Glucose density was defined as total glucose content divided by total fluid volume (g/dl) on day 1, and was considered high if the level exceeded the median. Endpoints were early organ failure (OF), including cardiovascular, renal, or respiratory system failure within 7 days; 30-day OF; ICU admission; and AP-related 90-day mortality. Logistic regression models, restricted cubic spline curves, and Cox proportional hazards models were used for statistical analysis. RESULTS From the database, 1,146 patients with AP were included. Early OF occurred in 8.8% of patients within 7 days. The high glucose-density group (>5 g/dl) had increased risk of early OF (9.7% vs. 8.2%; adjusted odds ratio [aOR], 1.69; 95% confidence interval [CI], 1.03-2.80; P = 0.039), respiratory failure (8.0% vs. 6.2%; aOR, 1.88; 95% CI, 1.09-3.24; P = 0.024), cardiovascular failure (3.4% vs. 2.4%; aOR, 3.59; 95% CI, 1.28-10.0; P = 0.015), and ICU admission (6.8% vs. 5.8%; aOR, 2.06; 95% CI, 1.08-3.94; P = 0.029), with a dose-response effect observed for cardiovascular failure and ICU admission. A significant increase 30-day OF risk (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.19-2.45) was also noted. CONCLUSION Excess glucose-containing fluid was associated with increased risks of overall, respiratory, and cardiovascular OF and ICU admission in AP.
Collapse
Affiliation(s)
- Hsing-Chien Wu
- Department of Medicine, National Taiwan University Cancer Center, National Taiwan University Hospital, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuo-Liong Chien
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Population Health Research Center, National Taiwan University, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Chieh-Chang Chen
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Jen Fang
- Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan
| | - Wen-Hao Hu
- Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan
| | - Min-Horn Tsai
- Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan
| | - Wei-Chih Liao
- Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
|
8
|
Zhu Q, Yuan C, Wang D, Tu B, Chen W, Dong X, Wu K, Tao L, Ding Y, Xiao W, Hu L, Gong W, Li Z, Lu G. The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis. Mol Ther 2024; 32:3025-3041. [PMID: 38872307 PMCID: PMC11403229 DOI: 10.1016/j.ymthe.2024.06.005] [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: 07/15/2023] [Revised: 04/05/2024] [Accepted: 06/07/2024] [Indexed: 06/15/2024] Open
Abstract
Efferocytosis, the clearance of apoptotic cells by macrophages, plays a crucial role in inflammatory responses and effectively prevents secondary necrosis. However, the mechanisms underlying efferocytosis in acute pancreatitis (AP) remain unclear. In this study, we demonstrated the presence of efferocytosis in injured human and mouse pancreatic tissues. We also observed significant upregulation of CD47, an efferocytosis-related the "do not eat me" molecule in injured acinar cells. Subsequently, we used CRISPR-Cas9 gene editing, anti-adeno-associated virus (AAV) gene modification, and anti-CD47 antibody to investigate the potential therapeutic role of AP. CD47 expression was negatively regulated by upstream miR133a, which is controlled by the transcription factor TRIM28. To further investigate the regulation of efferocytosis and reduction of pancreatic necrosis in AP, we used miR-133a-agomir and pancreas-specific AAV-shTRIM28 to modulate CD47 expression. Our findings confirmed that CD47-mediated efferocytosis is critical for preventing pancreatic necrosis and suggest that targeting the TRIM28-miR133a-CD47 axis is clinically relevant for the treatment of AP.
Collapse
Affiliation(s)
- Qingtian Zhu
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China
| | - Chenchen Yuan
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China
| | - Dan Wang
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Bo Tu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Weiwei Chen
- Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou 225000, China
| | - Xiaowu Dong
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China
| | - Keyan Wu
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China
| | - Lide Tao
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China
| | - Yanbing Ding
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China
| | - Weiming Xiao
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China
| | - Lianghao Hu
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China.
| | - Weijuan Gong
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China.
| | - Zhaoshen Li
- Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China.
| | - Guotao Lu
- Pancreatic Center, Department of Gastroenterology, Yangzhou Key Laboratory of Pancreatic Disease, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225000, China.
| |
Collapse
|
|
9
|
Hong W, Zippi M, Wang G, Jin X, He W, Goyal H. Editorial: Immune dysfunction in acute pancreatitis: from bench to bedside research. Front Immunol 2024; 15:1462563. [PMID: 39100664 PMCID: PMC11294211 DOI: 10.3389/fimmu.2024.1462563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 08/06/2024] Open
Affiliation(s)
- Wandong Hong
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Maddalena Zippi
- Unit of Gastroenterology and Digestive Endoscopy, Sandro Pertini Hospital, Rome, Italy
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xi Jin
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenhua He
- Pancreatic Disease Centre, Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hemant Goyal
- Department of Surgery, University of Texas Health Sciences Center, Houston, TX, United States
| |
Collapse
|
|
10
|
Liu Q, Zhu X, Guo S. From pancreas to lungs: The role of immune cells in severe acute pancreatitis and acute lung injury. Immun Inflamm Dis 2024; 12:e1351. [PMID: 39023414 PMCID: PMC11256889 DOI: 10.1002/iid3.1351] [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: 03/28/2024] [Revised: 06/25/2024] [Accepted: 07/08/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Severe acute pancreatitis (SAP) is a potentially lethal inflammatory pancreatitis condition that is usually linked to multiple organ failure. When it comes to SAP, the lung is the main organ that is frequently involved. Many SAP patients experience respiratory failure following an acute lung injury (ALI). Clinicians provide insufficient care for compounded ALI since the underlying pathophysiology is unknown. The mortality rate of SAP patients is severely impacted by it. OBJECTIVE The study aims to provide insight into immune cells, specifically their roles and modifications during SAP and ALI, through a comprehensive literature review. The emphasis is on immune cells as a therapeutic approach for treating SAP and ALI. FINDINGS Immune cells play an important role in the complicated pathophysiology ofSAP and ALI by maintaining the right balance of pro- and anti-inflammatory responses. Immunomodulatory drugs now in the market have low thepeutic efficacy because they selectively target one immune cell while ignoring immune cell interactions. Accurate management of dysregulated immune responses is necessary. A critical initial step is precisely characterizing the activity of the immune cells during SAP and ALI. CONCLUSION Given the increasing incidence of SAP, immunotherapy is emerging as a potential treatment option for these patients. Interactions among immune cells improve our understanding of the intricacy of concurrent ALI in SAP patients. Acquiring expertise in these domains will stimulate the development of innovative immunomodulation therapies that will improve the outlook for patients with SAP and ALI.
Collapse
Affiliation(s)
- Qi Liu
- Emergency Medicine Clinical Research Center, Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Beijing Key Laboratory of Cardiopulmonary Cerebral ResuscitationBeijingChina
| | - Xiaomei Zhu
- Emergency Medicine Clinical Research Center, Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Beijing Key Laboratory of Cardiopulmonary Cerebral ResuscitationBeijingChina
| | - Shubin Guo
- Emergency Medicine Clinical Research Center, Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
- Beijing Key Laboratory of Cardiopulmonary Cerebral ResuscitationBeijingChina
| |
Collapse
|
|
11
|
Willems P, Esmail E, Paquin S, Sahai A. Safety and efficacy of early versus late removal of LAMS for pancreatic fluid collections. Endosc Int Open 2024; 12:E317-E323. [PMID: 38420155 PMCID: PMC10901640 DOI: 10.1055/a-2226-0840] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 12/07/2023] [Indexed: 03/02/2024] Open
Abstract
Background and study aims Optimal timing for removal of lumen-apposing metal stents (LAMS) for effective drainage of pancreatic fluid collections (PFC) while minimizing adverse events (AE) is unknown. Outcomes of early (≤ 4 weeks) or delayed (> 4 weeks) LAMS removal on both clinical efficacy and the incidence of AE were assessed. Patients and methods This was a retrospective analysis of a prospectively maintained registry of PFC drainage between November 2016 and September 2021. Clinical success was defined as a 75% decrease in fluid collection volume with no need for reintervention at 6 months. AE were defined using the American Society for Gastrointestinal Endoscopy lexicon. Multiple logistic regression analysis was performed to determine variables associated with clinical success and AE. Results A total of 108 consecutive PFCs were included. LAMS deployment was technically successful in 103 of 108 cases (95.4%). Failure was associated with collection diameter ≤ 4 cm (odds ratio [OR] 24.0, P = 0.005) and presence of more than 50% necrotic material (OR 20.1, P = 0.01). Stents were left in place for a median of 48 days. Patients with early stent removal (< 4 weeks) had clinical success in 70.0% of cases, which was significantly less than in the group with delayed stent removal (96.4%, P = 0.03). On multiple regression analysis, clinical failure was associated with early stent removal (OR 25.5, P = 0.003). AEs occurred in 8.7% of cases (9/103). There were no predictors of AE. Notably, delayed stent removal did not predict the occurrence of AE. Conclusions Early LAMS removal (< 4 weeks) did not prevent AEs but did lead to increased clinical failure.
