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DeLano FA, Schmid-Schönbein GW. Aging by autodigestion. PLoS One 2024; 19:e0312149. [PMID: 39418235 PMCID: PMC11486419 DOI: 10.1371/journal.pone.0312149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024] Open
Abstract
The mechanism that triggers the progressive dysregulation of cell functions, inflammation, and breakdown of tissues during aging is currently unknown. We propose here a previously unknown mechanism due to tissue autodigestion by the digestive enzymes. After synthesis in the pancreas, these powerful enzymes are activated and transported inside the lumen of the small intestine to which they are compartmentalized by the mucin/epithelial barrier. We hypothesize that this barrier leaks active digestive enzymes (e.g. during meals) and leads to their accumulation in tissues outside the gastrointestinal tract. Using immune-histochemistry we provide evidence in young (4 months) and old (24 months) rats for significant accumulation of pancreatic trypsin, elastase, lipase, and amylase in peripheral organs, including liver, lung, heart, kidney, brain, and skin. The mucin layer density on the small intestine barrier is attenuated in the old and trypsin leaks across the tip region of intestinal villi with depleted mucin. The accumulation of digestive enzymes is accompanied in the same tissues of the old by damage to collagen, as detected with collagen fragment hybridizing peptides. We provide evidence that the hyperglycemia in the old is accompanied by proteolytic cleavage of the extracellular domain of the insulin receptor. Blockade of pancreatic trypsin in the old by a two-week oral treatment with a serine protease inhibitor (tranexamic acid) serves to significantly reduce trypsin accumulation in organs outside the intestine, collagen damage, as well as hyperglycemia and insulin receptor cleavage. These results support the hypothesis that the breakdown of tissues in aging is due to autodigestion and a side-effect of the fundamental requirement for digestion.
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Affiliation(s)
- Frank A. DeLano
- Shu Chien-Gene Ley Department of Bioengineering, Center for Autodigestion Innovation, University of California San Diego, La Jolla, California, United States of America
| | - Geert W. Schmid-Schönbein
- Shu Chien-Gene Ley Department of Bioengineering, Center for Autodigestion Innovation, University of California San Diego, La Jolla, California, United States of America
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Straarup D, Gotschalck KA, Christensen PA, Rasmussen RW, Krarup H, Lundbye-Christensen S, Handberg A, Thorlacius-Ussing O. Exploring D-Lactate as a Biomarker for Acute Intestinal Necrosis in 2958 Patients: A Prospective Cross-Sectional Study. J Emerg Med 2024; 66:e619-e631. [PMID: 38556374 DOI: 10.1016/j.jemermed.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 12/16/2023] [Accepted: 01/06/2024] [Indexed: 04/02/2024]
Abstract
BACKGROUND Timely diagnosis of acute intestinal necrosis (AIN) is lifesaving, but challenging due to unclear clinical presentation. D-lactate has been proposed as an AIN biomarker. OBJECTIVES We aimed to test the diagnostic performance in a clinical setting. METHODS We performed a cross-sectional prospective study, including all adult patients with acute referral to a single tertiary gastrointestinal surgical department during 2015-2016 and supplemented by enrollment of high-risk in-hospital patients suspected of having AIN during 2016-2019. AIN was verified intraoperatively, and D-lactate was analyzed using an automatic spectrophotometric set-up. A D-lactate cut-off for AIN was estimated using the receiver operating characteristic curve. The performance according to patient subgroups was estimated using the area under the receiver operating characteristic curve (AUC). Given the exploratory nature of this study, a formal power calculation was not feasible. RESULTS Forty-four AIN patients and 2914 controls were enrolled. The D-lactate cut-off was found to be 0.0925 mM. Due to lipemic interference, D-lactate could not be quantified in half of the patients, leaving 23 AIN patients and 1456 controls for analysis. The AUC for the diagnosis of AIN by D-lactate was 0.588 (95% confidence interval 0.475-0.712), with a sensitivity of 0.261 and specificity of 0.892. Analysis of high-risk patients showed similar results (AUC 0.579; 95% confidence interval 0.422-0.736). CONCLUSION D-lactate showed low sensitivity for AIN in both average-risk and high-risk patients. Moreover, lipemic interference precluded valid spectrophotometric assessment of D-lactate in half of the patients, further disqualifying the clinical utility of D-lactate as a diagnostic marker for AIN.
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Affiliation(s)
- David Straarup
- Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark
| | - Kåre A Gotschalck
- Department of Gastrointestinal Surgery, Horsens Regional Hospital, Horsens, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Peter A Christensen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Department of Clinical Biochemistry
| | | | - Henrik Krarup
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Department of Clinical Biochemistry; Department of Molecular Diagnostics
| | | | - Aase Handberg
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Department of Clinical Biochemistry
| | - Ole Thorlacius-Ussing
- Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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Kim GE, Siddiqui UD. Endoscopic Resection Techniques for Duodenal and Ampullary Adenomas. VIDEOGIE : AN OFFICIAL VIDEO JOURNAL OF THE AMERICAN SOCIETY FOR GASTROINTESTINAL ENDOSCOPY 2023; 8:330-335. [PMID: 37575136 PMCID: PMC10422085 DOI: 10.1016/j.vgie.2023.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Background and Aims Duodenal polyps have a reported incidence of 0.3% to 4.6%. Sporadic, nonampullary duodenal adenomas (SNDAs) comprise less than 10% of all duodenal polyps, and ampullary adenomas are even less common. Nonetheless, the incidence continues to rise because of widespread endoscopy use. Duodenal polyps with villous features or those that are larger than 10 mm may raise concern for malignancy and require removal. We demonstrate endoscopic resection of SNDAs and ampullary adenomas using some of our preferred techniques. Methods The duodenum has several components that can make EMR of duodenal polyps technically challenging. Not only does the duodenum have a thin muscle layer, but it is also highly mobile and vascular, which may explain higher rates of perforation and bleeding of duodenal EMR reported in the literature compared with colon EMR. A standard adult gastroscope with a distal cap is commonly used for duodenal EMRs. Based on the location, however, side-viewing duodenoscopes or pediatric colonoscopes may be used. To prepare for EMR, a submucosal injection is performed for an adequate lift. The polyp is then resected via stiff monofilament snares and subsequently closed with hemostatic clips if feasible. The ampullectomy technique differs slightly from duodenal EMRs and carries the additional risk of pancreatitis. Submucosal injection in the ampulla may not lift well; thus, its utility is debatable. Biliary sphincterotomy should be performed, and based on endoscopist preference, the pancreatic duct (PD) guidewire can be left during resection to maintain access. After resection, a PD stent is placed to minimize pancreatitis risk. Results The video shows the aforementioned duodenal EMR techniques. Two clips of ampullectomy are also shown in the video. Conclusions A few common techniques used to perform duodenal EMR and ampullectomy are highlighted in the video. It is important to understand and manage adverse events associated with these procedures and to have established surveillance plans.
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Affiliation(s)
- Grace E Kim
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, University of Chicago, Chicago, Illinois
| | - Uzma D Siddiqui
- Center for Endoscopic Research and Therapeutics, University of Chicago, Chicago, Illinois
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Chen A, Zhang J, Zhang Y. Gut microbiota in heart failure and related interventions. IMETA 2023; 2:e125. [PMID: 38867928 PMCID: PMC10989798 DOI: 10.1002/imt2.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/28/2023] [Accepted: 06/04/2023] [Indexed: 06/14/2024]
Abstract
Heart failure (HF) is a sophisticated syndrome with structural or functional impairment of ventricular filling or ejection of blood, either causing symptoms and signs or being asymptomatic. HF is a major global health issue affecting about 64.3 million people worldwide. The gut microbiota refers to the complex ecosystem of microorganisms, mainly bacteria, in the gut. Studies have revealed that the gut microbiota is associated with many diseases ranging from neurodegenerative diseases to inflammatory bowel disease and cardiovascular diseases. The gut hypothesis of HF suggests that low cardiac output and systemic circulation congestion would cause insufficient intestinal perfusion, leading to ischemia and intestinal barrier dysfunction. The resulting bacterial translocation would contribute to inflammation. Recent studies have refined the hypothesis that changes of metabolites in the gut microbiota have a close relationship with HF. Thus, the gut microbiota has emerged as a potential therapeutic target for HF due to both its critical role in regulating host physiology and metabolism and its pivotal role in the development of HF. This review article aims to provide an overview of the current understanding of the gut microbiota's involvement in HF, including the introduction of the gut hypothesis of HF, its association with HF progression, the potential mechanisms involved mediated by the gut microbiota metabolites, and the impact of various interventions on the gut microbiota, including dietary interventions, probiotic therapy, fecal microbiota transplantation, antibiotics, and so on. While the gut hypothesis of HF is refined with up-to-date knowledge and the gut microbiota presents a promising target for HF therapy, further research is still needed to further understand the underlying mechanisms between gut microbiota and HF, the efficacy of these interventions, and contribute to the health of HF patients.
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Affiliation(s)
- An‐Tian Chen
- Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai HospitalChinese Academy of Medical Sciences & Peking Union Medical College/National Center for Cardiovascular DiseasesBeijingChina
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, Fuwai HospitalChinese Academy of Medical Sciences & Peking Union Medical College/National Center for Cardiovascular DiseasesBeijingChina
| | - Jian Zhang
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, Fuwai HospitalChinese Academy of Medical Sciences & Peking Union Medical College/National Center for Cardiovascular DiseasesBeijingChina
- Key Laboratory of Clinical Research for Cardiovascular MedicationsNational Health CommitteeBeijingChina
| | - Yuhui Zhang
- State Key Laboratory of Cardiovascular Disease, Heart Failure Center, Fuwai HospitalChinese Academy of Medical Sciences & Peking Union Medical College/National Center for Cardiovascular DiseasesBeijingChina
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Deeb AP, Hoteit L, Li S, Guyette FX, Eastridge BJ, Nirula R, Vercruysse GA, O'Keeffe T, Joseph B, Neal MD, Sperry JL, Brown JB. Prehospital synergy: Tranexamic acid and blood transfusion in patients at risk for hemorrhage. J Trauma Acute Care Surg 2022; 93:52-58. [PMID: 35393385 PMCID: PMC9233003 DOI: 10.1097/ta.0000000000003620] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Growing evidence supports improved survival with prehospital blood products. Recent trials show a benefit of prehospital tranexamic acid (TXA) administration in select subgroups. Our objective was to determine if receiving prehospital packed red blood cells (pRBC) in addition to TXA improved survival in injured patients at risk of hemorrhage. METHODS We performed a secondary analysis of all scene patients from the Study of Tranexamic Acid during Air and ground Medical Prehospital transport trial. Patients were randomized to prehospital TXA or placebo. Some participating EMS services utilized pRBC. Four resuscitation groups resulted: TXA, pRBC, pRBC+TXA, and neither. Our primary outcome was 30-day mortality and secondary outcome was 24-hour mortality. Cox regression tested the association between resuscitation group and mortality while adjusting for confounders. RESULTS A total of 763 patients were included. Patients receiving prehospital blood had higher Injury Severity Scores in the pRBC (22 [10, 34]) and pRBC+TXA (22 [17, 36]) groups than the TXA (12 [5, 21]) and neither (10 [4, 20]) groups (p < 0.01). Mortality at 30 days was greatest in the pRBC+TXA and pRBC groups at 18.2% and 28.6% compared with the TXA only and neither groups at 6.6% and 7.4%, respectively. Resuscitation with pRBC+TXA was associated with a 35% reduction in relative hazards of 30-day mortality compared with neither (hazard ratio, 0.65; 95% confidence interval, 0.45-0.94; p = 0.02). No survival benefit was observed in 24-hour mortality for pRBC+TXA, but pRBC alone was associated with a 61% reduction in relative hazards of 24-hour mortality compared with neither (hazard ratio, 0.39; 95% confidence interval, 0.17-0.88; p = 0.02). CONCLUSION For injured patients at risk of hemorrhage, prehospital pRBC+TXA is associated with reduced 30-day mortality. Use of pRBC transfusion alone was associated with a reduction in early mortality. Potential synergy appeared only in longer-term mortality and further work to investigate mechanisms of this therapeutic benefit is needed to optimize the prehospital resuscitation of trauma patients. LEVEL OF EVIDENCE Therapeutic/Care Management; Level III.
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Affiliation(s)
- Andrew-Paul Deeb
- From the Division of Trauma and General Surgery, Department of Surgery (A.-P.D., L.H., S.L., M.D.N., J.L.S., J.B.B.), Department of Emergency Medicine (F.X.G.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Surgery (B.J.E.), University of Texas Health San Antonio, San Antonio, Texas; Department of Surgery (R.N.), University of Utah, Salt Lake City, Utah; and Department of Surgery (G.A.V., T.O.K., B.J.), University of Arizona, Tucson, Arizona
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Kip AM, Valverde JM, Altelaar M, Heeren RMA, Hundscheid IHR, Dejong CHC, Olde Damink SWM, Balluff B, Lenaerts K. Combined Quantitative (Phospho)proteomics and Mass Spectrometry Imaging Reveal Temporal and Spatial Protein Changes in Human Intestinal Ischemia-Reperfusion. J Proteome Res 2021; 21:49-66. [PMID: 34874173 PMCID: PMC8750167 DOI: 10.1021/acs.jproteome.1c00447] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
![]()
Intestinal ischemia–reperfusion
(IR) injury is a severe
clinical condition, and unraveling its pathophysiology is crucial
to improve therapeutic strategies and reduce the high morbidity and
mortality rates. Here, we studied the dynamic proteome and phosphoproteome
in the human intestine during ischemia and reperfusion, using liquid
chromatography-tandem mass spectrometry (LC-MS/MS) analysis to gain
quantitative information of thousands of proteins and phosphorylation
sites, as well as mass spectrometry imaging (MSI) to obtain spatial
information. We identified a significant decrease in abundance of
proteins related to intestinal absorption, microvillus, and cell junction,
whereas proteins involved in innate immunity, in particular the complement
cascade, and extracellular matrix organization increased in abundance
after IR. Differentially phosphorylated proteins were involved in
RNA splicing events and cytoskeletal and cell junction organization.
In addition, our analysis points to mitogen-activated protein kinase
(MAPK) and cyclin-dependent kinase (CDK) families to be active kinases
during IR. Finally, matrix-assisted laser desorption ionization time-of-flight
(MALDI-TOF) MSI presented peptide alterations in abundance and distribution,
which resulted, in combination with Fourier-transform ion cyclotron
resonance (FTICR) MSI and LC-MS/MS, in the annotation of proteins
related to RNA splicing, the complement cascade, and extracellular
matrix organization. This study expanded our understanding of the
molecular changes that occur during IR in the human intestine and
highlights the value of the complementary use of different MS-based
methodologies.
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Affiliation(s)
- Anna M Kip
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Juan Manuel Valverde
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, Utrecht 3584 CH, The Netherlands
| | - Maarten Altelaar
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, Utrecht 3584 CH, The Netherlands
| | - Ron M A Heeren
- Maastricht Multimodal Molecular Imaging Institute (M4i), Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Inca H R Hundscheid
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Cornelis H C Dejong
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.,Department of General, Visceral- and Transplantation Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Steven W M Olde Damink
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.,Department of General, Visceral- and Transplantation Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Benjamin Balluff
- Maastricht Multimodal Molecular Imaging Institute (M4i), Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Kaatje Lenaerts
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
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Fung AA, Zhou A, Vanos JK, Schmid-Schönbein GW. Enhanced intestinal permeability and intestinal co-morbidities in heat strain: A review and case for autodigestion. Temperature (Austin) 2021; 8:223-244. [PMID: 34527763 PMCID: PMC8436972 DOI: 10.1080/23328940.2021.1922261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 11/05/2022] Open
Abstract
Enhanced intestinal permeability is a pervasive issue in modern medicine, with implications demonstrably associated with significant health consequences such as sepsis, multiorgan failure, and death. Key issues involve the trigger mechanisms that could compromise intestinal integrity and increase local permeability allowing the passage of larger, potentially dangerous molecules. Heat stress, whether exertional or environmental, may modulate intestinal permeability and begs interesting questions in the context of global climate change, increasing population vulnerabilities, and public health. Emerging evidence indicates that intestinal leakage of digestive enzymes and associated cell dysfunctions--a process referred to as autodigestion--may play a critical role in systemic physiological damage within the body. This increased permeability is exacerbated in the presence of elevated core temperatures. We employed Latent Dirichlet Allocation (LDA) topic modeling methods to analyze the relationship between heat stress and the nascent theory of autodigestion in a systematic, quantifiable, and unbiased manner. From a corpus of 11,233 scientific articles across four relevant scientific journals (Gut, Shock, Temperature, Gastroenterology), it was found that over 1,000 documents expressed a relationship between intestine, enhanced permeability, core temperature, and heat stress. The association has grown stronger in recent years, as heat stress and potential autodigestion are investigated in tandem, yet still by a limited number of specific research studies. Such findings justify the design of future studies to critically test novel interventions against digestive enzymes permeating the intestinal tract, especially the small intestine.
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Affiliation(s)
- Anthony A. Fung
- Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
| | - Andy Zhou
- Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
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Dominowski L, Kirsch M. Synergistic Effect of β-alanine and Aprotinin on Mesenteric Ischemia. J Surg Res 2021; 263:78-88. [PMID: 33639373 DOI: 10.1016/j.jss.2021.01.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 01/10/2021] [Accepted: 01/25/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Acute mesenteric ischemia arises through sudden interruption of mesenteric blood flow, mostly due to an occlusion of the superior mesenteric artery and is associated with a high mortality of approximately 50% to 90%. In previous studies, the single application of β-alanine or aprotinin caused an ameliorated intestinal damage but without any systemic effects. METHODS To analyze the combined effect of β-alanine and aprotinin on acute ischemia and reperfusion of the small intestine, a model with anesthetized rats was used. Ischemia and reperfusion were initiated by occluding and reopening the superior mesenteric artery. After 120 min of ischemia and 180 min of reperfusion, the intestine was analyzed for tissue damage, the activity of the saccharase, and accumulation of granulocytes. In addition, systemic and metabolic as well as inflammatory parameters were measured in blood at certain points in time. RESULTS The combination of β-alanine and aprotinin resulted in a clearly stabilized mean arterial blood pressure and blood glucose level during the reperfusion period. Furthermore, the combined administration resulted in significantly reduced tissue damage parameters, cytokine and cell-free hemoglobin concentrations in blood plasma. In addition, the damage to the small intestine was significantly attenuated, so that the animals ultimately survived the entire test period because of the administration of both substances. CONCLUSIONS Overall, the simultaneous application of both substances leads to a synergistic protection without the occurrence of undesirable side effects. The combined usage of β-alanine and aprotinin can be seen as a promising approach to inhibit the onset of acute mesenteric ischemia.
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Affiliation(s)
- Lisa Dominowski
- Institut für Physiologische Chemie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Michael Kirsch
- Institut für Physiologische Chemie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
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Ma Y, Yang X, Chatterjee V, Wu MH, Yuan SY. The Gut-Lung Axis in Systemic Inflammation. Role of Mesenteric Lymph as a Conduit. Am J Respir Cell Mol Biol 2021; 64:19-28. [PMID: 32877613 DOI: 10.1165/rcmb.2020-0196tr] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Emerging evidence shows that after injury or infection, the mesenteric lymph acts as a conduit for gut-derived toxic factors to enter the blood circulation, causing systemic inflammation and acute lung injury. Neither the cellular and molecular identity of lymph factors nor their mechanisms of action have been well understood and thus have become a timely topic of investigation. This review will first provide a summary of background knowledge on gut barrier and mesenteric lymphatics, followed by a discussion focusing on the current understanding of potential injurious factors in the lymph and their mechanistic contributions to lung injury. We also examine lymph factors with antiinflammatory properties as well as the bidirectional nature of the gut-lung axis in inflammation.
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Affiliation(s)
- Yonggang Ma
- Department of Molecular Pharmacology and Physiology, and
| | - Xiaoyuan Yang
- Department of Molecular Pharmacology and Physiology, and
| | | | - Mack H Wu
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Sarah Y Yuan
- Department of Molecular Pharmacology and Physiology, and.,Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida
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Stewart RH. A Modern View of the Interstitial Space in Health and Disease. Front Vet Sci 2020; 7:609583. [PMID: 33251275 PMCID: PMC7674635 DOI: 10.3389/fvets.2020.609583] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/14/2020] [Indexed: 12/15/2022] Open
Abstract
Increases in the volume of the interstitial space are readily recognized clinically as interstitial edema formation in the loose connective tissue of skin, mucosa, and lung. However, the contents and the hydrostatic pressure of this interstitial fluid can be very difficult to determine even in experimental settings. These difficulties have long obscured what we are beginning to appreciate is a dynamic milieu that is subject to both intrinsic and extrinsic regulation. This review examines current concepts regarding regulation of interstitial volume, pressure, and flow and utilizes that background to address three major topics of interest that impact IV fluid administration. The first of these started with the discovery that excess dietary salt can be stored non-osmotically in the interstitial space with minimal impact on vascular volume and pressures. This led to the hypothesis that, along with the kidney, the interstitial space plays an active role in the long-term regulation of blood pressure. Second, it now appears that hypovolemic shock leads to systemic inflammatory response syndrome principally through the entry of digestive enzymes into the intestinal interstitial space and the subsequent progression of enzymes and inflammatory agents through the mesenteric lymphatic system to the general circulation. Lastly, current evidence strongly supports the non-intuitive view that the primary factor leading to inflammatory edema formation is a decrease in interstitial hydrostatic pressure that dramatically increases microvascular filtration.
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Affiliation(s)
- Randolph H Stewart
- Department of Veterinary Physiology and Pharmacology, Michael E. DeBakey Institute, Texas A&M University, College Station, TX, United States
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Belov DV, Garbuzenko DV, Lukin OP, Anufrieva SS. ROLE OF LABORATORY METHODS IN INTEGRATED DIAGNOSTICS OF ACUTE MESENTERIAL ISCHEMIA. MEDICAL JOURNAL OF THE RUSSIAN FEDERATION 2019; 25:316-323. [DOI: 10.18821/0869-2106-2019-25-5-6-316-323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
The aim of the review: to present literature data on the role of laboratory methods in the complex diagnosis of acute mesenteric ischemia. The main provisions. To search for scientific publications, we used the PubMed database, the RSCI, the Google Scholar search engine, as well as cited references. Articles relevant to the purpose of the review were selected for the period from 1999 to 2019 in the following terms: “acute mesenteric ischemia”, “pathogenesis”, “diagnosis”, “biomarkers”. Inclusion criteria were limited to acute arterial mesenteric ischemia. Acute mesenteric ischemia is an emergency condition caused by a sudden violation of the blood flow through the mesenteric vessels, which rapidly progresses to a heart attack of the intestinal wall and is accompanied by high mortality. Four main mechanisms of OMI are distinguished: embolism from the left parts of the heart or aorta, thrombosis of arteries or veins of the intestine, non-occlusive acute mesenteric ischemia (NOMI), due to vascular spasm. In this case, destructive disorders occur in the intestinal wall, starting from the mucous membrane to the serous, which leads to bacterial translocation and the development of a systemic inflammatory response syndrome. Early bowel revascularization is a key factor in reducing complications and mortality associated with it. However, in the initial stages of the disease has no specific signs, which complicate its diagnosis. The only way to detect mesenteric blood flow disorders is MSCT with angiography, and with non-occlusive lesions, mesenteric angiography, which in normal clinical practice is not always possible. Conclusion. It can be assumed that the use of laboratory methods will expand the range of diagnostic measures and will make it possible to conduct timely treatment aimed at restoring the mesenteric blood flow and improve the prognosis in patients with acute mesenteric ischemia.