Collapse
Affiliation(s)
- Philippe Willems
- Gastroenterology, University of Montreal Hospital Centre, Montréal, Canada
- Gastroenterology, CRCHUM, Montreal, Canada
| | - Eslam Esmail
- Gastroenterology, CRCHUM, Montreal, Canada
- Tropical medicine, Tanta University Faculty of Medicine, Tanta, Egypt
| | - Sarto Paquin
- Gastroenterology, University of Montreal Hospital Centre, Montréal, Canada
- Gastroenterology, CRCHUM, Montreal, Canada
| | - Anand Sahai
- Gastroenterology, University of Montreal Hospital Centre, Montréal, Canada
- Gastroenterology, CRCHUM, Montreal, Canada
| |
Collapse
|
|
12
|
Gao Y, Gong B, Chen Z, Song J, Xu N, Weng Z. Damage-Associated Molecular Patterns, a Class of Potential Psoriasis Drug Targets. Int J Mol Sci 2024; 25:771. [PMID: 38255845 PMCID: PMC10815563 DOI: 10.3390/ijms25020771] [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: 12/07/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Psoriasis is a chronic skin disorder that involves both innate and adaptive immune responses in its pathogenesis. Local tissue damage is a hallmark feature of psoriasis and other autoimmune diseases. In psoriasis, damage-associated molecular patterns (DAMPs) released by damaged local tissue act as danger signals and trigger inflammatory responses by recruiting and activating immune cells. They also stimulate the release of pro-inflammatory cytokines and chemokines, which exacerbate the inflammatory response and contribute to disease progression. Recent studies have highlighted the role of DAMPs as key regulators of immune responses involved in the initiation and maintenance of psoriatic inflammation. This review summarizes the current understanding of the immune mechanism of psoriasis, focusing on several important DAMPs and their mechanisms of action. We also discussed the potential of DAMPs as diagnostic and therapeutic targets for psoriasis, offering new insights into the development of more effective treatments for this challenging skin disease.
Collapse
Affiliation(s)
| | | | | | | | - Na Xu
- Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (Y.G.); (B.G.); (Z.C.); (J.S.)
| | - Zhuangfeng Weng
- Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (Y.G.); (B.G.); (Z.C.); (J.S.)
| |
Collapse
|
|
13
|
Rayman S, Jacoby H, Guenoun K, Oliphant U, Nelson D, Kaiser A, Sucandy I. Diagnosis and Contemporary Management of Necrotizing Pancreatitis. Am Surg 2023; 89:4817-4825. [PMID: 36940369 DOI: 10.1177/00031348231156781] [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: 03/22/2023]
Abstract
BACKGROUND Acute pancreatitis is a common diagnosis which requires a prompt diagnosis and management by a multidisciplinary team with often general surgeons as the initial provider. Morbidity and mortality from an acute pancreatitis can be very high, especially in patients with a progressive worsening acute pancreatitis developing into pancreatic necrosis in the setting of multiple underlying medical comorbidities. PURPOSE In this review paper, we discuss all aspects of acute pancreatitis and its potential complications, as well providing updates in the modern management of necrotizing pancreatitis. Practicing general surgeons need to be aware of the evolution in the diagnosis and treatment of this disease. RESEARCH DESIGN We conducted a review of literature of evidence and management options for acute pancreatitis, including all published manuscripts from 2012 to 2022. RESULTS Diagnosis and management of this disease can vary among specialiaties. The decision to utilize a percutaneous or endoscopic techniques are relevant points of discussion within general surgery and gastroenterology societies. In the past decade, the use of advanced endoscopic interventions has slowly replaced conventional open surgery in managing complications of acute severe pancreatitis. CONCLUSION Acute pancreatitis is a disease which requires multidisciplinary approach with evolving treatment options to less invasive nonsurgical methods.
Collapse
Affiliation(s)
- Shlomi Rayman
- Digestive Health Institute, AdventHealth, Tampa, FL, USA
| | - Harel Jacoby
- Digestive Health Institute, AdventHealth, Tampa, FL, USA
| | - Kawtar Guenoun
- Digestive Health Institute, AdventHealth, Tampa, FL, USA
| | - Uretz Oliphant
- Department of Surgery, Carle Foundation Hospital, Urbana, IL, USA
| | - Daniel Nelson
- Department of Surgery, William Beaumont Army Medical Center, El Paso, TX, USA
| | - Andreas Kaiser
- Division of Colorectal Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | | |
Collapse
|
|
14
|
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.
Collapse
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
| |
Collapse
|
|
15
|
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: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [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.
Collapse
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
| |
Collapse
|
|
16
|
Wang Y, Xia Y, Chen Y, Xu L, Sun X, Li J, Huang G, Li X, Xie Z, Zhou Z. Association analysis between the TLR9 gene polymorphism rs352140 and type 1 diabetes. Front Endocrinol (Lausanne) 2023; 14:1030736. [PMID: 37139337 PMCID: PMC10150994 DOI: 10.3389/fendo.2023.1030736] [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: 08/29/2022] [Accepted: 03/24/2023] [Indexed: 05/05/2023] Open
Abstract
Background To a great extent, genetic factors contribute to the susceptibility to type 1 diabetes (T1D) development, and by triggering immune imbalance, Toll-like receptor (TLR) 9 is involved in the development of T1D. However, there is a lack of evidence supporting a genetic association between polymorphisms in the TLR9 gene and T1D. Methods In total, 1513 individuals, including T1D patients (n=738) and healthy control individuals (n=775), from the Han Chinese population were recruited for an association analysis of the rs352140 polymorphism of the TLR9 gene and T1D. rs352140 was genotyped by MassARRAY. The allele and genotype distributions of rs352140 in the T1D and healthy groups and those in different T1D subgroups were analyzed by the chi-squared test and binary logistic regression model. The chi-square test and Kruskal-Wallis H test were performed to explore the association between genotype and phenotype in T1D patients. Results The allele and genotype distributions of rs352140 were significantly different in T1D patients and healthy control individuals (p=0.019, p=0.035). Specifically, the T allele and TT genotype of rs352140 conferred a higher risk of T1D (OR=1.194, 95% CI=1.029-1.385, p=0.019, OR=1.535, 95% CI=1.108-2.126, p=0.010). The allele and genotype distributions of rs352140 were not significantly different between childhood-onset and adult-onset T1D and between T1D with a single islet autoantibody and T1D with multiple islet autoantibodies (p=0.603, p=0.743). rs352140 was associated with T1D susceptibility according to the recessive and additive models (p=0.015, p=0.019) but was not associated with T1D susceptibility in the dominant and overdominant models (p=0.117, p=0.928). Moreover, genotype-phenotype association analysis showed that the TT genotype of rs352140 was associated with higher fasting C-peptide levels (p=0.017). Conclusion In the Han Chinese population, the TLR9 polymorphism rs352140 is associated with T1D and is a risk factor for susceptibility to T1D.
Collapse
|
|
17
|
Zhou X, Jin S, Pan J, Lin Q, Yang S, Ambe PC, Basharat Z, Zimmer V, Wang W, Hong W. Damage associated molecular patterns and neutrophil extracellular traps in acute pancreatitis. Front Cell Infect Microbiol 2022; 12:927193. [PMID: 36034701 PMCID: PMC9411527 DOI: 10.3389/fcimb.2022.927193] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/21/2022] [Indexed: 11/15/2022] Open
Abstract
Previous researches have emphasized a trypsin-centered theory of acute pancreatitis (AP) for more than a century. With additional studies into the pathogenesis of AP, new mechanisms have been explored. Among them, the role of immune response bears great importance. Pro-inflammatory substances, especially damage-associated molecular patterns (DAMPs), play an essential role in activating, signaling, and steering inflammation. Meanwhile, activated neutrophils attach great importance to the immune defense by forming neutrophil extracellular traps (NETs), which cause ductal obstruction, premature trypsinogen activation, and modulate inflammation. In this review, we discuss the latest advances in understanding the pathological role of DAMPs and NETs in AP and shed light on the flexible crosstalk between these vital inflammatory mediators. We, then highlight the potentially promising treatment for AP targeting DAMPs and NETs, with a focus on novel insights into the mechanism, diagnosis, and management of AP.
Collapse
Affiliation(s)
- Xiaoying Zhou
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shengchun Jin
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jingyi Pan
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qingyi Lin
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shaopeng Yang
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Peter C. Ambe
- Department of General Surgery, Visceral Surgery and Coloproctology, Vinzenz-Pallotti-Hospital Bensberg, Bensberg, Germany
| | - Zarrin Basharat
- Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Vincent Zimmer
- Department of Medicine, Marienhausklinik St. Josef Kohlhof, Neunkirchen, Germany
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Wei Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Wandong Hong, ; Wei Wang,
| | - Wandong Hong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Wandong Hong, ; Wei Wang,
| |
Collapse
|
|
18
|
Zhong R, Farag MA, Chen M, He C, Xiao J. Recent advances in the biosynthesis, structure–activity relationships, formulations, pharmacology, and clinical trials of fisetin. EFOOD 2022. [DOI: 10.1002/efd2.3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Ruting Zhong
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine University of Macau Macau China
| | - Mohamed A. Farag
- Pharmacognosy Department, College of Pharmacy Cairo University Cairo Egypt
| | - Meiwan Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine University of Macau Macau China
| | - Chengwei He
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine University of Macau Macau China
| | - Jianbo Xiao
- Department of Analytical and Food Chemistry, Faculty of Sciences Universidade de Vigo Ourense Spain
| |
Collapse
|
|
19
|
New challenges for microRNAs in acute pancreatitis: progress and treatment. J Transl Med 2022; 20:192. [PMID: 35509084 PMCID: PMC9066850 DOI: 10.1186/s12967-022-03338-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/06/2022] [Indexed: 12/17/2022] Open
Abstract
Acute pancreatitis (AP) is a common clinical abdominal emergency, with a high and increasing incidence each year. Severe AP can easily cause systemic inflammatory response syndrome, multiple organ dysfunction and other complications, leading to higher hospitalization rates and mortality. Currently, there is no specific treatment for AP. Thus, we still need to understand the exact AP pathogenesis to effectively cure AP. With the rise of transcriptomics, RNA molecules, such as microRNAs (miRNAs) transcribed from nonprotein-coding regions of biological genomes, have been found to be of great significance in the regulation of gene expression and to be involved in the occurrence and development of many diseases. Increasing evidence has shown that miRNAs, as regulatory RNAs, can regulate pancreatic acinar necrosis and apoptosis and local and systemic inflammation and play an important role in the development and thus potentially the diagnosis and treatment of AP. Therefore, here, the current research on the relationship between miRNAs and AP is reviewed.
Collapse
|
|
20
|
Wang Y, Li Y, Gao S, Yu X, Chen Y, Lin Y. Tetrahedral Framework Nucleic Acids Can Alleviate Taurocholate-Induced Severe Acute Pancreatitis and Its Subsequent Multiorgan Injury in Mice. NANO LETTERS 2022; 22:1759-1768. [PMID: 35138113 DOI: 10.1021/acs.nanolett.1c05003] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas accompanied by tissue injury and necrosis. It not only affects the pancreas but also triggers a systemic inflammatory response that leads to multiorgan failure or even death. Moreover, there is no effective treatment currently that can reverse the disease progression. In this study, tetrahedral framework nucleic acids (tFNAs) were utilized to treat SAP in mice for the first time and proved to be effective in suppressing inflammation and preventing pathological cell death. Serum levels of pancreatitis-related biomarkers witnessed significant changes after tFNAs treatment. Reduction in the expression of certain cytokines involved in local and systemic inflammatory response were observed, together with alteration in proteins related to cell death and apoptosis. Collectively, our results demonstrate that tFNAs could both alleviate SAP and its subsequent multiorgan injury in mice, thus offering a novel and effective option to deal with SAP in the future.
Collapse
Affiliation(s)
- Yun Wang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanjing Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shaojingya Gao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xi Yu
- Department of Orthopedic Surgery and Orthopedic Research Institute Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yu Chen
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.,College of Biomedical Engineering, Sichuan University, Chengdu, Sichuan 610041, China
| |
Collapse
|
|
21
|
Gao L, Chong E, Pendharkar S, Hong J, Windsor JA, Ke L, Li W, Phillips A. The Effects of NLRP3 Inflammasome Inhibition in Experimental Acute Pancreatitis: A Systematic Review and Meta-Analysis. Pancreas 2022; 51:13-24. [PMID: 35195590 DOI: 10.1097/mpa.0000000000001971] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ABSTRACT Acute pancreatitis (AP) is an inflammatory disease, and NLRP3 inflammasome activation is involved in the pathogenesis of AP. Previous research showed that inhibition of NLRP3 inflammasome may exert protective effects on animal models of AP and reduces disease severity. The aim of this systematic review and meta-analysis is to evaluate the effects of drug treatment of NLRP3 inflammasome on the outcomes of experimental AP. PubMed, Embase, Medline, and Web of Science databases were searched for relevant articles without language restrictions. The main outcomes for this study included local pancreatic injury, the incidence of systemic inflammatory responses, and the incidence of organ failure. Twenty-eight animal studies including 556 animals with AP were included in the meta-analysis. Compared with controls, inhibition of NLRP3 inflammasome significantly reduced the pancreatic histopathological scores, serum amylase, and lipase levels. In addition, inhibition of NLRP3 inflammasome reduced the levels of circulating inflammatory cytokines, as well as mitigating severity of AP-associated acute lung injury and acute intestinal injury. To conclude, inhibition of NLRP3 inflammasome has protective effects on AP by mitigating organ injury and systemic inflammation in animal studies, indicating that NLRP3 inflammasome holds promise as a target for specific AP therapy.
Collapse
Affiliation(s)
| | - Eric Chong
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, School of Medicine, University of Auckland, Auckland, New Zealand
| | - Sayali Pendharkar
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, School of Medicine, University of Auckland, Auckland, New Zealand
| | | | | | - Lu Ke
- From the Center of Severe Acute Pancreatitis, Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Weiqin Li
- From the Center of Severe Acute Pancreatitis, Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | | |
Collapse
|
|
22
|
Li G, Chen H, Liu L, Xiao P, Xie Y, Geng X, Zhang T, Zhang Y, Lu T, Tan H, Li L, Sun B. Role of Interleukin-17 in Acute Pancreatitis. Front Immunol 2021; 12:674803. [PMID: 34594321 PMCID: PMC8476864 DOI: 10.3389/fimmu.2021.674803] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 08/31/2021] [Indexed: 11/24/2022] Open
Abstract
Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.
Collapse
Affiliation(s)
- Guanqun Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongze Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liwei Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Peng Xiao
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yu Xie
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinglong Geng
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tao Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yang Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tianqi Lu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongtao Tan
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| |
Collapse
|
|
23
|
Zhou J, Zhou P, Zhang Y, Wang G, Fan Z. Signal Pathways and Markers Involved in Acute Lung Injury Induced by Acute Pancreatitis. DISEASE MARKERS 2021; 2021:9947047. [PMID: 34497676 PMCID: PMC8419500 DOI: 10.1155/2021/9947047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/10/2021] [Accepted: 08/18/2021] [Indexed: 12/23/2022]
Abstract
Acute pancreatitis (AP) is a common acute abdominal disease with a mortality rate of about 30%. Acute lung injury (ALI) is a common systemic complication of acute pancreatitis, with progressive hypoxemia and respiratory distress as the main manifestations, which can develop into acute respiratory distress syndrome or even multiple organ dysfunction syndrome (MODS) in severe cases, endangering human health. In the model of AP, pathophysiological process of the lung can be summarized as oxidative stress injury, inflammatory factor infiltration, and alveolar cell apoptosis. However, the intrinsic mechanisms underlying AP and how it leads to ALI are not fully understood. In this paper, we summarize recent articles related to AP leading to ALI, including the signal transduction pathways and biomarkers of AP-ALI. There are factors or pathway aggravating ALI, the JAK2-STAT3 signaling pathway, NLRP3/NF-κB pathway, mitogen-activated protein kinase, PKC pathway, neutrophil protease (NP)-LAMC2-neutrophil pathway, and the P2X7 pathway, and there are important transcription factors in the NRF2 signal transduction pathway which could give researchers better understanding of the underlying mechanisms controlling AP and ALI and lay the foundation for finally curing ALI induced by AP.
Collapse
Affiliation(s)
- Jialin Zhou
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China
| | - Pengcheng Zhou
- School of Medicine, Southeast University, Nanjing, China
| | - Yingyi Zhang
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China
| | - Guangzhi Wang
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Zhe Fan
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China
- School of Medicine, Southeast University, Nanjing, China
| |
Collapse
|
|
24
|
PPAR-Alpha Agonist Fenofibrate Combined with Octreotide Acetate in the Treatment of Acute Hyperlipidemia Pancreatitis. PPAR Res 2021; 2021:6629455. [PMID: 33968146 PMCID: PMC8081610 DOI: 10.1155/2021/6629455] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/25/2021] [Accepted: 04/13/2021] [Indexed: 11/17/2022] Open
Abstract
At present, there are more and more patients with acute hypertriglyceridemia pancreatitis in clinical practice. Common treatment measures include fasting and water withdrawal, fluid resuscitation, and somatostatin. In recent years, studies have pointed out that the PPARa agonist fenofibrate may help improve the condition of such patients. Therefore, through clinical research and analysis, we reported for the first time that fenofibrate combined with octreotide acetate has a more excellent effect in the treatment of patients with acute hypertriglyceridemia pancreatitis, and from the perspective of signal pathways, we revealed that the combination of the two drugs has an effect on NF-κB P65. The synergistic inhibitory effect proves that the combined treatment is beneficial to control inflammation, protect liver function, and improve the prognosis of patients. It is worthy of clinical promotion.
Collapse
|
|
25
|
Ma Z, Zhou J, Yang T, Xie W, Song G, Song Z, Chen J. Mesenchymal stromal cell therapy for pancreatitis: Progress and challenges. Med Res Rev 2021; 41:2474-2488. [PMID: 33840113 DOI: 10.1002/med.21801] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/17/2020] [Accepted: 03/23/2021] [Indexed: 12/15/2022]
Abstract
Pancreatitis is a common gastrointestinal disease with no effective therapeutic options, particularly for cases of severe acute and chronic pancreatitis (CP). Mesenchymal stromal cells (MSCs) are multipotent cells with diverse biological properties, including directional migration, paracrine, immunosuppressive, and antiinflammatory effects, which are considered an ideal candidate cell type for repairing tissue damage caused by various pathogenies. Several researchers have reported significant therapeutic efficacy of MSCs in animal models of acute and CP. However, the specific underlying mechanisms are yet to be clarified and clinical application of MSCs as pancreatitis therapy has rarely been reported. This review mainly focuses on the potential and challenges in clinical application of MSCs for treatment of acute and CP, along with discussion of the underlying molecular mechanisms.
Collapse
Affiliation(s)
- Zhilong Ma
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jia Zhou
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tingsong Yang
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wangcheng Xie
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guodong Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhenshun Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ji Chen
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
26
|
Hidalgo-Sastre A, Kuebelsbeck LA, Jochheim LS, Staufer LM, Altmayr F, Johannes W, Steiger K, Ronderos M, Hartmann D, Hüser N, Schmid RM, Holzmann B, von Figura G. Toll-like receptor 3 expression in myeloid cells is essential for efficient regeneration after acute pancreatitis in mice. Eur J Immunol 2021; 51:1182-1194. [PMID: 33521935 DOI: 10.1002/eji.202048771] [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: 05/28/2020] [Revised: 11/12/2020] [Accepted: 01/29/2021] [Indexed: 11/09/2022]
Abstract
Stringent regulation of the inflammatory response is crucial for normal tissue regeneration. Here, we analyzed the role of Toll-like receptor 3 (TLR3) in pancreatic regeneration after acute pancreatitis (AP). AP was induced by caerulein treatment in mice with global TLR3 deficiency (TLR3OFF ) or in mice re-expressing TLR3 exclusively in the myeloid cell lineage (TLR3Mye ). Compared to WT mice, TLR3OFF mice had a markedly increased formation of acinar-to-ductal metaplasia (ADM) that persisted until day 7 after initiation of AP. Pancreatic tissue of WT mice was completely regenerated after 5 days with no detectable ADM structures. The enhancing effect of TLR3-deficiency on ADM formation was closely linked with an increased and prolonged accumulation of macrophages in pancreata of TLR3OFF mice. Importantly, the phenotype of TLR3OFF mice was rescued in TLR3Mye mice, demonstrating the causative role of myeloid cell selective TLR3 signaling. Moreover, in vitro stimulation of macrophages through TLR3 initiated cell death by a caspase-8-associated mechanism. Therefore, these findings provide evidence that TLR3 signaling in myeloid cells is sufficient to limit inflammation and ADM formation and to promote regeneration after AP. Notably, resolution of inflammation after AP was associated with macrophage sensitivity to TLR3-mediated cell death.