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Aletti F, Santamaria M, Chin K, Mazor R, Kistler EB. Enteral Tranexamic Acid Decreases Proteolytic Activity in the Heart in Acute Experimental Hemorrhagic Shock. J Cardiovasc Pharmacol Ther 2019; 24:484-493. [PMID: 31035788 DOI: 10.1177/1074248419841630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The mechanisms for cardiac injury after hemorrhagic shock (HS) are unresolved. We hypothesize that remote organ damage can be caused by uncontrolled pancreatic proteolytic activity, as enteral protease inhibition improves outcomes in experimental HS. Uncontrolled proteolysis in the heart may disrupt cardiac metabolism and adrenergic control with subsequent deleterious outcomes. To test this hypothesis, the heart rate-pressure product (RPP) as an index of myocardial oxygen consumption and the levels of fatty acid transporter proteins CD36 and FATP6 as surrogates for metabolic activity in the heart were measured in rats subjected to experimental HS (n = 6/group) with and without the enteral protease inhibitor tranexamic acid (TXA). Plasma troponin I and heart fatty acid-binding protein (HFABP) concentrations were measured as indices of myocardial damage. Expression of the adrenergic receptors β1, α1D, and β2 was also measured in the heart to determine the possible effects of shock with and without enteral TXA on the adrenergic control of heart function. Hemorrhagic shock was induced by reduction in mean arterial blood pressure to 35 mm Hg for 2 hours before reperfusion of shed blood. The RPP was maintained in shocked animals treated enterally with TXA but not in those subjected to HS alone; this group also demonstrated decreased HFABP and plasma troponin I levels. Serine protease (trypsin, chymotrypsin, and elastase) and matrix metalloproteinase (MMP)-2 and MMP-9 activity was elevated in cardiac tissue and plasma after HS and abrogated by enteral TXA. Levels of CD36, FATP6, β1, α1D, and β2 were also increased after HS in cardiac tissue, and the increases were mitigated by TXA treatment. These results suggest that increased proteolytic activity may contribute to cardiac injury after HS. Enteral TXA prevents these changes, indicating a potential therapeutic option in the management of shock with resultant cardiac injury.
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Affiliation(s)
- Federico Aletti
- 1 Department of Bioengineering, University of California-San Diego, San Diego, CA, USA
| | - Marco Santamaria
- 1 Department of Bioengineering, University of California-San Diego, San Diego, CA, USA
| | - Kevin Chin
- 1 Department of Bioengineering, University of California-San Diego, San Diego, CA, USA
| | - Rafi Mazor
- 2 Department of Anesthesiology & Critical Care, VA San Diego Healthcare System, San Diego, CA, USA
| | - Erik B Kistler
- 2 Department of Anesthesiology & Critical Care, VA San Diego Healthcare System, San Diego, CA, USA
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Ruiz-Luque V, Parra-Membrives P, Escudero-Severín C, Aguilar-Luque J. Effect of Alprostadil on Colorectal Anastomoses Under Relative Ischemia. J Surg Res 2019; 236:230-237. [PMID: 30694761 DOI: 10.1016/j.jss.2018.11.046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 11/06/2018] [Accepted: 11/21/2018] [Indexed: 10/27/2022]
Abstract
BACKGROUND Anastomotic leak after colorectal surgery, which remains a serious clinical problem that causes augmented morbidity and mortality, is usually favored by ischemia. The aim of this study was to determine whether alprostadil may improve anastomotic wound healing under ischemic condition. METHODS Ninety-three adult Wistar rats were randomized into three groups: control, ischemia (by devascularization along the first 2 cm at each anastomotic end), and ischemia plus alprostadil. Resection of a colonic segment at the colorectal junction and an anastomosis was performed. Animals were euthanized at 8 d. Surgical site infection, anastomotic leak, and grade of intra-abdominal adhesions using a validated scale were determined. Bursting pressure and tension were calculated and histologic examination of the anastomosis was performed. RESULTS The ischemic group revealed an increased anastomotic leak rate (14/31 versus 3/31) and a lower bursting pressure and tension when compared to control group, validating therefore the experimental model. After intraperitoneal injection of alprostadil, anastomotic leak rate was significantly lower (5/31) and the bursting pressure and tension were significantly increased. Histologic examination revealed a lower presence of inflammatory cells, and a significantly higher neovascularization and a higher presence of fibroblasts in treated animals when compared with the ischemic group. CONCLUSIONS Alprostadil may have a positive effect on colonic anastomotic wound healing under relative ischemic condition. Alprostadil administration increases anastomotic bursting pressure, decreases leak rate, and reverses most of the histological changes caused by blood flow decrease. These protective effects could be caused by vasodilation, stimulation of neovascularization, and immunomodulatory properties.
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Affiliation(s)
- Virgilio Ruiz-Luque
- Department of General and Digestive Surgery, Valme University Hospital, Seville, Spain; Department of Surgery, University of Seville, Seville, Spain.
| | - Pablo Parra-Membrives
- Department of General and Digestive Surgery, Valme University Hospital, Seville, Spain; Department of Surgery, University of Seville, Seville, Spain
| | | | - José Aguilar-Luque
- Department of General and Digestive Surgery, Valme University Hospital, Seville, Spain; Department of Surgery, University of Seville, Seville, Spain
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Liao XL, Danzeng QZ, Zhang W, Hou CS, Xu BB, Yang J, Kang Y. Role of using two-route ulinastatin injection to alleviate intestinal injury in septic rats. Chin J Traumatol 2018; 21:323-328. [PMID: 30591258 PMCID: PMC6354214 DOI: 10.1016/j.cjtee.2018.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 07/08/2018] [Accepted: 08/15/2018] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Early application of protease inhibitors through the intestinal lumen could increase survival following experimental shock by blocking the pancreatic digestive enzymes. Hence, it was hypothesized that two-route injection (intraintestinal + intravenous) of ulinastatin (UTI), a broad-spectrum protease inhibitor, could better alleviate intestinal injury than single-route injection (either intravenous or intraintestinal). METHODS A sepsis model induced by lipopolysaccharide on rats was established. The rats were randomly divided into five groups: sham, sepsis, UTI intravenous injection (Uiv), UTI intraintestinal injection (Uii), and UTI intraintestinal + intravenous injection (Uii + Uiv) groups. The mucosal barrier function, enzyme-blocking effect, levels of systemic inflammatory cytokines, and 5-day survival rate were compared among groups. The small intestinal villus height (VH), crypt depth (CD), and two components of mucosal barrier (E-cadherin and mucin-2) were measured to evaluate the mucosal barrier function. The levels of trypsin and neutrophil elastase (NE) in the intestine, serum, and vital organs were measured to determine the enzyme-blocking effect. RESULTS Compared with the single-route injection group (Uiv or Uii), the two-route injection (Uii + Uiv) group displayed: (1) significantly higher levels of VH, VH/CD, E-cadherin, and mucin-2; (2) decreased trypsin and NE levels in intestine, plasma, and vital organs; (3) reduced systemic inflammatory cytokine levels; and (4) improved survival of septic rats. CONCLUSION Two-route UTI injection was superior to single-route injection in terms of alleviating intestinal injury, which might be explained by extensive blockade of proteases through different ways.
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Affiliation(s)
- Xue-Lian Liao
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qu-Zhen Danzeng
- Department of Critical Care Medicine, Tibet Autonomous Region People's Hospital, Lhasa 850000, Tibet, China
| | - Wei Zhang
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou Province, China
| | - Chen-Shu Hou
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bin-Bin Xu
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Yang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yan Kang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China,Corresponding author.
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Mazor R, Friedmann-Morvinski D, Alsaigh T, Kleifeld O, Kistler EB, Rousso-Noori L, Huang C, Li JB, Verma IM, Schmid-Schönbein GW. Cleavage of the leptin receptor by matrix metalloproteinase-2 promotes leptin resistance and obesity in mice. Sci Transl Med 2018; 10:eaah6324. [PMID: 30135249 PMCID: PMC9678493 DOI: 10.1126/scitranslmed.aah6324] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 05/01/2017] [Accepted: 03/22/2018] [Indexed: 08/08/2023]
Abstract
Obesity and related morbidities pose a major health threat. Obesity is associated with increased blood concentrations of the anorexigenic hormone leptin; however, obese individuals are resistant to its anorexigenic effects. We examined the phenomenon of reduced leptin signaling in a high-fat diet-induced obesity model in mice. Obesity promoted matrix metalloproteinase-2 (Mmp-2) activation in the hypothalamus, which cleaved the leptin receptor's extracellular domain and impaired leptin-mediated signaling. Deletion of Mmp-2 restored leptin receptor expression and reduced circulating leptin concentrations in obese mice. Lentiviral delivery of short hairpin RNA to silence Mmp-2 in the hypothalamus of wild-type mice prevented leptin receptor cleavage and reduced fat accumulation. In contrast, lentiviral delivery of Mmp-2 in the hypothalamus of Mmp-2-/- mice promoted leptin receptor cleavage and higher body weight. In a genetic mouse model of obesity, transduction of cleavage-resistant leptin receptor in the hypothalamus reduced the rate of weight gain compared to uninfected mice or mice infected with the wild-type receptor. Immunofluorescence analysis showed that astrocytes and agouti-related peptide neurons were responsible for Mmp-2 secretion in mice fed a high-fat diet. These results suggest a mechanism for leptin resistance through activation of Mmp-2 and subsequent cleavage of the extracellular domain of the leptin receptor.