Collapse
Affiliation(s)
- Ana Hidalgo-Sastre
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Ludwig A Kuebelsbeck
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Leonie S Jochheim
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Lina M Staufer
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Felicitas Altmayr
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Widya Johannes
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Katja Steiger
- Technical University of Munich, School of Medicine, Department of Pathology, Munich, Germany
| | - Monica Ronderos
- Technical University of Munich, School of Medicine, Department of Pathology, Munich, Germany
| | - Daniel Hartmann
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Norbert Hüser
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Roland M Schmid
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Bernhard Holzmann
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Munich, Germany
| | - Guido von Figura
- School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| |
Collapse
|
|
27
|
Chen S, Zhu J, Sun LQ, Liu S, Zhang T, Jin Y, Huang C, Li D, Yao H, Huang J, Qin Y, Zhou M, Chen G, Zhang Q, Ma F. LincRNA-EPS alleviates severe acute pancreatitis by suppressing HMGB1-triggered inflammation in pancreatic macrophages. Immunology 2021; 163:201-219. [PMID: 33512718 DOI: 10.1111/imm.13313] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/30/2020] [Accepted: 01/14/2021] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP), an inflammatory disorder of the pancreas with a high hospitalization rate, frequently leads to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). However, therapeutic targets for effective treatment and early intervention of AP are still urgently required to be identified. Here, we have observed that the expression of pancreatic lincRNA-EPS, a long intergenic non-coding RNA, is dynamically changed during both caerulein-induced AP (Cer-AP) and sodium taurocholate-induced severe AP (NaTc-SAP). The expression pattern of lincRNA-EPS is negatively correlated with the typical inflammatory genes such as IL-6, IL-1β, CXCL1, and CXCL2. Further studies indicate that knockout of lincRNA-EPS aggravates the pathological symptoms of AP including more induction of serum amylase and lipase, severe edema, inflammatory cells infiltration and acinar necrosis in both experimental AP mouse models. Besides these intrapancreatic effects, lincRNA-EPS also protects against tissue damages in the extra-pancreatic organs such as lung, liver, and gut in the NaTc-SAP mouse model. In addition, we have observed more serum pro-inflammatory cytokines TNF-α and IL-6 in the lincRNA-EPS-/- NaTc-SAP mice and more extracellular HMGB1 around injured acinar cells in the pancreas from lincRNA-EPS-/- NaTc-SAP mice, compared with their respective controls. Pharmacological inhibition of NF- κ B activity by BAY11-7082 significantly abolishes the suppressive effect of lincRNA-EPS on TLR4 ligand-induced inflammatory genes in macrophages. Our study has described a protective role of lincRNA-EPS in alleviating AP and SAP, outlined a novel pathway that lincRNA-EPS suppresses HMGB1-NF- κ B-dependent inflammatory response in pancreatic macrophages and provided a potential therapeutic target for SAP.
Collapse
Affiliation(s)
- Shengchuan Chen
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Jingfei Zhu
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Li-Qiong Sun
- Institute of Chinese Medicinal Materials, Nanjing Agricultural University, Nanjing, China
| | - Siying Liu
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Tan Zhang
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Yuepeng Jin
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chaohao Huang
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Dapei Li
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Haiping Yao
- Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| | - Jian Huang
- Department of Emergency, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanghua Qin
- Department of Laboratory Diagnosis, Changhai Hospital of the Second Military Medical University, Shanghai, China
| | - Mengtao Zhou
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gang Chen
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qiyu Zhang
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Feng Ma
- Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Suzhou Institute of Systems Medicine, Suzhou, China
| |
Collapse
|
|
28
|
Kuwabara R, Hu S, Smink AM, Orive G, Lakey JRT, de Vos P. Applying Immunomodulation to Promote Longevity of Immunoisolated Pancreatic Islet Grafts. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:129-140. [PMID: 33397201 DOI: 10.1089/ten.teb.2020.0326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Islet transplantation is a promising therapy for insulin-dependent diabetes, but large-scale application is hampered by the lack of a consistent source of insulin-producing cells and need for lifelong administration of immunosuppressive drugs, which are associated with severe side effects. To avoid chronic immunosuppression, islet grafts can be enveloped in immunoisolating polymeric membranes. These immunoisolating polymeric membranes protect islet grafts from cell-mediated rejection while allowing diffusion of oxygen, nutrients, and insulin. Although clinical trials have shown the safety and feasibility of encapsulated islets to control glucose homeostasis, the strategy does up till now not support long-term graft survival. This partly can be explained by a significant loss of insulin-producing cells in the immediate period after implantation. The loss can be prevented by combining immunoisolation with immunomodulation, such as combined administration of immunomodulating cytokines or coencapsulation of immunomodulating cell types such as regulatory T cells, mesenchymal stem cells, or Sertoli cells. Also, administration of specific antibodies or apoptotic donor leucocytes is considered to create a tolerant microenvironment around immunoisolated grafts. In this review, we describe the outcomes and limitations of these approaches, as well as the recent progress in immunoisolating devices. Impact statement Immunoisolation by enveloping islets in semipermeable membranes allows for successful transplantation of islet grafts in the absence of chronic immunosuppression, but the duration of graft survival is still not permanent. The reasons for long-term final graft failure is not fully understood, but combining immunoisolation with immunomodulation of tissues or host immune system has been proposed to enhance the longevity of grafts. This article reviews the recent progress and challenges of immunoisolation, as well as the benefits and feasibility of combining encapsulation approaches with immunomodulation to promote longevity of encapsulated grafts.
Collapse
Affiliation(s)
- Rei Kuwabara
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Biomaterials, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shuxian Hu
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexandra M Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Jonathan R T Lakey
- Department of Surgery and Biomedical Engineering, University of California Irvine, Irvine, California, USA
| | - Paul de Vos
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| |
Collapse
|
|
29
|
Peng C, Li Z, Yu X. The Role of Pancreatic Infiltrating Innate Immune Cells in Acute Pancreatitis. Int J Med Sci 2021; 18:534-545. [PMID: 33390823 PMCID: PMC7757151 DOI: 10.7150/ijms.51618] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022] Open
Abstract
Acute pancreatitis (AP) is a leading cause of gastrointestinal-related hospital admissions with significant morbidity and mortality. Although the underlying pathophysiology of AP is rather complex, which greatly limits the treatment options, more and more studies have revealed that infiltrating immune cells play a critical role in the pathogenesis of AP and determine disease severity. Thus, immunomodulatory therapy targeting immune cells and related inflammatory mediators is expected to be a novel treatment modality for AP which may improve the prognosis of patients. Cells of the innate immune system, including macrophages, neutrophils, dendritic cells, and mast cells, represent the majority of infiltrating cells during AP. In this review, an overview of different populations of innate immune cells and their role during AP will be discussed, with a special focus on neutrophils and macrophages.
Collapse
Affiliation(s)
- Cheng Peng
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Zhiqiang Li
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| | - Xiao Yu
- Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
| |
Collapse
|
|
30
|
Luo ZL, Sun HY, Wu XB, Cheng L, Ren JD. Epigallocatechin-3-gallate attenuates acute pancreatitis induced lung injury by targeting mitochondrial reactive oxygen species triggered NLRP3 inflammasome activation. Food Funct 2021; 12:5658-5667. [PMID: 34018522 DOI: 10.1039/d1fo01154e] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Green tea has been considered as a health-promoting beverage and is widely consumed worldwide. Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol derived from green tea leaves with potent antioxidative and chemopreventive activities, has been reported to offer protection against inflammation-driven tissue damage. Here, we evaluated the protective effects of EGCG against lung injury during acute pancreatitis (AP) and further revealed the detailed mechanism. The results showed that EGCG significantly attenuated l-arginine-induced AP and the consequent pulmonary damage in mice. Moreover, EGCG substantially attenuated oxidative stress and concurrently suppressed NOD-like receptor protein 3 (NLRP3) inflammasome activation in the lung. In vitro, EGCG considerably reduced the production of mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (ox-mtDNA) in alveolar macrophages (AMs) challenged with AP-conditioned plasma. Meanwhile, the amount of ox-mtDNA bound to NLRP3 decreased significantly by the treatment with EGCG, resulting in impaired NLRP3 inflammasome activation. In addition, the antagonism of NLRP3 signaling by EGCG was affected in the presence of the mtROS stimulant rotenone or scavenger Mito-TEMPO. Altogether, EGCG possesses potent activity to attenuate lung injury during AP progression by inhibiting NLRP3 inflammasome activation. As for the mechanism, the EGCG-conferred restriction of NLRP3 inflammasome activation probably arises from the elimination of mtROS as well as its oxidative product ox-mtDNA, which consequently enables the protection against AP-associated lung injury.
Collapse
Affiliation(s)
- Zhu-Lin Luo
- General Surgery Center of PLA, the General Hospital of Western Theater Command, Chengdu 610083, China and Department of Pharmacy, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China.
| | - Hong-Yu Sun
- Central Laboratory, the General Hospital of Western Theater Command, Chengdu 610083, China
| | - Xiao-Bo Wu
- Department of Ultrasound, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu 610041, China
| | - Long Cheng
- General Surgery Center of PLA, the General Hospital of Western Theater Command, Chengdu 610083, China
| | - Jian-Dong Ren
- Department of Pharmacy, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China. and Department of Pharmacy, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| |
Collapse
|
|
31
|
Singh A, Bandyopadhyay A, Mukherjee N, Basu A. Toll-Like Receptor 9 Expression Levels in Breast Carcinoma Correlate with Improved Overall Survival in Patients Treated with Neoadjuvant Chemotherapy and Could Serve as a Prognostic Marker. Genet Test Mol Biomarkers 2020; 25:12-19. [PMID: 33372855 DOI: 10.1089/gtmb.2020.0170] [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: 10/22/2022] Open
Abstract
Aim: Toll-like receptor 9 (TLR9) can recognize the DNA fragments released from chemotherapy-treated cancer cells in tumor tissues and induce an inflammatory response. The aim of the present study was to evaluate the survivability benefit of TLR9 expression levels as a potential prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy (NACT). Methods: To study the expression of TLR9 in breast tumor, immunohistochemical (IHC) analyses were performed on two patient cohorts, with NACT (n = 19) and without NACT (n = 23). To corroborate the findings from the in-house cohort, we also used publicly available datasets including SurvExpress (GSE 20685) and the Kaplan-Meier plotter tool (GSE 16446) to analyze the relationship between the expression of TLR9 and overall survivability for NACT. Results: The IHC analyses of our inhouse cohort demonstrated that TLR9 was expressed in both malignant breast epithelial cancer cells as well as in the adjacent stromal cells. The IHC results also indicated that, the percentage of malignant epithelial cells (54.76%) expressing TLR9 was higher than in the adjacent stromal compartment (11.9%). We also observed an increase in the expression levels of TLR9 in the patients who were given NACT (p = 0.0379). Further, the analysis of publicly available datasets demonstrated that elevated TLR9 expression was related to increased overall survival in patients treated with NACT. Conclusions: In this study, we show for the first time that elevated TLR9 tissue expression levels in breast cancer may serve as a prognostic marker for patients treated with NACT and could potentially be used to select the neoadjuvant regime.
Collapse
Affiliation(s)
- Aradhana Singh
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Burdwan, India
| | - Arghya Bandyopadhyay
- Department of Pathology and Burdwan Medical College and Hospital, Burdwan, India
| | | | - Anupam Basu
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Burdwan, India
| |
Collapse
|
|
32
|
Hu J, Zhang YM, Miao YF, Zhu L, Yi XL, Chen H, Yang XJ, Wan MH, Tang WF. Effects of Yue-Bi-Tang on water metabolism in severe acute pancreatitis rats with acute lung-kidney injury. World J Gastroenterol 2020; 26:6810-6821. [PMID: 33268963 PMCID: PMC7684462 DOI: 10.3748/wjg.v26.i43.6810] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/07/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The complications acute lung injury and acute kidney injury caused by severe inflammation are the main reasons of high mortality of severe acute pancreatitis (SAP). These two complications can both lead to water metabolism and acid-base balance disorders, which could act as additional critical factors affecting the disease trend. Aquaporins (AQPs), which can regulate the transmembrane water transport, have been proved to participate in the pathophysiological process of SAP and the associated complications, such as acute lung injury and acute kidney injury. Thus, exploring herbs that can effectively regulate the expression of AQP in SAP could benefit the prognosis of this disease.
AIM To determine whether Yue-Bi-Tang (YBT) can regulate the water metabolism in rats with severe acute pancreatitis via regulating the expression of aquaporins.
METHODS Sprague-Dawley rats were randomly divided into three groups, sham operation group (SOG), model group (MG), and treatment group (TG). SAP was induced with 3.5% sodium taurocholate in the MG and TG. Rats in the TG were administered with YBT while SOG and MG rats were given the same volume of saline. Blood and tissue samples were harvested to detect serum inflammatory cytokines, histopathological changes, malondialdehyde and superoxide dismutase in the lung, and protein and mRNA expression of kidney injury molecule-1, α-smooth muscle actin, and vimentin in the kidney, and AQP1 and 4 in the lung, pancreas, and kidney.
RESULTS The serum interleukin-10, tumor necrosis factor α, and creatinine levels were higher in the MG than in the SOG. Tumor necrosis factor α level in the TG was lower than that in the MG. Malondialdehyde level in lung tissues was higher than in the SOG. The pathological scores and edema scores of the pancreas, lung, and kidney tissues in the MG were all higher than those in the SOG and TG. The protein expression of AQP4 in lung tissues and AQP1 in kidney tissues in the MG were higher than those in the SOG and TG. The expression of vimentin was significantly higher in the MG than in the SOG. The expression of AQP1 mRNA in the lung and kidney, and AQP4 mRNA in the kidney was up-regulated in the MG compared to the SOG.
CONCLUSION YBT might regulate water metabolism to reduce lung and kidney edema of SAP rats via decreasing AQP expression, and alleviate the tissue inflammatory injury.
Collapse
Affiliation(s)
- Jing Hu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Mei Zhang
- Department of Traditional Chinese Medicine, Xiang’an Hospital of Xiamen University, Xiamen 361101, Fujian Province, China
| | - Yi-Fan Miao
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lv Zhu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Lin Yi
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Huan Chen
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xi-Jing Yang
- Animal Experiment Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mei-Hua Wan
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Fu Tang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| |
Collapse
|
|
33
|
Li Y, Li G, Suo L, Zhang J. Recent advances in studies of molecular hydrogen in the treatment of pancreatitis. Life Sci 2020; 264:118641. [PMID: 33148420 DOI: 10.1016/j.lfs.2020.118641] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/10/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023]
Abstract
Pancreatitis is an inflammatory disease of the pancreas characterized by acinar cell injury and is associated with the abnormal release of trypsin, which results in high mortality due to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). The inflammatory response, impaired autophagic flux, endoplasmic reticulum stress (ERS) and their interactions are involved in the development of pancreatitis. Molecular hydrogen (H2) is a novel antioxidant that possesses the features of selective scavenging of oxygen free radicals and nontoxic metabolites and has been shown to be efficacious for treating infection, injury, tumors, ischemia-reperfusion organ injury, metabolic disease and several other diseases. Recent studies have found that H2 is also useful in the treatment of pancreatitis, which may be related to the mechanism of antioxidative stress, anti-inflammation, anti-apoptosis, regulation of immunity and regulation of molecular pathways. This review focuses on the pathogenesis of pancreatitis and the research progress and potential mechanisms of H2 against pancreatitis to provide theoretical bases for future research and clinical application of H2 therapy for pancreatitis.
Collapse
Affiliation(s)
- Yuexian Li
- Department of Anesthesiology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, Liaoning 110004, PR China
| | - Guoqing Li
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Dalian, Liaoning 116001, PR China
| | - Liangyuan Suo
- Department of Anesthesiology, Cancer Hospital of China Medical University, No.44 Xiaoheyan Road, Shenyang, Liaoning 110042, PR China
| | - Jin Zhang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang, Liaoning 110004, PR China.
| |
Collapse
|
|
34
|
Wang B, Lin W. Edaravone Protects against Pancreatic and Intestinal Injury after Acute Pancreatitis via Nuclear Factor-κB Signaling in Mice. Biol Pharm Bull 2020; 43:509-515. [PMID: 32115510 DOI: 10.1248/bpb.b19-00944] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Acute pancreatitis (AP) is one kind of acute surgical abdominal disease in the world. It causes intestinal damage with subsequent bacterial migration, endotoxemia and secondary pancreatic infections. In this investigation, we determined that edaravone (EDA) reduces pancreatic and intestinal injury after AP in mice. This was demonstrated by a reduction in histological score, apoptosis, interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α, along with obstructing activation of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NFκB). Our study results suggested that EDA exerts its protective effects against pancreatic and intestinal injury after AP via regulation of the TLR4/NFκB pathway. Our findings provide the basis for EDA to treat AP-induced pancreatic and intestinal injury, even might develop as a potential therapy for other inflammatory diseases.
Collapse
Affiliation(s)
- Bingbin Wang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University
| | - Wendong Lin
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University
| |
Collapse
|
|
35
|
Kuzi S, Mazaki-Tovi M, Suchodolski JS, Rimer D, Lidbury JA, Steiner JM, Buono A, Nivy R, Segev G, Aroch I. Protease inhibitors, inflammatory markers, and their association with outcome in dogs with naturally occurring acute pancreatitis. J Vet Intern Med 2020; 34:1801-1812. [PMID: 32893923 PMCID: PMC7517856 DOI: 10.1111/jvim.15895] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 08/15/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022] Open
Abstract
Background Acute pancreatitis (AP) presumably is associated with pancreatic protease activation, protease inhibitor (PI) depletion, and inflammatory mediator secretion. Objectives Examine PIs and inflammatory mediator concentrations in dogs with AP and their association with death. Animals Thirty‐one dogs diagnosed with AP based on clinical signs, ultrasonographic findings, and increased canine pancreatic lipase immunoreactivity (cPLI) and 51 healthy control dogs. Methods Antithrombin and α2‐antiplasmin activity (ATA and α2AP, respectively) and concentrations of α1‐proteinase inhibitor (α1PI), α2‐macroglobulin (α2MG), C‐reactive protein (CRP), interleukins (ILs)‐2,6,8 and tumor necrosis factor‐α (TNF‐α) were prospectively measured. Severity of AP was assessed by clinical severity scoring systems. Results Mortality rate was 19%. Antithrombin activity was lower (P = .004) and maximal CRP, IL‐6, and TNF‐α concentrations higher (P < .04) in the AP group compared to the controls, whereas IL‐2, IL‐8, α1PI, and α2AP concentrations did not differ between groups. Serum α2MG concentration was not reliably detected. Serum cPLI, CRP, and IL‐6 concentrations were significantly and positively correlated. The ATA was lower (P = .04), and canine acute pancreatitis severity (CAPS) scores higher (P = .009) in nonsurvivors compared to survivors. Higher CAPS scores were associated (P < .05) with decreased ATA and increased cPLI, CRP, and IL‐6 concentrations. Conclusions and Clinical Importance Systemic inflammation in dogs with AP is manifested by increased inflammatory mediator concentrations, correlating with cPLI and CRP concentrations. Hypoantithrombinemia is associated with death. Serum concentrations of α2AP and α1PI are less useful prognostic markers. The CAPS score is a useful prognostic marker in dogs with AP.