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Affiliation(s)
- Rafi Mazor
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
| | - Dinorah Friedmann-Morvinski
- Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
- Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
- Sagol School of Neurosciences, Tel Aviv University, Tel Aviv 69978, Israel
| | - Tom Alsaigh
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Oded Kleifeld
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Erik B Kistler
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
- Veterans Affairs San Diego Healthcare System, San Diego, CA 92093, USA
- Department of Anesthesiology and Critical Care, University of California, San Diego, La Jolla, CA 92093, USA
| | - Liat Rousso-Noori
- Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
- Sagol School of Neurosciences, Tel Aviv University, Tel Aviv 69978, Israel
| | - Cheng Huang
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
| | - Joyce B Li
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Inder M Verma
- Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Geert W Schmid-Schönbein
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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Nuzzo A, Huguet A, Corcos O. [Modern treatment of mesenteric ischemia]. Presse Med 2018; 47:519-530. [PMID: 29776790 DOI: 10.1016/j.lpm.2018.03.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 03/27/2018] [Indexed: 01/16/2023] Open
Abstract
Acute mesenteric ischemia is a highly morbid affliction which requires urgent care. Acute mesenteric ischemia consists in an ischemia injury of the small bowel, secondary to vascular insufficiency, either occlusive (thrombosis, embolism, arterial, venous) or non-occlusive (low flow or vasospasm). Given that the superior mesenteric artery supplies the small bowel as well as the right part of the colon, any ischemic process involving the right colon should be considered an acute mesenteric ischemia until proven otherwise. Acute mesenteric ischemia should always be suspected in the setting of a sudden, unusual and intense abdominal pain requiring opioids. Chronic mesenteric ischemia can also be revealed by postprandial abdominal pain associated with significant weight loss. The clinical presentation of mesenteric ischemia is nonspecific. Thus, a suspected diagnosis must be confirmed by imaging usually consisting in an abdominal computed tomography scan. Imaging will also provide guidance with regards to treatment decision. Organ failure, serum lactate elevation as well as bowel loop dilationper imaging are predictive of irreversible intestinal necrosis. In the presence of any of these predictive factors, surgical management should be considered. The modern treatment of mesenteric ischemia in Intestinal Stroke Centers has allowed rates of resection-free survival in nearly two-thirds of patients. The management of mesenteric ischemia relies in a combination of: (1) a medical protocol including oral/enteral antibiotics; (2) the revascularization of viable bowel and (3) the surgical resection of necrosic, non viable intestinal tissue. The inception and development of Intestinal Stroke Centers has been the cornerstone of significantly improved management and survival rates as well as crucial asset in research, specifically in the field of biomarkers associated with early diagnosis.
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Affiliation(s)
- Alexandre Nuzzo
- AP-HP, hôpital Beaujon, structure d'urgence vasculaire intestinale (SURVI), service de gastroentérologie, MICI et assistance nutritive, 100, boulevard du Général-Leclerc, 92100 Clichy, France; Université Sorbonne-Paris Cité, 2, rue Albert-Einstein, 75013 Paris, France; Hôpital Bichat, Laboratory for Vascular Translationnal Science, Inserm U1148, 75018 Paris, France.
| | - Audrey Huguet
- AP-HP, hôpital Beaujon, structure d'urgence vasculaire intestinale (SURVI), service de gastroentérologie, MICI et assistance nutritive, 100, boulevard du Général-Leclerc, 92100 Clichy, France
| | - Olivier Corcos
- AP-HP, hôpital Beaujon, structure d'urgence vasculaire intestinale (SURVI), service de gastroentérologie, MICI et assistance nutritive, 100, boulevard du Général-Leclerc, 92100 Clichy, France; Université Sorbonne-Paris Cité, 2, rue Albert-Einstein, 75013 Paris, France; Hôpital Bichat, Laboratory for Vascular Translationnal Science, Inserm U1148, 75018 Paris, France
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Volatile Decay Products in Breath During Peritonitis Shock are Attenuated by Enteral Blockade of Pancreatic Digestive Proteases. Shock 2018; 48:571-575. [PMID: 28498300 PMCID: PMC5626116 DOI: 10.1097/shk.0000000000000888] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
There is a need to develop markers for early detection of organ failure in shock that can be noninvasively measured at point of care. We explore here the use of volatile organic compounds (VOCs) in expired air in a rat peritonitis shock model. Expired breath samples were collected into Tedlar gas bags and analyzed by standardized gas chromatography. The gas chromatograms were digitally analyzed for presence of peak amounts over a range of Kovach indices. Following the induction of peritonitis, selected volatile compounds were detected within about 1 h, which remained at elevated amounts over a 6 h observation period. These VOCs were not present in control animals without peritonitis. Comparisons with know VOCs indicate that they include 1,4-diaminobutane and trimethylamine N-oxide. When pancreatic digestive proteases were blocked with tranexamic acid in the intestine and peritoneum, a procedure that serves to reduce organ failure in shock, the amounts of VOCs in the breath decreased spontaneously to control values without peritonitis. These results indicate that peritonitis shock is accompanied by development of volatile organic compounds that may be generated by digestive enzymes in the small intestine. VOCs may serve as indicators for detection of early forms of autodigestion by digestive proteases.
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de Andrade LS, Ramos CI, Cuppari L. The cross-talk between the kidney and the gut: implications for chronic kidney disease. ACTA ACUST UNITED AC 2017. [DOI: 10.1186/s41110-017-0054-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Verhaegh R, Petrat F, Brencher L, Kirsch M, de Groot H. Autodigestion by migrated trypsin is a major factor in small intestinal ischemia-reperfusion injury. J Surg Res 2017; 219:266-278. [DOI: 10.1016/j.jss.2017.05.084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 04/16/2017] [Accepted: 05/23/2017] [Indexed: 01/01/2023]
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Patel S. A critical review on serine protease: Key immune manipulator and pathology mediator. Allergol Immunopathol (Madr) 2017; 45:579-591. [PMID: 28236540 PMCID: PMC7126602 DOI: 10.1016/j.aller.2016.10.011] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 10/31/2016] [Indexed: 11/29/2022]
Abstract
Proteolytic activity is fundamental to survival, so it is not surprising that all living organisms have proteases, especially seine protease. This enzyme in its numerous isoforms and homologues, constitutes the quintessential offence and defence factors, in the form of surface proteins, secreted molecules, gut digestive enzymes, venom in specialised glands or plant latex, among other manifestations. Occurring as trypsin, chymotrypsin, elastase, collagenase, thrombin, subtilisin etc., it mediates a diverse array of functions, including pathological roles as inflammatory, coagulatory to haemorrhagic. This review emphasizes that despite the superficial differences in mechanisms, most health issues, be they infectious, allergic, metabolic, or neural have a common conduit. This enzyme, in its various glycosylated forms leads to signal misinterpretations, wreaking havoc. However, organisms are endowed with serine protease inhibitors which might restrain this ubiquitous yet deleterious enzyme. Hence, serine proteases-driven pathogenesis and antagonising role of inhibitors is the focal point of this critical review.
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Enteral tranexamic acid attenuates vasopressor resistance and changes in α1-adrenergic receptor expression in hemorrhagic shock. J Trauma Acute Care Surg 2017; 83:263-270. [PMID: 28422915 DOI: 10.1097/ta.0000000000001513] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Irreversible hemorrhagic shock is characterized by hyporesponsiveness to vasopressor and fluid therapy. Little is known, however, about the mechanisms that contribute to this phenomenon. Previous studies have shown that decreased intestinal perfusion in hemorrhagic shock leads to proteolytically mediated increases in gut permeability, with subsequent egress of vasoactive substances systemically. Maintenance of blood pressure is achieved in part by α1 receptor modulation, which may be affected by vasoactive factors; we thus hypothesized that decreases in hemodynamic stability and vasopressor response in shock can be prevented by enteral protease inhibition. METHODS Rats were exposed to experimental hemorrhagic shock (35 mm Hg mean arterial blood pressure for 2 hours, followed by reperfusion for 2 hours) and challenged with phenylephrine (2 μg/kg) at discrete intervals to measure vasopressor responsiveness. A second group of animals received enteral injections with the protease inhibitor tranexamic acid (TXA) (127 mM) along the small intestine and cecum 1 hour after induction of hemorrhagic shock. RESULTS Blood pressure response (duration and amplitude) to phenylephrine after reperfusion was significantly attenuated in animals subjected to hemorrhagic shock compared with baseline and control nonshocked animals and was restored to near baseline by enteral TXA. Arteries from shocked animals also displayed decreased α1 receptor density with restoration to baseline after enteral TXA treatment. In vitro, rat shock plasma decreased α1 receptor density in smooth muscle cells, which was also abrogated by enteral TXA treatment. CONCLUSION Results from this study demonstrate that experimental hemorrhagic shock leads to decreased response to the α1-selective agonist phenylephrine and decreased α1 receptor density via circulating shock factors. These changes are mitigated by enteral TXA with correspondingly improved hemodynamics. Proteolytic inhibition in the lumen of the small intestine improves hemodynamics in hemorrhagic shock, possibly by restoring α1 adrenergic functionality necessary to maintain systemic blood pressure and perfusion.
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Paul PK, Nopparat J, Nuanplub M, Treetong A, Suedee R. Improvement in insulin absorption into gastrointestinal epithelial cells by using molecularly imprinted polymer nanoparticles: Microscopic evaluation and ultrastructure. Int J Pharm 2017; 530:279-290. [DOI: 10.1016/j.ijpharm.2017.07.071] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 07/22/2017] [Accepted: 07/24/2017] [Indexed: 01/15/2023]
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Peoc’h K, Nuzzo A, Guedj K, Paugam C, Corcos O. Diagnosis biomarkers in acute intestinal ischemic injury: so close, yet so far. ACTA ACUST UNITED AC 2017; 56:373-385. [DOI: 10.1515/cclm-2017-0291] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 07/21/2017] [Indexed: 12/20/2022]
Abstract
Abstract
Acute intestinal ischemic injury (i3) is a life-threatening condition with disastrous prognosis, which is currently difficult to diagnose at the early stages of the disease; a rapid diagnosis is mandatory to avoid irreversible ischemia, extensive bowel resection, sepsis and death. The overlapping protein expression of liver and gut related to the complex physiopathology of the disease, the heterogeneity of the disease and its relative rarity could explain the lack of a useful early biochemical marker of i3. Apart from non-specific biological markers of thrombosis, hypoxia inflammation, and infection, several more specific biomarkers in relation with the gut barrier dysfunction, the villi injury and the enterocyte mass have been used in the diagnosis of acute i3. It includes particularly D-lactate, intestinal fatty acid-binding protein (FABP) and citrulline. Herein, we will discuss leading publications concerning these historical markers that point out the main limitations reagrding their use in routine clinical practice. We will also introduce the first and limited results arising from omic studies, underlying the remaining effort that needs to be done in the field of acute i3 biological diagnosis, which remains a challenge.