Collapse
Affiliation(s)
- Sharon Kuzi
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Michal Mazaki-Tovi
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Jan S Suchodolski
- Gastrointestinal Laboratory, Texas A&M University, College Station, Texas, USA
| | - Dar Rimer
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Jonathan A Lidbury
- Gastrointestinal Laboratory, Texas A&M University, College Station, Texas, USA
| | - Joerg M Steiner
- Gastrointestinal Laboratory, Texas A&M University, College Station, Texas, USA
| | - Agostino Buono
- Gastrointestinal Laboratory, Texas A&M University, College Station, Texas, USA
| | - Ran Nivy
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Gilad Segev
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Itamar Aroch
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| |
Collapse
|
|
36
|
Chaiqin chengqi decoction alleviates severity of acute pancreatitis via inhibition of TLR4 and NLRP3 inflammasome: Identification of bioactive ingredients via pharmacological sub-network analysis and experimental validation. PHYTOMEDICINE 2020; 79:153328. [PMID: 33007730 DOI: 10.1016/j.phymed.2020.153328] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/08/2020] [Accepted: 06/22/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chaiqin chengqi decoction (CQCQD) is a Chinese herbal formula derived from dachengqi decoction. CQCQD has been used for the management of acute pancreatitis (AP) in the West China Hospital for more than 30 years. Although CQCQD has a well-established clinical efficacy, little is known about its bioactive ingredients, how they interact with different therapeutic targets and the pathways to produce anti-inflammatory effects. PURPOSE Toll-like receptor 4 (TLR4) and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pro-inflammatory signaling pathways, play a central role in AP in determining the extent of pancreatic injury and systemic inflammation. In this study, we screened the bioactive ingredients using a pharmacological sub-network analysis based on the TLR4/NLRP3 signaling pathways followed by experimental validation. METHODS The main CQCQD bioactive compounds were identified by UPLC-QTOF/MS. The TLR4/NLRP3 targets in AP for CQCQD active ingredients were confirmed through a pharmacological sub-network analysis. Mice received 7 intraperitoneal injections of cerulein (50 μg/kg; hourly) to induce AP (CER-AP), while oral gavage of CQCQD (5, 10, 15 and 20 g/kg; 3 doses, 2 hourly) was commenced at the 3rd injection of cerulein. Histopathology and biochemical indices were used for assessing AP severity, while polymerase chain reaction, Western blot and immunohistochemistry analyses were used to study the mechanisms. Identified active CQCQD compounds were further validated in freshly isolated mouse pancreatic acinar cells and cultured RAW264.7 macrophages. RESULTS The main compounds from CQCQD belonged to flavonoids, iridoids, phenols, lignans, anthraquinones and corresponding glycosides. The sub-network analysis revealed that emodin, rhein, baicalin and chrysin were the compounds most relevant for directly regulating the TLR4/NLRP3-related proteins TLR4, RelA, NF-κB and TNF-α. In vivo, CQCQD attenuated the pancreatic injury and systemic inflammation of CER-AP and was associated with reduced expression of TLR4/NLRP3-related mRNAs and proteins. Emodin, rhein, baicalin and chrysin significantly diminished pancreatic acinar cell necrosis with varied effects on suppressing the expression of TLR4/NLRP3-related mRNAs. Emodin, rhein and chrysin also decreased nitric oxide production in macrophages and their combination had synergistic effects on alleviating cell death as well as expression of TLR4/NLRP3-related proteins. CONCLUSIONS CQCQD attenuated the severity of AP at least in part by inhibiting the TLR4/NLRP3 pro-inflammatory pathways. Its active ingredients, emodin, baicalin, rhein and chrysin contributed to these beneficial effects.
Collapse
|
|
37
|
Ruan Q, Lu H, Zhu H, Guo Y, Bai Y. A network-regulative pattern in the pathogenesis of kidney injury following severe acute pancreatitis. Biomed Pharmacother 2020; 125:109978. [DOI: 10.1016/j.biopha.2020.109978] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/17/2020] [Accepted: 01/27/2020] [Indexed: 01/04/2023] Open
|
|
38
|
Biberci Keskin E, İnce AT, Sümbül Gültepe B, Köker İH, Şentürk H. The relationship between serum histon levels and the severity of acute pancreatitis. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 30:807-810. [PMID: 31530525 DOI: 10.5152/tjg.2019.18592] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND/AIMS Despite various scoring systems and imaging methods, it is hard to predict the severity and the course of acute pancreatitis (AP), thereby necessitating better and more reliable markers. Since inflammation plays a key role in the pathogenesis of AP, we sought to determine whether histone, which is a novel inflammatory marker, may play a role in the prediction of severity and prognosis. MATERIALS AND METHODS A total of 88 consecutive adult patients (>18 years) with a first AP episode were prospectively enrolled in the study. Severe AP was defined as having a revised Atlanta score >3 in the first 48 h after admission. Circulating histone 3 and 4 levels were measured using the enzyme-linked immunosorbent assay method. RESULTS Eighty-eight consecutive adult patients with a first episode of AP were divided into two groups according to severity, in which 56 (63.6%) were assigned to the mild AP group and 32 (36.4%) to the severe AP group. White blood cell, hemoglobin, creatinine, and aspartate aminotransferase levels were significantly higher in the severe AP group. However, there was no difference in serum histone levels between the groups, and there was no correlation between revised Atlanta score and serum histone levels either. CONCLUSION Serum histone levels did not significantly differ between the severe and mild AP groups. Therefore, these markers may not provide additional benefit for determining the severity of AP.
Collapse
Affiliation(s)
- Elmas Biberci Keskin
- Department of Gastroenterology, Bezmialem Vakıf University School of Medicine, İstanbul, Turkey
| | - Ali Tüzün İnce
- Department of Gastroenterology, Bezmialem Vakif University Medical School, İstanbul, Turkey
| | - Bilge Sümbül Gültepe
- Department of Gastroenterology, Bezmialem Vakıf University School of Medicine, İstanbul, Turkey; Department of Microbiology, Bezmialem Vakıf University School of Medicine, İstanbul, Turkey
| | - İbrahim Hakkı Köker
- Department of Gastroenterology, Bezmialem Vakıf University School of Medicine, İstanbul, Turkey
| | - Hakan Şentürk
- Department of Gastroenterology, Bezmialem Vakıf University School of Medicine, İstanbul, Turkey
| |
Collapse
|
|
39
|
Böhme R, Becker C, Keil B, Damm M, Rasch S, Beer S, Schneider R, Kovacs P, Bugert P, Riedel J, Griesmann H, Ruffert C, Kaune T, Michl P, Hesselbarth N, Rosendahl J. Serum levels of advanced glycation end products and their receptors sRAGE and Galectin-3 in chronic pancreatitis. Pancreatology 2020; 20:187-192. [PMID: 31870801 DOI: 10.1016/j.pan.2019.12.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 12/09/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND /Objectives: AGE and their receptors like RAGE and Galectin-3 can activate inflammatory pathways and have been associated with chronic inflammatory diseases. Several studies investigated the role of AGE, Galectin-3 and sRAGE in pancreatic diseases, whereas no comprehensive data for chronic pancreatitis (CP) are available. METHODS Serum samples from CP patients without an active inflammatory process (85 ACP; 26 NACP patients) and 40 healthy controls were collected. Levels of AGE, sRAGE and Galectin-3 were measured by ELISA. To exclude potential influences of previously described RAGE SNPs on detected serum levels, we analyzed variants rs207128, rs207060, rs1800625, and rs1800624 by melting curve technique in 378 CP patients and 338 controls. RESULTS AGE and Galectin-3 serum levels were significantly elevated in both ACP and NACP patients compared to controls (AGE: 56.61 ± 3.043 vs. 31.71 ± 2.308 ng/mL; p < 0.001; Galectin-3: 16.63 ± 0.6297 vs. 10.81 ± 0.4835 ng/mL; p < 0.001). In contrast, mean serum sRAGE levels were significantly reduced in CP patients compared to controls (sRAGE: 829.7 ± 37.10 vs. 1135 ± 55.74 ng/mL; p < 0.001). All results were consistent after correction for gender, age and diabetes mellitus. No genetic association with CP was found. CONCLUSIONS Our extensive analysis demonstrated the importance of aging related pathways in the pathogenesis of CP. As the results were consistent in ACP and NACP, both entities most likely share common pathomechanisms. Most probably the involved pathways are a general hallmark of an inflammatory state in CP that is even present in symptom-free intervals.
Collapse
Affiliation(s)
- Richard Böhme
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Carla Becker
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Bettina Keil
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Marko Damm
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Sebastian Rasch
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675, München, Germany
| | - Sebastian Beer
- Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology, University of Leipzig, Leipzig, Germany
| | - Rick Schneider
- Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, 06120, Halle (Saale), Germany
| | - Peter Kovacs
- Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, 04103, Germany
| | - Peter Bugert
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany
| | - Jan Riedel
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Heidi Griesmann
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Claudia Ruffert
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Tom Kaune
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Patrick Michl
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Nico Hesselbarth
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Jonas Rosendahl
- Department of Internal Medicine I, Martin Luther University, Halle, Germany.
| |
Collapse
|
|
40
|
Liu D, Song G, Ma Z, Geng X, Dai Y, Yang T, Meng H, Gong J, Zhou B, Song Z. Resveratrol improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in rats with severe acute pancreatitis. Int Immunopharmacol 2020; 80:106128. [PMID: 31978799 DOI: 10.1016/j.intimp.2019.106128] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/12/2019] [Accepted: 12/15/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Bone marrow-derived mesenchymal stem cells (BMSCs) are effective in the treatment of severe acute pancreatitis (SAP), but their therapeutic effects could still be improved. In order to optimize the clinical application of BMSCs, we adopted the strategy of resveratrol (Res) pretreatment of BMSCs (Res-BMSCs) and applied it to a rat model of sodium taurocholate (NaT)-induced acute pancreatitis. METHODS SAP was induced by injection of 3% NaT into the pancreatic duct and successful induction of SAP occurred after 12 h. Rats were treated with BMSCs, Res or BMSCs primed with Res at 40 mmol/L, Vandetanib (ZD6474) daily oral dosages of 50 mg/kg vandetanib. RESULTS Res stimulated BMSCs to secrete vascular endothelial growth factor A (VEGFA), activated the downstream phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and inhibited pancreatic cell apoptosis. In addition, conditioned medium (CM) from Res-BMSCs enhanced the proliferation of human umbilical vein endothelial cells (HUVECs) in vitro, increased resistance to apoptosis and promoted the expression of angiogenesis-related proteins CD31, VEGF and VEGFR2 in pancreatic tissue, but Vandetanib partly abolished these effects by blocking the VEGFA- mediated pathway. CONCLUSION Resveratrol-preprocessed BMSCs can activate the PI3K/AKT signaling pathway in pancreatic cells and HUVECs through paracrine release of VEGFA; thus, achieving the therapeutic effect of resisting apoptosis of pancreatic cells and promoting regeneration of damaged blood vessels. Res pretreatment may be a new strategy to improve the therapeutic effect of BMSCs on SAP.