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Affiliation(s)
- Katell Peoc’h
- Biochimie Clinique, Hôpital Beaujon , Université Paris Diderot, UFR de Médecine Xavier Bichat and APHP, HUPNVS, DHU Unity , Clichy , France
- INSERM, UMRs 1149, CRI , Université Paris Diderot , Paris , France , Phone: +33 (0)1 40 87 54 36
| | - Alexandre Nuzzo
- SURVI, Hôpital Beaujon, APHP, HUPNVS, DHU Unity , Clichy , France
- Gastroenterologie, Hôpital Beaujon, APHP, HUPNVS , Clichy , France
| | - Kevin Guedj
- SURVI, Hôpital Beaujon, APHP, HUPNVS, DHU Unity , Clichy , France
- INSERM, UMRs 1148, LVTS , Paris , France
| | - Catherine Paugam
- Anesthésie Réanimation, Hôpital Beaujon , Université Paris Diderot, UFR de Médecine Xavier Bichat and APHP, HUPNVS , Clichy , France
| | - Olivier Corcos
- SURVI, Hôpital Beaujon, APHP, HUPNVS, DHU Unity , Clichy , France
- Gastroenterologie, Hôpital Beaujon, APHP, HUPNVS , Clichy , France
- INSERM, UMRs 1148, LVTS , Paris , France
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Schmid-Schönbein GW. The autodigestion hypothesis: Proteolytic receptor cleavage in rheological and cardiovascular cell dysfunction1. Biorheology 2017; 53:179-191. [PMID: 28269737 PMCID: PMC5389039 DOI: 10.3233/bir-17131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Transformation of circulating leukocytes from a dormant into an activated state with changing rheological properties leads to a major shift of their behavior in the microcirculation. Low levels of pseudopod formation or expression of adhesion molecules facilitate relatively free passage through microvessels while activated leukocytes with pseudopods and enhanced levels of adhesion membrane proteins become trapped in microvessels, attach to the endothelium and migrate into the tissue. The transformation of leukocytes into an activated state is seen in many diseases. While mechanisms for activation due to infections, tissue trauma, as well as non-physiological biochemical or biophysical exposures are well recognized, the mechanisms for activation in many diseases have not been conclusively liked to these traditional mechanisms and remain unknown. We summarize our recent evidence suggesting a major and surprising role of digestive enzymes in the small intestine as root causes for leukocyte activation and microvascular disturbances. During normal digestion of food digestive enzymes are compartmentalized in the lumen of the intestine by the mucosal epithelial barrier. When permeability of this barrier increases, these powerful degrading enzymes leak into the wall of the intestine and into the systemic circulation. Leakage of digestive enzymes occurs for example in physiological shock and multi-organ failure. Entry of digestive enzymes into the wall of the small intestine leads to degradation of the intestinal tissue in an autodigestion process. The digestive enzymes and tissue/food fragments generate not only activate leukocytes but also cause numerous cell dysfunctions. For example, proteolytic destruction of membrane receptors, plasma proteins and other biomolecules occurs. We conclude that escape of digestive enzymes from the intestinal track serves as a major source of cell dysfunction, morbidity and even mortality, including abnormal leukocyte activation seen in rheological studies.
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Affiliation(s)
- Geert W Schmid-Schönbein
- Department of Bioengineering, The Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA
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Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock. J Trauma Acute Care Surg 2017; 81:358-65. [PMID: 27027557 DOI: 10.1097/ta.0000000000001056] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Intravenous tranexamic acid (TXA) is an effective adjunct after hemorrhagic shock (HS) because of its antifibrinolytic properties. TXA is also a serine protease inhibitor, and recent laboratory data demonstrated that intraluminal TXA into the small bowel inhibited digestive proteases and protected the gut. A Disintegrin And Metalloproteinase 17 (ADAM-17) and tumor necrosis factor α (TNF-α) are effective sheddases of intestinal syndecan-1, which when shed, exposes the underlying intestinal epithelium to digestive proteases and subsequent systemic insult. We therefore hypothesized that intraluminal TXA as a serine protease inhibitor would reduce intestinal sheddases and syndecan-1 shedding, mitigating gut and distant organ (lung) damage. METHODS Mice underwent 90 minutes of HS to a mean arterial pressure of 35 ± 5 mm Hg followed by the intraluminal administration of TXA or vehicle. After 3 hours, the small intestine, lung, and blood were collected for analysis. RESULTS Intraluminal TXA significantly reduced gut and lung histopathologic injury and inflammation compared with HS alone. Gut, lung, and systemic ADAM-17 and TNF-α were significantly increased by HS but lessened by TXA. In addition, gut and lung syndecan-1 immunostaining were preserved and systemic shedding lessened after TXA. TXA reduced ADAM-17 and TNF-α, but not syndecan-1, in TXA-sham animals compared with sham vehicles. CONCLUSION Results of the present study demonstrate a beneficial effect of intraluminal TXA in the gut and lung after experimental HS in part because of the inhibition of the syndecan-1 shedding by ADAM-17 and TNF-α. Further studies are needed to determine if orally administered TXA could provide similar intestinal protection and thus be of potential benefit to patients with survivable hemorrhage at risk for organ injury. This is particularly relevant in patients or soldiers who may not have access to timely medical care.
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Abstract
There is currently no effective treatment for multiorgan failure following shock other than supportive care. A better understanding of the pathogenesis of these sequelae to shock is required. The intestine plays a central role in multiorgan failure. It was previously suggested that bacteria and their toxins are responsible for the organ failure seen in circulatory shock, but clinical trials in septic patients have not confirmed this hypothesis. Instead, we review here evidence that the digestive enzymes, synthesized in the pancreas and discharged into the small intestine as requirement for normal digestion, may play a role in multiorgan failure. These powerful enzymes are nonspecific, highly concentrated, and fully activated in the lumen of the intestine. During normal digestion they are compartmentalized in the lumen of the intestine by the mucosal epithelial barrier. However, if this barrier becomes permeable, e.g. in an ischemic state, the digestive enzymes escape into the wall of the intestine. They digest tissues in the mucosa and generate small molecular weight cytotoxic fragments such as unbound free fatty acids. Digestive enzymes may also escape into the systemic circulation and activate other degrading proteases. These proteases have the ability to clip the ectodomain of surface receptors and compromise their function, for example cleaving the insulin receptor causing insulin resistance. The combination of digestive enzymes and cytotoxic fragments leaking into the central circulation causes cell and organ dysfunction, and ultimately may lead to complete organ failure and death. We summarize current evidence suggesting that enteral blockade of digestive enzymes inside the lumen of the intestine may serve to reduce acute cell and organ damage and improve survival in experimental shock.
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Cucolas C, Daneasa AI, Olteanu D, Decea N, Moldovan R, Tabaran F, Filip GA. Resveratrol and curcumin as protective agents in an experimental rat model of intestinal ischemia and reperfusion. Can J Physiol Pharmacol 2016; 94:1151-1158. [DOI: 10.1139/cjpp-2016-0085] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
The aim of this study was to evaluate the protective effects of resveratrol and curcumin in an experimental rat model of intestinal ischemia–reperfusion (I/R). Forty-eight adult Wistar rats were used: 12 animals undergoing the sham surgery and 36 animals undergoing laparotomy, with 15 min of mesentric artery clamping. The animals from the latter group (n = 12) were pretreated, for 1 week, with vehicle (CTR), resveratrol (RES), and curcumin (CUR). After 1 h and 6 h of reperfusion, respectively, cyclooxigenase (COX)-2, mucin-1, E-cadherin, nuclear factor (NK)-κB expressions, and tumor necrosis factor related apoptosis-inducing ligand (TRAIL) were assessed in the small intestine. Oxidative stress markers were determined in tissue homogenate and serum, and histopathological analysis was performed. Pretreatment with RES decreased the expression of COX-2 and NF-κB at both intervals and increased E-cadherin (p < 0.05) and mucin-1 production after 1 h. CUR had a beneficial effect on COX-2, NF-κB, and E-cadherin expressions, both after 1 h and after 6 h (p < 0.0001). The two compounds increased TRAIL levels and had a protective effect on oxidative stress and histopathological lesions, both after 1 h and after 6 h. Our results suggested that RES and CUR had beneficial effects in intestinal I/R and may represent a promising option for complementary treatment of this pathological condition.
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Affiliation(s)
- Cristina Cucolas
- Department of Physiology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Alexandra Ioana Daneasa
- Department of Physiology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Olteanu
- Department of Physiology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Nicoleta Decea
- Department of Physiology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Remus Moldovan
- Department of Physiology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Flaviu Tabaran
- Department of Pathology, University of Agricultural Sciences and Veterinary Medicine, 400372, Cluj-Napoca, Romania
| | - Gabriela Adriana Filip
- Department of Physiology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Mazor R, Schmid-Schönbein GW. Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion. Biorheology 2016; 52:337-52. [PMID: 26600265 DOI: 10.3233/bir-15045] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Abnormal blood rheological properties seldom occur in isolation and instead are accompanied by other complications, often designated as co-morbidities. In the metabolic syndrome with complications like hypertension, diabetes and lack of normal microvascular blood flow, the underlying molecular mechanisms that simultaneously lead to elevated blood pressure and diabetes as well as abnormal microvascular rheology and other cell dysfunctions have remained largely unknown. In this review, we propose a new hypothesis for the origin of abnormal cell functions as well as multiple co-morbidities. Utilizing experimental models for the metabolic disease with diverse co-morbidities we summarize evidence for the presence of an uncontrolled extracellular proteolytic activity that causes ectodomain receptor cleavage and loss of their associated cell function. We summarize evidence for unchecked degrading proteinase activity, e.g. due to matrix metalloproteases, in patients with hypertension, Type II diabetes and obesity, in addition to evidence for receptor cleavage in the form of receptor fragments and decreased extracellular membrane expression levels. The evidence suggest that a shift in blood rheological properties and other co-morbidities may in fact be derived from a common mechanism that is due to uncontrolled proteolytic activity, i.e. an early form of autodigestion. Identification of the particular proteases involved and the mechanisms of their activation may open the door to treatment that simultaneously targets multiple co-morbidities in the metabolic syndrome.
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Affiliation(s)
- Rafi Mazor
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Geert W Schmid-Schönbein
- Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA, USA
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de Jong PR, González-Navajas JM, Jansen NJG. The digestive tract as the origin of systemic inflammation. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2016; 20:279. [PMID: 27751165 PMCID: PMC5067918 DOI: 10.1186/s13054-016-1458-3] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Failure of gut homeostasis is an important factor in the pathogenesis and progression of systemic inflammation, which can culminate in multiple organ failure and fatality. Pathogenic events in critically ill patients include mesenteric hypoperfusion, dysregulation of gut motility, and failure of the gut barrier with resultant translocation of luminal substrates. This is followed by the exacerbation of local and systemic immune responses. All these events can contribute to pathogenic crosstalk between the gut, circulating cells, and other organs like the liver, pancreas, and lungs. Here we review recent insights into the identity of the cellular and biochemical players from the gut that have key roles in the pathogenic turn of events in these organ systems that derange the systemic inflammatory homeostasis. In particular, we discuss the dangers from within the gastrointestinal tract, including metabolic products from the liver (bile acids), digestive enzymes produced by the pancreas, and inflammatory components of the mesenteric lymph.
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Affiliation(s)
- Petrus R de Jong
- Department of Pediatric Intensive Care, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. .,Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
| | - José M González-Navajas
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Hospital General Universitario de Alicante, Alicante, Spain.,Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain
| | - Nicolaas J G Jansen
- Department of Pediatric Intensive Care, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
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Moderate Hypothermia Provides Better Protection of the Intestinal Barrier than Deep Hypothermia during Circulatory Arrest in a Piglet Model: A Microdialysis Study. PLoS One 2016; 11:e0163684. [PMID: 27685257 PMCID: PMC5042434 DOI: 10.1371/journal.pone.0163684] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 09/11/2016] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION This study aimed to assess the effects of different temperature settings of hypothermic circulatory arrest (HCA) on intestinal barrier function in a piglet model. METHODS Twenty Wuzhishan piglets were randomly assigned to 40 min of HCA at 18°C (DHCA group, n = 5), 40 min of HCA at 24°C (MHCA group, n = 5), normothermic cardiopulmonary bypass (CPB group, n = 5) or sham operation (SO group, n = 5). Serum D-lactate (SDL) and lipopolysaccharide (LPS) levels were determined. Microdialysis parameters (glucose, lactate, pyruvate and glycerol) in the intestinal dialysate were measured. After 180 min of reperfusion, intestinal samples were harvested for real-time polymerase chain reaction and western blotting measurements for E-cadherin and Claudin-1. RESULTS Higher levels of SDL and LPS were detected in the DHCA group than in the MHCA group (P < 0.001). Both MHCA and DHCA groups exhibited lower glucose levels, higher lactate and glycerol levels and a higher lactate to pyruvate (L/P) ratio compared with the CPB group (p<0.05); the DHCA group had higher lactate and glycerol levels and a higher L/P ratio (p<0.05) but similar glucose levels compared to the MHCA group. No significant differences in E-cadherin mRNA or protein levels were noted. Upregulation of claudin-1 mRNA levels was detected in both the DHCA and MHCA animals' intestines (P < 0.01), but only the DHCA group exhibited a decrease in claudin-1 protein expression (P < 0.01). CONCLUSION HCA altered the energy metabolism and expression of epithelial junctions in the intestine. Moderate hypothermia (24°C) was less detrimental to the markers of normal functioning of the intestinal barrier than deep hypothermia (18°C).