Collapse
Affiliation(s)
- Dalu Liu
- Shanghai Clinical Medical College of Anhui Medical University, Hefei 230032, China; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China
| | - Guodong Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China
| | - Zhilong Ma
- Department of General Surgery, Tongren Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200072, China
| | - Xiang Geng
- The Affiliated Changzhou NO. 2 People's Hospital of Najing Medical University, Changzhou 213000, China
| | - Yuxiang Dai
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China
| | - Tingsong Yang
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China.
| | - Hongbo Meng
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China
| | - Jian Gong
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China
| | - Bo Zhou
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China
| | - Zhenshun Song
- Shanghai Clinical Medical College of Anhui Medical University, Hefei 230032, China; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, China.
| |
Collapse
|
|
41
|
Dixit A, Cheema H, George J, Iyer S, Dudeja V, Dawra R, Saluja AK. Extracellular release of ATP promotes systemic inflammation during acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2019; 317:G463-G475. [PMID: 31433214 PMCID: PMC6842987 DOI: 10.1152/ajpgi.00395.2018] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 07/12/2019] [Accepted: 07/27/2019] [Indexed: 02/07/2023]
Abstract
In the current study, we explored the role of extracellular ATP (eATP) in promoting systemic inflammation during development of acute pancreatitis (AP). Release of extracellular (e)ATP was evaluated in plasma and bronchoalveolar lavage fluid (BALF) of mice with experimental acute pancreatitis (AP). Prophylactic intervention using apyrase or suramin was used to understand the role and contribution of eATP in pancreatitis-associated systemic injury. AP of varying severity was induced in C57BL/6 mice using 1-day or 2-day caerulein, caerulein + LPS and l-arginine models. eATP was measured in plasma and BALF. Mice were treated with suramin or apyrase in the caerulein and l-arginine models of AP. Plasma cytokines, lung, and pancreatic myeloperoxidase, and morphometric analysis of pancreatic and lung histology, were used to assess the severity of pancreatitis. Plasma eATP and purinergic 2 (P2) receptors in the pancreas and lungs were significantly elevated in the experimental models of AP. Blocking the effect of eATP by suramin led to reduced levels of plasma IL-6 and TNFα as well as reduced lung, and pancreatic injury. Neutralizing eATP with apyrase reduced systemic injury but did not ameliorate local injury. The results of this study support the role of eATP and P2 receptors in promoting systemic inflammation during AP. Modulating purinergic signaling during AP can be an important therapeutic strategy in controlling systemic inflammation and, thus, systemic inflammatory response syndrome during AP.NEW & NOTEWORTHY Released ATP from injured cells promotes systemic inflammation in acute pancreatitis.
Collapse
Affiliation(s)
- Ajay Dixit
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Hassam Cheema
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - John George
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Srikanth Iyer
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Vikas Dudeja
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Rajinder Dawra
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Ashok K Saluja
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| |
Collapse
|
|
42
|
Choi JW, Shin JY, Jo IJ, Kim DG, Song HJ, Yoon CS, Oh H, Kim YC, Bae GS, Park SJ. 8α-Hydroxypinoresinol isolated from Nardostachys jatamansi ameliorates cerulein-induced acute pancreatitis through inhibition of NF-κB activation. Mol Immunol 2019; 114:620-628. [PMID: 31542607 DOI: 10.1016/j.molimm.2019.09.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/26/2019] [Accepted: 09/04/2019] [Indexed: 12/16/2022]
Abstract
Acute pancreatitis (AP) is a severe inflammatory condition of the pancreas, with no specific treatment available. We have previously reported that Nardostachys jatamansi (NJ) ameliorates cerulein-induced AP. However, the specific compound responsible for this inhibitory effect has not been identified. Therefore, in the present study, we focused on a single compound, 8α-hydroxypinoresinol (HP), from NJ. The aim of this study was to determine the effect of HP on the development of pancreatitis in mice and to explore the underlying mechanism(s). AP was induced by the injection of cerulein (50 μg/kg/h) for 6 h. HP (0.5, 5 or 10 mg/kg, i.p.) was administered 1 h prior to and 1, 3 or 5 h after the first cerulein injection, with vehicle- and DMSO-treated groups as controls. Blood samples were collected to determine serum levels of amylase, lipase, and cytokines. The pancreas was removed for morphological examination, myeloperoxidase (MPO) assays, cytokine assays, and assessment of nuclear factor (NF)-κB activation. The lungs were removed for morphological examination and MPO assays. Administration of HP dramatically improved pancreatic damage and pancreatitis-associated lung damage and also reduced amylase and lipase activities in serum. Moreover, administration of HP reduced the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the pancreas and serum during AP. In addition, the administration of HP inhibited degradation of inhibitory κ-Bα (Iκ-Bα), NF-κB p65 translocation into nucleus and NF-κB binding activity in the pancreas. Our results suggest that HP exerted therapeutic effects on pancreatitis and these beneficial effects may be due to the inhibition of NF-κB activation.
Collapse
Affiliation(s)
- Ji-Won Choi
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea; Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea
| | - Joon Yeon Shin
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea
| | - Il-Joo Jo
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea; Division of Beauty Sciences, School of Natural sciences, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea
| | - Dong-Gu Kim
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea
| | - Ho-Joon Song
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea
| | - Chi-Su Yoon
- Korea Research Institute of Bioscience & Biotechnology, Yeongudanjiro 30, Cheongju, Chungbuk 28116, South Korea
| | - Hyuncheol Oh
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea
| | - Youn-Chul Kim
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea
| | - Gi-Sang Bae
- Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea; Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea.
| | - Sung-Joo Park
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea; Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, Iksandaero 460, Iksan, Jeonbuk 54538, South Korea.
| |
Collapse
|
|
43
|
Liu J, Gao M, Nipper M, Deng J, Sharkey FE, Johnson RL, Crawford HC, Chen Y, Wang P. Activation of the intrinsic fibroinflammatory program in adult pancreatic acinar cells triggered by Hippo signaling disruption. PLoS Biol 2019; 17:e3000418. [PMID: 31513574 PMCID: PMC6742234 DOI: 10.1371/journal.pbio.3000418] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration. The mechanisms by which epithelial cells orchestrate the intrinsic fibro-inflammatory response and cell proliferation during the repair of injured tissues remains unclear. A study of molecular and cellular changes in pancreatic acinar cells suggests that the Hippo pathway acts as an intrinsic link to coordinate fibro-inflammatory response and proliferation process in epithelial cells.
Collapse
Affiliation(s)
- Jun Liu
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Ming Gao
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Michael Nipper
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Janice Deng
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Francis E Sharkey
- Department of Pathology, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Randy L Johnson
- Department of Cancer Biology, Division of Basic Science Research, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Howard C Crawford
- Department of Molecular and Integrative Physiology & Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America
| | - Yidong Chen
- Department of Epidemiology Biostatistics, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Pei Wang
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| |
Collapse
|
|
44
|
Lin M, Huang J, Huang J, Liu SL, Chen WC. Level of serum soluble Tim-3 expression in early-phase acute pancreatitis. TURKISH JOURNAL OF GASTROENTEROLOGY 2019; 30:188-191. [PMID: 30459127 DOI: 10.5152/tjg.2018.18137] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIMS T-cell immunoglobulin and mucin domain 3 (Tim-3) assumedly play a crucial immunomodulatory role in inflammatory response. Data on the potential role of soluble Tim-3 (sTim-3) in acute pancreatitis (AP) are scarce. We conducted a prospective clinical study to characterize its role in the early-phase AP. METHODS In total, 44 patients with AP (16 mild and 28 none-mild) who presented within 24 hours on admission and 20 healthy volunteers (NC) were included in our study. Serum interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and sTim-3 levels were detected using enzyme-linked immunosorbent assay (ELISA). RESULTS Levels of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 in the none-mild and mild groups were significantly elevated compared with those of the NC group. The sTim-3 levels of the none-mild and mild group were significantly increased compared with the NC. The sTim-3 level positively correlated with the IL-6 and TNF-α but showed no obvious correlations with the IL-10 level. The sTim-3 level positively correlated with the APACHE II score. CONCLUSION The results indicate that sTim-3 participates in the early progression of AP by positively regulating the pro-inflammatory cytokines and that the measurement of serum sTim-3 is an early marker for predicting AP.