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Early tranexamic acid administration: A protective effect on gut barrier function following ischemia/reperfusion injury. J Trauma Acute Care Surg 2016; 79:1015-22. [PMID: 26317817 DOI: 10.1097/ta.0000000000000703] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The mucus barrier is a critical component of the gut barrier and may be disrupted by pancreatic enzymes following trauma/hemorrhagic shock (T/HS). Luminal strategies against pancreatic enzyme activation or contact with the intestine are protective of the mucus layer and gut barrier integrity following T/HS. There is increasing evidence the use of tranexamic acid (TA) attenuates inflammatory responses in cardiac surgery and is readily absorbed from the gut. We therefore postulated that systemic administration of TA would attenuate mucus degradation and gut barrier failure following T/HS. This was studied in an in vitro model. METHODS Confluent monolayers of HT29-MTX (mucus-producing clone) and Caco-2 cocultures were exposed to 90 minutes of hypoxia followed by reoxygenation (H/R), luminal trypsin (5 μM), or both treatment groups. In a subset of experiments, TA (40 μM or 150 μM) was added to the basal chamber (systemic side) of intestinal cell cultures immediately following the hypoxic period. Mucus barrier function was indexed by rheologic measurement of both mucus thickness and viscosity (G', dyne/cm) and oxidant stress. Intestinal cell barrier integrity was indexed by transepithelial electrical resistance, permeability to fluorescein isothiocyanate-dextran, and apoptosis by flow cytometry. RESULTS Exposure to both trypsin and H/R of Caco-2/HT29-MTX cocultures led to the most severe effect on mucus barrier function. Administration of TA immediately following hypoxia abrogated the effects noted on mucus barrier function. The epithelial barrier was also most severely impacted by both trypsin and H/R. Addition of TA after the hypoxic event was shown to be protective. CONCLUSION Intestinal mucus physiochemical properties and intestinal barrier function were most severely impacted by exposure to both trypsin (concentration related) and H/R. The "systemic" administration of TA immediately after the hypoxic period was protective and suggests an additional role for early administration of TA in trauma patients in shock.
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Vaziri ND, Zhao YY, Pahl MV. Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment. Nephrol Dial Transplant 2016; 31:737-746. [PMID: 25883197 DOI: 10.1093/ndt/gfv095] [Citation(s) in RCA: 262] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 03/16/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) results in systemic inflammation and oxidative stress which play a central role in CKD progression and its adverse consequences. Although many of the causes and consequences of oxidative stress and inflammation in CKD have been extensively explored, little attention had been paid to the intestine and its microbial flora as a potential source of these problems. Our recent studies have revealed significant disruption of the colonic, ileal, jejunal and gastric epithelial tight junction in different models of CKD in rats. Moreover, the disruption of the epithelial barrier structure and function found in uremic animals was replicated in cultured human colonocytes exposed to uremic human plasma in vitro We have further found significant changes in the composition and function of colonic bacterial flora in humans and animals with advanced CKD. Together, uremia-induced impairment of the intestinal epithelial barrier structure and function and changes in composition of the gut microbiome contribute to the systemic inflammation and uremic toxicity by accommodating the translocation of endotoxin, microbial fragments and other noxious luminal products in the circulation. In addition, colonic bacteria are the main source of several well-known pro-inflammatory uremic toxins such as indoxyl sulfate, p-cresol sulfate, trimethylamine-N-oxide and many as-yet unidentified retained compounds in end-stage renal disease patients. This review is intended to provide an overview of the effects of CKD on the gut microbiome and intestinal epithelial barrier structure and their role in the pathogenesis of systemic inflammation and uremic toxicity. In addition, potential interventions aimed at mitigating these abnormalities are briefly discussed.
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Affiliation(s)
- Nosratola D Vaziri
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine Medical Center, Orange, CA, USA
| | - Ying-Yong Zhao
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine Medical Center, Orange, CA, USA
| | - Madeleine V Pahl
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine Medical Center, Orange, CA, USA
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Alsaigh T, Chang M, Richter M, Mazor R, Kistler EB. In vivo analysis of intestinal permeability following hemorrhagic shock. World J Crit Care Med 2015; 4:287-295. [PMID: 26557479 PMCID: PMC4631874 DOI: 10.5492/wjccm.v4.i4.287] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 07/07/2015] [Accepted: 08/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the time course of intestinal permeability changes to proteolytically-derived bowel peptides in experimental hemorrhagic shock.
METHODS: We injected fluorescently-conjugated casein protein into the small bowel of anesthetized Wistar rats prior to induction of experimental hemorrhagic shock. These molecules, which fluoresce when proteolytically cleaved, were used as markers for the ability of proteolytically cleaved intestinal products to access the central circulation. Blood was serially sampled to quantify the relative change in concentration of proteolytically-cleaved particles in the systemic circulation. To provide spatial resolution of their location, particles in the mesenteric microvasculature were imaged using in vivo intravital fluorescent microscopy. The experiments were then repeated using an alternate measurement technique, fluorescein isothiocyanate (FITC)-labeled dextrans 20, to semi-quantitatively verify the ability of bowel-derived low-molecular weight molecules (< 20 kD) to access the central circulation.
RESULTS: Results demonstrate a significant increase in systemic permeability to gut-derived peptides within 20 min after induction of hemorrhage (1.11 ± 0.19 vs 0.86 ± 0.07, P < 0.05) compared to control animals. Reperfusion resulted in a second, sustained increase in systemic permeability to gut-derived peptides in hemorrhaged animals compared to controls (1.2 ± 0.18 vs 0.97 ± 0.1, P < 0.05). Intravital microscopy of the mesentery also showed marked accumulation of fluorescent particles in the microcirculation of hemorrhaged animals compared to controls. These results were replicated using FITC dextrans 20 [10.85 ± 6.52 vs 3.38 ± 1.11 fluorescent intensity units (× 105, P < 0.05, hemorrhagic shock vs controls)], confirming that small bowel ischemia in response to experimental hemorrhagic shock results in marked and early increases in gut membrane permeability.
CONCLUSION: Increased small bowel permeability in hemorrhagic shock may allow for systemic absorption of otherwise retained proteolytically-generated peptides, with consequent hemodynamic instability and remote organ failure.
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Affiliation(s)
- Madeleine V. Pahl
- Division of Nephrology and Hypertension; Department of Medicine; University of California; Irvine Orange California
| | - Nosratola D. Vaziri
- Division of Nephrology and Hypertension; Department of Medicine; University of California; Irvine Orange California
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Phillips NA, Welc SS, Wallet SM, King MA, Clanton TL. Protection of intestinal injury during heat stroke in mice by interleukin-6 pretreatment. J Physiol 2015; 593:739-52; discussion 753. [PMID: 25433073 DOI: 10.1113/jphysiol.2014.283416] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 11/20/2014] [Indexed: 12/21/2022] Open
Abstract
KEY POINTS Heat stroke afflicts thousands of humans each year, worldwide. The immune system responds to hyperthermia exposure resulting in heat stroke by producing an array of immunological proteins, such as interleukin-6 (IL-6). However, the physiological functions of IL-6 and other cytokines in hyperthermia are poorly understood. We hypothesized that IL-6 plays a protective role in conditions of heat stroke. To test this, we gave small IL-6 supplements to mice prior to exposing them to hot environments sufficient to induce conditions of heat stroke. Pretreatment with IL-6 resulted in improved ability to withstand heat exposure in anaesthetized mice, it protected the intestine from injury, reducing the permeability of the intestinal barrier, and it attenuated the release of other cytokines involved in inflammation. The results support the hypothesis that IL-6 is a 'physiological stress hormone' that plays an important role in survival during acute life-threatening conditions such as heat stroke. ABSTRACT The role of interleukin-6 (IL-6) in hyperthermia and heat stroke is poorly understood. Plasma IL-6 is elevated following hyperthermia in animals and humans, and IL-6 knockout mice are more intolerant of severe hyperthermia. We evaluated the effect of IL-6 supplementation on organ injury following severe hyperthermia exposure in anaesthetized mice. Two hours prior to hyperthermia, mice were treated with 0.6 μg intraperitoneal IL-6, or identical volumes of saline in controls. Mice were anaesthetized, gavaged with FITC-dextran for measures of gastrointestinal permeability, and exposed to incremental (0.5°C every 30 min) increases in temperature. Heating stopped when maximum core temperature (Tc) of 42.4°C was attained (Tc,max). The mice recovered at room temperature (≈22°C) for 30 or 120 min, at which time plasma and tissues were collected. IL-6-treated mice, on average, required ≈25 min longer to attain Tc,max . Injury and swelling of the villi in the duodenum was present in untreated mice after 30 min of recovery. These changes were blocked by IL-6 treatment. IL-6 also reduced gastrointestinal permeability, assayed by the accumulation of FITC-dextran in plasma. Plasma cytokines were also attenuated in IL-6-treated animals, including significant reductions in TNFα, MCP-1 (CXCL2), RANTES (CCL5) and KC (CCL5). The results demonstrate that IL-6 has a protective influence on the pattern of physiological responses to severe hyperthermia, suggesting that early endogenous expression of IL-6 may provide a protection from the development of organ damage and inflammation.
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Affiliation(s)
- Neil A Phillips
- Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, USA
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Brown JB, Neal MD, Guyette FX, Peitzman AB, Billiar TR, Zuckerbraun BS, Sperry JL. Design of the Study of Tranexamic Acid during Air Medical Prehospital Transport (STAAMP) Trial: Addressing the Knowledge Gaps. PREHOSP EMERG CARE 2015; 19:79-86. [PMID: 25076119 PMCID: PMC4623322 DOI: 10.3109/10903127.2014.936635] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Abstract Hemorrhage and coagulopathy remain major drivers of early preventable mortality in military and civilian trauma. The development of trauma-induced coagulopathy and hyperfibrinolysis is associated with poor outcomes. Interest in the use of tranexamic acid (TXA) in hemorrhaging patients as an antifibrinolytic agent has grown recently. Additionally, several reports describe immunomodulatory effects of TXA that may confer benefit independent of its antifibrinolytic actions. A large trial demonstrated a mortality benefit for early TXA administration in patients at risk for hemorrhage; however, questions remain about the applicability in developed trauma systems and the mechanism by which TXA reduces mortality. We describe here the rationale, design, and challenges of the Study of Tranexamic Acid during Air Medical Prehospital transport (STAAMP) trial. The primary objective is to determine the effect of prehospital TXA infusion during air medical transport on 30-day mortality in patients at risk of traumatic hemorrhage. This study is a multicenter, placebo-controlled, double-blind, randomized clinical trial. The trial will enroll trauma patients with hypotension and tachycardia from 4 level I trauma center air medical transport programs. It includes a 2-phase intervention, with a prehospital and in-hospital phase to investigate multiple dosing regimens. The trial will also explore the effects of TXA on the coagulation and inflammatory response following injury. The trial will be conducted under exception for informed consent for emergency research and thus required an investigational new drug approval from the U.S. Food and Drug Administration as well as a community consultation process. It was designed to address several existing knowledge gaps and research priorities regarding TXA use in trauma.
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Kano H, Okada K, Morimoto K, Bao W, Fukase K, Ito A, Okita Y. Prediction of reversibility of intestinal mucosal damage after ischemia-reperfusion injury by plasma intestinal fatty acid-binding protein levels in pigs. Perfusion 2014; 30:617-25. [DOI: 10.1177/0267659114566063] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Objective: The aims of this study were to elucidate the association between plasma intestinal fatty acid-binding protein (I-FABP) level and actual pathological damage of intestinal mucosa and its reversibility. Methods: An intestinal ischemia-reperfusion model was created by temporary occlusion of the descending aorta in 9 pigs which were divided into 3 groups according to the duration of visceral ischemic insult: 15-minute ischemia (n=3), 30-minute ischemia (n=3) and 60-minute ischemia (n=3). Blood samples and short segments of the jejunum for pathological examinations, including immunohistochemical staining of I-FABP, Ki-67 and E-cadherin, were taken at the beginning of the operation (T1) and 15 minutes (T2), 30 minutes (T3), 45 minutes (T4) and 60 minutes (T5) after reperfusion. Results: Plasma I-FABP after 15 minutes of ischemia reached a peak of 1859±1089 pg/ml at T3, while the level after 30 minutes of ischemia achieved a peak level of 5053±1717 pg/ml at T5. The level after 60 minutes of ischemia demonstrated a rapid increment up to 10734±93 pg/ml at T3. There was a significant difference in the trend of plasma I-FABP levels between 30 minutes and 60 minutes of ischemia (p=0.01). The strongest immunohistochemical staining of the intestinal epithelium for I-FABP was observed at T4 after 30 minutes of ischemia, with the shedding of injured epithelium followed by re-epithelialisation, with sequential up-regulation of Ki67 and E-cadherin. However, the intestinal epithelium after 60 minutes of ischemia demonstrated the lack of I-FABP expression with irreversible damage. Conclusion: Plasma I-FABP levels may be a crucial marker to recognize the reversibility of damage of the intestinal epithelium after an ischemic insult and the level of 5000 pg/ml is considered to be the critical borderline for irreversibility, which might prevent diagnostic delay in the clinical setting.
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Affiliation(s)
- H Kano
- Division of Cardiovascular Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - K Okada
- Division of Cardiovascular Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - K Morimoto
- Division of Cardiovascular Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - W Bao
- Division of Cardiovascular Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - K Fukase
- Division of Cardiovascular Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - A Ito
- Department of Pathology, Kinki University Faculty of Medicine, Osaka, Japan
| | - Y Okita
- Division of Cardiovascular Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
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Fishman JE, Sheth SU, Levy G, Alli V, Lu Q, Xu D, Qin Y, Qin X, Deitch EA. Intraluminal nonbacterial intestinal components control gut and lung injury after trauma hemorrhagic shock. Ann Surg 2014; 260:1112-1120. [PMID: 24646554 PMCID: PMC4168009 DOI: 10.1097/sla.0000000000000631] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To test whether the mucus layer, luminal digestive enzymes, and intestinal mast cells are critical components in the pathogenesis of trauma shock-induced gut and lung injury. BACKGROUND Gut origin sepsis studies have highlighted the importance of the systemic component (ischemia-reperfusion) of gut injury, whereas the intraluminal component is less well studied. METHODS In rats subjected to trauma hemorrhagic shock (T/HS) or sham shock, the role of pancreatic enzymes in gut injury was tested by diversion of pancreatic enzymes via pancreatic duct exteriorization whereas the role of the mucus layer was tested via the enteral administration of a mucus surrogate. In addition, the role of mast cells was assessed by measuring mast cell activation and the ability of pharmacologic inhibition of mast cells to abrogate gut and lung injury. Gut and mucus injury was characterized functionally, morphologically, and chemically. RESULTS Pancreatic duct exteriorization abrogated T/HS-induced gut barrier loss and limited chemical mucus changes. The mucus surrogate prevented T/HS-induced gut and lung injury. Finally, pancreatic enzyme-induced gut and lung injury seems to involve mast cell activation because T/HS activates mast cells and pharmacologic inhibition of intestinal mast cells prevented T/HS-induced gut and lung injury. CONCLUSIONS These results indicate that gut and gut-induced lung injury after T/HS involves a complex process consisting of intraluminal digestive enzymes, the unstirred mucus layer, and a systemic ischemic-reperfusion injury. This suggests the possibility of intraluminal therapeutic strategies.
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Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock. Shock 2014; 41:55-61. [PMID: 24088998 DOI: 10.1097/shk.0000000000000048] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hemorrhagic shock is associated with metabolic defects, including hyperglycemia and insulin resistance, but the mechanisms are unknown. We recently demonstrated that reduction of the extracellular domain of the insulin receptor by degrading proteases may lead to a reduced ability to maintain normal plasma glucose values. In shock, transfer of digestive enzymes from the lumen of the intestine into the systemic circulation after breakdown of the intestinal mucosal barrier causes inflammation and organ dysfunction. Suppression of the digestive enzymes in the lumen of the intestine with protease inhibitors is effective in reducing the level of the inflammatory reactions. To determine the degree to which blockade of digestive enzymes affects insulin resistance in shock, rats were exposed to acute hemorrhagic shock (mean arterial pressure of 30 mmHg for 2 h) at which time all shed blood volume was returned. Digestive proteases in the intestine were blocked with a serine protease inhibitor (tranexamic acid in polyethylene glycol and physiological electrolyte solution), and the density of the insulin receptor was measured with immunohistochemistry in the mesentery microcirculation. The untreated rat without enzyme blockade had significantly attenuated levels of insulin receptor density as compared with control and treated rats. Blockade of the digestive proteases after 60 min of hypotension in the lumen of the small intestine led to a lesser decrease in insulin receptor density compared with controls without protease blockade. Glucose tolerance test indicates a significant increase in plasma glucose levels 2 h after hemorrhagic shock, which are reduced to control values in the presence of protease inhibition in the lumen of the intestine. The transient reduction of the plasma glucose levels after an insulin bolus is significantly attenuated after shock but is restored when digestive enzymes in the lumen of the intestine are blocked. These results suggest that in hemorrhagic shock elevated microvascular extracellular digestive enzyme activity causes insulin receptor dysfunction, hyperglycemia, and reduced ability to regulate blood glucose values.
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Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice. PLoS One 2014; 9:e101828. [PMID: 25010671 PMCID: PMC4092051 DOI: 10.1371/journal.pone.0101828] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 06/11/2014] [Indexed: 12/16/2022] Open
Abstract
Background Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8–10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis. Methods Aged (20–24 months) Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival. Results In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005). Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice. Conclusions Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.
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Altshuler AE, Lamadrid I, Li D, Ma SR, Kurre L, Schmid-Schönbein GW, Penn AH. Transmural intestinal wall permeability in severe ischemia after enteral protease inhibition. PLoS One 2014; 9:e96655. [PMID: 24805256 PMCID: PMC4013012 DOI: 10.1371/journal.pone.0096655] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 04/10/2014] [Indexed: 01/13/2023] Open
Abstract
In intestinal ischemia, inflammatory mediators in the small intestine's lumen such as food byproducts, bacteria, and digestive enzymes leak into the peritoneal space, lymph, and circulation, but the mechanisms by which the intestinal wall permeability initially increases are not well defined. We hypothesize that wall protease activity (independent of luminal proteases) and apoptosis contribute to the increased transmural permeability of the intestine's wall in an acutely ischemic small intestine. To model intestinal ischemia, the proximal jejunum to the distal ileum in the rat was excised, the lumen was rapidly flushed with saline to remove luminal contents, sectioned into equal length segments, and filled with a tracer (fluorescein) in saline, glucose, or protease inhibitors. The transmural fluorescein transport was determined over 2 hours. Villi structure and epithelial junctional proteins were analyzed. After ischemia, there was increased transmural permeability, loss of villi structure, and destruction of epithelial proteins. Supplementation with luminal glucose preserved the epithelium and significantly attenuated permeability and villi damage. Matrix metalloproteinase (MMP) inhibitors (doxycycline, GM 6001), and serine protease inhibitor (tranexamic acid) in the lumen, significantly reduced the fluorescein transport compared to saline for 90 min of ischemia. Based on these results, we tested in an in-vivo model of hemorrhagic shock (90 min 30 mmHg, 3 hours observation) for intestinal lesion formation. Single enteral interventions (saline, glucose, tranexamic acid) did not prevent intestinal lesions, while the combination of enteral glucose and tranexamic acid prevented lesion formation after hemorrhagic shock. The results suggest that apoptotic and protease mediated breakdown cause increased permeability and damage to the intestinal wall. Metabolic support in the lumen of an ischemic intestine with glucose reduces the transport from the lumen across the wall and enteral proteolytic inhibition attenuates tissue breakdown. These combined interventions ameliorate lesion formation in the small intestine after hemorrhagic shock.
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Affiliation(s)
- Angelina E. Altshuler
- Department of Bioengineering, The Institute of Engineering in Medicine, University Of California San Diego, La Jolla, California, United States of America
- * E-mail:
| | - Itze Lamadrid
- Department of Bioengineering, The Institute of Engineering in Medicine, University Of California San Diego, La Jolla, California, United States of America
| | - Diana Li
- Department of Bioengineering, The Institute of Engineering in Medicine, University Of California San Diego, La Jolla, California, United States of America
| | - Stephanie R. Ma
- Department of Bioengineering, The Institute of Engineering in Medicine, University Of California San Diego, La Jolla, California, United States of America
| | - Leena Kurre
- Department of Bioengineering, The Institute of Engineering in Medicine, University Of California San Diego, La Jolla, California, United States of America
| | - Geert W. Schmid-Schönbein
- Department of Bioengineering, The Institute of Engineering in Medicine, University Of California San Diego, La Jolla, California, United States of America
| | - Alexander H. Penn
- Department of Bioengineering, The Institute of Engineering in Medicine, University Of California San Diego, La Jolla, California, United States of America
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Altshuler AE, Richter MD, Modestino AE, Penn AH, Heller MJ, Schmid-Schönbein GW. Removal of luminal content protects the small intestine during hemorrhagic shock but is not sufficient to prevent lung injury. Physiol Rep 2013; 1:e00109. [PMID: 24303180 PMCID: PMC3841044 DOI: 10.1002/phy2.109] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 09/07/2013] [Accepted: 09/11/2013] [Indexed: 12/21/2022] Open
Abstract
The small intestine plays a key role in the pathogenesis of multiple organ failure following circulatory shock. Current results show that reduced perfusion of the small intestine compromises the mucosal epithelial barrier, and the intestinal contents (including pancreatic digestive enzymes and partially digested food) can enter the intestinal wall and transport through the circulation or mesenteric lymph to other organs such as the lung. The extent to which the luminal contents of the small intestine mediate tissue damage in the intestine and lung is poorly understood in shock. Therefore, rats were assigned to three groups: No-hemorrhagic shock (HS) control and HS with or without a flushed intestine. HS was induced by reducing the mean arterial pressure (30 mmHg; 90 min) followed by return of shed blood and observation (3 h). The small intestine and lung were analyzed for hemorrhage, neutrophil accumulation, and cellular membrane protein degradation. After HS, animals with luminal contents had increased neutrophil accumulation, bleeding, and destruction of E-cadherin in the intestine. Serine protease activity was elevated in mesenteric lymph fluid collected from a separate group of animals subjected to intestinal ischemia/reperfusion. Serine protease activity was elevated in the plasma after HS but was detected in lungs only in animals with nonflushed lumens. Despite removal of the luminal contents, lung injury occurred in both groups as determined by elevated neutrophil accumulation, permeability, and lung protein destruction. In conclusion, luminal contents significantly increase intestinal damage during experimental HS, suggesting transport of luminal contents across the intestinal wall should be minimized.