Collapse
Affiliation(s)
- Min Lin
- Department of Gastroenterology, the Affiliated Changzhou No.2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Jin Huang
- Department of Gastroenterology, the Affiliated Changzhou No.2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Jian Huang
- Department of Gastroenterology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Sheng-Lan Liu
- Department of ICU, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wei-Chang Chen
- Department of Gastroenterology, the First Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
45
|
Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis by inhibiting necroptosis in rats. Mol Cell Biochem 2019; 459:7-19. [DOI: 10.1007/s11010-019-03546-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 05/02/2019] [Indexed: 12/25/2022]
|
|
46
|
Garg PK, Singh VP. Organ Failure Due to Systemic Injury in Acute Pancreatitis. Gastroenterology 2019; 156:2008-2023. [PMID: 30768987 PMCID: PMC6486861 DOI: 10.1053/j.gastro.2018.12.041] [Citation(s) in RCA: 352] [Impact Index Per Article: 58.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/07/2018] [Accepted: 12/29/2018] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines "severe acute pancreatitis." Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis-induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
Collapse
|
|
47
|
de Oliveira C, Khatua B, Bag A, El-Kurdi B, Patel K, Mishra V, Navina S, Singh VP. Multimodal Transgastric Local Pancreatic Hypothermia Reduces Severity of Acute Pancreatitis in Rats and Increases Survival. Gastroenterology 2019; 156:735-747.e10. [PMID: 30518512 PMCID: PMC6368865 DOI: 10.1053/j.gastro.2018.10.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/11/2018] [Accepted: 10/20/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Acute pancreatitis (AP) of different etiologies is associated with the activation of different signaling pathways in pancreatic cells, posing challenges to the development of targeted therapies. We investigated whether local pancreatic hypothermia, without systemic hypothermia, could lessen the severity of AP induced by different methods in rats. METHODS A urethane balloon with 2 polyurethane tubes was placed inside the stomach of rats. AP was induced in Wistar rats by the administration of cerulein or glyceryl tri-linoleate (GTL). Then, cold water was infused into the balloon to cool the pancreas. Pancreatic temperatures were selected based on those found to decrease acinar cell injury. An un-perfused balloon was used as a control. Pancreatic and rectal temperatures were monitored, and an infrared lamp or heating pad was used to avoid generalized hypothermia. We collected blood, pancreas, kidney, and lung tissues and analyzed them by histology, immunofluorescence, immunoblot, cytokine and chemokine magnetic bead, and DNA damage assays. The effect of hypothermia on signaling pathways initiated by cerulein and GTL was studied in acinar cells. RESULTS Rats with pancreatic cooling developed less severe GTL-induced AP compared with rats that received the control balloon. In acinar cells, cooling decreased the lipolysis induced by GTL, increased the micellar form of its fatty acid, lowered the increase in cytosolic calcium, prevented the loss of mitochondrial membrane potential (by 70%-80%), and resulted in a 40%-50% decrease in the uptake of a fatty acid tracer. In rats with AP, cooling decreased pancreatic necrosis by 48%, decreased serum levels of cytokines and markers of cell damage, and decreased markers of lung and renal damage. Pancreatic cooling increased the proportions of rats surviving 6 hours after induction of AP (to 90%, from <10% of rats that received the control balloon). In rats with cerulein-induced AP, pancreatic cooling decreased pancreatic markers of apoptosis and inflammation. CONCLUSIONS In rats with AP, transgastric local pancreatic hypothermia decreases pancreatic necrosis, apoptosis, inflammation, and markers of pancreatitis severity and increases survival.
Collapse
Affiliation(s)
- Cristiane de Oliveira
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Biswajit Khatua
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Arup Bag
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Bara El-Kurdi
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Krutika Patel
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| | - Vivek Mishra
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Sarah Navina
- Pathology, University of Pittsburgh, Pittsburgh, PA
| | - Vijay P. Singh
- Department of Medicine, Mayo Clinic, Scottsdale, AZ, University of Pittsburgh, Pittsburgh, PA
| |
Collapse
|
|
48
|
Regel I, Raulefs S, Benitz S, Mihaljevic C, Rieder S, Leinenkugel G, Steiger K, Schlitter AM, Esposito I, Mayerle J, Kong B, Kleeff J, Michalski CW. Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis. Pancreatology 2019; 19:149-157. [PMID: 30583980 DOI: 10.1016/j.pan.2018.12.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/06/2018] [Accepted: 12/14/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute pancreatitis is accompanied by acinar cell damage releasing potential toll-like receptor 3 (TLR3) ligands. So far, TLR3 is known as a pattern recognition receptor in the immune signaling cascade triggering a type I interferon response. In addition, TLR3 signaling contributes to programmed cell death through the activation of caspase 8. However, the functional role of TLR3 and its downstream toll-like receptor adaptor molecule 1 (TICAM1) in the inflamed pancreas is unknown. METHODS To uncover the role of TLR3 signaling in acute pancreatitis, we induced a cerulein-mediated pancreatitis in Tlr3 and Ticam1 knockout (KO) mice and in wildtype animals. The exocrine damage was determined by blood serum analysis and histological examination. Immunohistochemistry, gene expression and immunoblot analysis were conducted to study TLR3 function. RESULTS After the induction of an acute pancreatitis, wildtype mice showed a high endosomal TLR3 expression in acinar cells. In comparison to wildtype and Ticam1 KO mice, Tlr3 KO mice exhibited the highest severity of pancreatitis with an increased NF-κB activation and elevated expression of the pro-inflammatory cytokines Il6 and Tnf, although the amount of infiltrating immune cells was unaffected. Additionally, we detected a strong elevation of acinar cell necrosis and reduced levels of cleaved caspase 8 in Tlr3 and Ticam1 KO mice. CONCLUSIONS TLR3 and its downstream adaptor TICAM1 are important mediators of acinar cell damage in acute pancreatitis. They possess a critical role in programmed cell death and our data suggest that TLR3 signaling controls the onset and severity of acute pancreatitis.
Collapse
Affiliation(s)
- Ivonne Regel
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Susanne Raulefs
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
| | - Simone Benitz
- Department of Medicine II, University Hospital, LMU Munich, Germany
| | - Charlotte Mihaljevic
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany; Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany
| | - Simon Rieder
- Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Georg Leinenkugel
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University Munich, Germany
| | | | - Irene Esposito
- Institute of Pathology, Heinrich-Heine University and University Hospital, Duesseldorf, Germany
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, Germany
| | - Bo Kong
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
| | - Jörg Kleeff
- Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Christoph W Michalski
- Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
| |
Collapse
|
|
49
|
Pharmacological stimulation of NQO1 decreases NADPH levels and ameliorates acute pancreatitis in mice. Cell Death Dis 2018; 10:5. [PMID: 30584237 PMCID: PMC6315021 DOI: 10.1038/s41419-018-1252-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 11/28/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species (ROS) regulates the activation of inflammatory cascades and tissue damage in acute pancreatitis. NADPH oxidase (NOX) is upregulated in pancreatitis and is one of the major enzymes involved in ROS production using NADPH as a general rate-limiting substrate. Dunnione, a well-known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), reduces the ratio of cellular NADPH/NADP+ through the enzymatic action of NQO1. This study assessed whether a reduction in cellular NADPH/NADP+ ratio can be used to regulate caerulein-induced pancreatic damage associated with NOX-induced ROS production in animal models. Dunnione treatment significantly reduced the cellular NADPH/NADP+ ratio and NOX activity through the enzymatic action of NQO1 in the pancreas of the caerulein-injection group. Similar to these results, total ROS production and expressions of mRNA and protein for NOX subunits Nox1, p27phox, p47phox, and p67phox also decreased in the dunnione-treated group. In addition, caerulein-induced pancreatic inflammation and acinar cell injury were significantly reduced by dunnione treatment. This study is the first to demonstrate that modulation of the cellular NADPH:NADP+ ratio by enzymatic action of NQO1 protects acute pancreatitis through the regulation of NOX activity. Furthermore, these results suggest that modulation of the NADPH:NADP+ ratio in cells by NQO1 may be a novel therapeutic strategy for acute pancreatitis.
Collapse
|
|
50
|
Zhang Q, Tao X, Xia S, Qu J, Song H, Liu J, Li H, Shang D. Emodin attenuated severe acute pancreatitis via the P2X ligand‑gated ion channel 7/NOD‑like receptor protein 3 signaling pathway. Oncol Rep 2018; 41:270-278. [PMID: 30542707 PMCID: PMC6278370 DOI: 10.3892/or.2018.6844] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/26/2018] [Indexed: 12/13/2022] Open
Abstract
Acute pancreatitis (AP) is an aseptic inflammation characterized with an annual incidence rate, and ~20% patients progressing to severe AP (SAP) with a high mortality rate. Although Qingyi decoction has been frequently used for SAP treatment over the past 3 decades in clinic, the actual mechanism of its protective effects remains unknown. As the major active ingredient of Qingyi decoction, emodin was selected in the present study to investigate the effect of emodin against severe acute pancreatitis (SAP) in rats through NOD-like receptor protein 3 (NLRP3) inflammasomes. The rats were randomly divided into a sham operation group, an SAP model group induced by a standard retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct, and low-dose (30 mg/kg) and high-dose (60 mg/kg) emodin-treated groups. At 12 h after the event, the plasma amylase, lipase, interleukin (IL)-1β, IL-18 and myeloperoxidase (MPO) activities were examined. Furthermore, the pathological scores of pancreases were evaluated by hematoxylin and eosin staining. The expression levels of P2X ligand-gated ion channel 7 (P2X7), NLRP3, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain and caspase-1 were also analyzed by western blot analysis. The data demonstrated that, compared with the SAP group, emodin could significantly relieve the pancreatic histopathology and acinar cellular structure injury, and notably downregulate the plasma amylase and lipase levels, as well as the MPO activities in pancreatic tissues, in a dose-dependent manner. Furthermore, emodin inhibited the P2X7/NLRP3 signaling pathway followed by the decrease of pro-inflammatory factors, and the latter is beneficial for the recovery of SAP. Collectively, the data indicated that emodin may be an efficient candidate natural product for SAP treatment.
Collapse
Affiliation(s)
- Qingkai Zhang
- Department of Integrative Medicine Surgery, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Xufeng Tao
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Shilin Xia
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Jialin Qu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Huiyi Song
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Jianjun Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Hailong Li
- Department of Psychology, University of South Carolina, Columbia, SC 29208, USA
| | - Dong Shang
- Department of Integrative Medicine Surgery, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| |
Collapse
|