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Affiliation(s)
- Angelina E Altshuler
- Department of Bioengineering, The Institute of Engineering in Medicine, University of California San Diego La Jolla, California, 92093-0412
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DeLano FA, Hoyt DB, Schmid-Schönbein GW. Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. Sci Transl Med 2013; 5:169ra11. [PMID: 23345609 DOI: 10.1126/scitranslmed.3005046] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Shock, sepsis, and multiorgan failure are associated with inflammation, morbidity, and high mortality. The underlying pathophysiological mechanism is unknown, but evidence suggests that pancreatic enzymes in the intestinal lumen autodigest the intestine and generate systemic inflammation. Blocking these enzymes in the intestine reduces inflammation and multiorgan dysfunction. We investigated whether enzymatic blockade also reduces mortality after shock. Three rat shock models were used here: hemorrhagic shock, peritonitis shock induced by placement of cecal material into the peritoneum, and endotoxin shock. One hour after initiation of hemorrhagic, peritonitis, or endotoxin shock, animals were administered one of three different pancreatic enzyme inhibitors--6-amidino-2-naphtyl p-guanidinobenzoate dimethanesulfate, tranexamic acid, or aprotinin--into the lumen of the small intestine. In all forms of shock, blockade of digestive proteases with protease inhibitor attenuated entry of digestive enzymes into the wall of the intestine and subsequent autodigestion and morphological damage to the intestine, lung, and heart. Animals treated with protease inhibitors also survived in larger numbers than untreated controls over a period of 12 weeks. Surviving animals recovered completely and returned to normal weight within 14 days after shock. The results suggest that the active and concentrated digestive enzymes in the lumen of the intestine play a central role in shock and multiorgan failure, which can be treated with protease inhibitors that are currently available for use in the clinic.
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Affiliation(s)
- Frank A DeLano
- Department of Bioengineering, The Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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Redefining the gut as the motor of critical illness. Trends Mol Med 2013; 20:214-23. [PMID: 24055446 DOI: 10.1016/j.molmed.2013.08.004] [Citation(s) in RCA: 234] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 08/13/2013] [Accepted: 08/20/2013] [Indexed: 12/11/2022]
Abstract
The gut is hypothesized to play a central role in the progression of sepsis and multiple organ dysfunction syndrome. Critical illness alters gut integrity by increasing epithelial apoptosis and permeability and by decreasing epithelial proliferation and mucus integrity. Additionally, toxic gut-derived lymph induces distant organ injury. Although the endogenous microflora ordinarily exist in a symbiotic relationship with the gut epithelium, severe physiological insults alter this relationship, leading to induction of virulence factors in the microbiome, which, in turn, can perpetuate or worsen critical illness. This review highlights newly discovered ways in which the gut acts as the motor that perpetuates the systemic inflammatory response in critical illness.
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Schmid-Schönbein GW, Chang M. The autodigestion hypothesis for shock and multi-organ failure. Ann Biomed Eng 2013; 42:405-14. [PMID: 23989761 DOI: 10.1007/s10439-013-0891-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 08/09/2013] [Indexed: 01/20/2023]
Abstract
An important medical problem with high mortality is shock, sepsis and multi-organ failure. They have currently no treatments other than alleviation of symptoms. Shock is accompanied by strong markers for inflammation and involves a cascade of events that leads to failure in organs even if they are not involved in the initial insult. Recent evidence indicates that pancreatic digestive enzymes carried in the small intestine after mixing with ingested food are a major cause for multi-organ failure. These concentrated and relatively non-specific enzymes are usually compartmentalized inside the intestinal lumen as requirement for normal digestion. But after breakdown of the mucosal barrier they leak into the wall of the intestine and start an autodigestion process that includes destruction of villi in the intestine. Digestive enzymes also generate cytotoxic mediators, which together are transported into the systemic circulation via the portal venous system, the intestinal lymphatics and via the peritoneum. They cause various degrees of cell and organ dysfunction that can reach the point of complete organ failure. Blockade of digestive enzymes in the lumen of the intestine in experimental forms of shock serves to reduce breakdown of the mucosal barrier and autodigestion of the intestine, organ dysfunctions and mortality.
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Affiliation(s)
- Geert W Schmid-Schönbein
- Department of Bioengineering, The Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, 92093, USA,
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Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock 2013; 39:121-6. [PMID: 23222525 DOI: 10.1097/shk.0b013e318280409a] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
A recent large civilian randomized controlled trial on the use of tranexamic acid (TXA) for trauma reported important survival benefits. Subsequently, successful use of TXA for combat casualties in Afghanistan was also reported. As a result of these promising studies, there has been growing interest in the use of TXA for trauma. Potential adverse effects of TXA have also been reported. A US Department of Defense committee conducted a review and assessment of knowledge gaps and research requirements regarding the use of TXA for the treatment of casualties that have experienced traumatic hemorrhage. We present identified knowledge gaps and associated research priorities. We believe that important knowledge gaps exist and that a targeted, prioritized research effort will contribute to the refinement of practice guidelines over time.
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Çakmaz R, Büyükaşık O, Kahramansoy N, Erkol H, Çöl C, Boran Ç, Buğdaycı G. A combination of plasma DAO and citrulline levels as a potential marker for acute mesenteric ischemia. Libyan J Med 2013; 8:20596. [PMID: 23534825 PMCID: PMC3609998 DOI: 10.3402/ljm.v8i0.20596] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 03/04/2013] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION There is no valid and reliable diagnostic test for early diagnosis of acute mesenteric ischemia (AMI). The aim of this study was to measure the plasma levels of diamine oxidase (DAO) and citrulline in AMI to gain insight into its early diagnosis. MATERIAL AND METHODS A total of 21 Wistar albino rats were divided into three groups, that is, control group, short-term ischemia group, and prolonged ischemia group. The superior mesenteric artery was occluded for 15 min in the short-term ischemia group and for 12 h in the prolonged ischemia group. Twelve hours later, the experiment was terminated and plasma DAO and citrulline levels were measured. Intestinal tissue was evaluated for the histopathological changes. RESULTS Compared to the control group, the short-term and prolonged ischemia groups showed significant increases in the plasma levels of DAO, whereas the plasma citrulline levels decreased significantly. Prolonged ischemia caused a larger increase in the plasma DAO levels and a larger decrease in the plasma citrulline levels compared to the short-term ischemia (p=0.011 and p=0.021, respectively). Intestinal damage was shown to develop more in the prolonged ischemia group (p=0.001). CONCLUSION In the early period of AMI, the plasma DAO levels increase while citrulline levels decrease, and the extent of these changes depends on the duration of ischemia.
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Affiliation(s)
- Rıdvan Çakmaz
- Department of General Surgery, State Hospital, Adıyaman, Turkey
| | - Oktay Büyükaşık
- Department of General Surgery, Lokman Hekim Hospital, Sincan, Turkey
| | - Nurettin Kahramansoy
- Department of General Surgery, Faculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey
| | - Hayri Erkol
- Department of General Surgery, Faculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey
| | - Cavit Çöl
- Department of General Surgery, Faculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey
| | - Çetin Boran
- Department of Pathology, Faculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey
| | - Güler Buğdaycı
- Department of Biochemistry, Faculty of Medicine, Abant Izzet Baysal University, Bolu, Turkey
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Rappold JF, Pusateri AE. Tranexamic acid in remote damage control resuscitation. Transfusion 2013; 53 Suppl 1:96S-99S. [PMID: 23301980 DOI: 10.1111/trf.12042] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
With the advent of remote damage control resuscitation and far-forward surgery, a renewed emphasis has been placed on examining a variety of pharmacologic adjuncts to controlling blood loss before definitive operative intervention. In this paper, the authors review the current state of the art for tranexamic acid (TXA) and its potential benefits to those patients who are in need of a massive transfusion. Specifically addressed are its biologic and pharmacologic properties, as well the results of a number of recent studies. The 2010 CRASH-2 trial randomized in excess of 20,000 patients and demonstrated a reduction in all-cause mortality from 16.0 to 14.5% and death due to bleeding from 5.7 to 4.9%. The 2012 Military Application of Tranexamic Acid in Trauma Emergency Resuscitation study provided a retrospective analysis of 896 wounded cared for at a military hospital in Afghanistan. This study demonstrated a 23.9%-17.4% reduction in all-cause mortality. Finally, they discuss the potential complications associated with TXA use as well as areas of future research, which are needed to solidify our knowledge of TXA and its potential beneficial effects on controlling bleeding.
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Affiliation(s)
- Joseph F Rappold
- Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
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Impaired small-bowel barrier integrity in the presence of lumenal pancreatic digestive enzymes leads to circulatory shock. Shock 2012; 38:262-7. [PMID: 22576000 DOI: 10.1097/shk.0b013e31825b1717] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In bowel ischemia, impaired mucosal integrity may allow intestinal pancreatic enzyme products to become systemic and precipitate irreversible shock and death. This can be attenuated by pancreatic enzyme inhibition in the small-bowel lumen. It is unresolved, however, whether ischemically mediated mucosal disruption is the key event allowing pancreatic enzyme products systemic access and whether intestinal digestive enzyme activity in concert with increased mucosal permeability leads to shock in the absence of ischemia. To test this possibility, the small intestinal lumen of nonischemic rats was perfused for 2 h with either digestive enzymes, a mucin disruption strategy (i.e., mucolytics) designed to increase mucosal permeability, or both, and animals were observed for shock. Digestive enzymes perfused included trypsin, chymotrypsin, elastase, amylase, and lipase. Control (n = 6) and experimental animals perfused with pancreatic enzymes only (n = 6) or single enzymes (n = 3 for each of the five enzyme groups) maintained stable hemodynamics. After mucin disruption using a combination of enteral N-acetylcysteine, atropine, and increased flow rates, rats (n = 6) developed mild hypotension (P < 0.001 compared with groups perfused with pancreatic enzymes only after 90 min) and increased intestinal permeability to intralumenally perfused fluorescein isothiocyanate-dextran 20 kd (P < 0.05) compared with control and enzyme-only groups, but there were no deaths. All animals perfused with both digestive enzymes and subjected to mucin disruption (n = 6) developed hypotension and increased intestinal permeability (P < 0.001 after 90 min). Pancreatic enzymes were measured in the intestinal wall of both groups subjected to mucin disruption, but not in the enzyme-only or control groups. Depletion of plasma protease inhibitors was found only in animals perfused with pancreatic enzymes plus mucin disruption, implicating increased permeability and intralumenal pancreatic enzyme egress in this group. These experiments demonstrate that increased bowel permeability via mucin disruption in the presence of pancreatic enzymes can induce shock and increase systemic protease activation in the absence of ischemia, implicating bowel mucin disruption as a key event in early ischemia. Digestive enzymes and their products, if allowed to penetrate the gut wall, may trigger multiorgan failure and death.
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