Effects of Mesalamine Treatment on Gut Barrier Integrity After Burn Injury

Gut barrier disruption is often implicated in pathogenesis associated with burn and other traumatic injuries. In this study, the authors examined whether therapeutic intervention with mesalamine (5-aminosalicylic acid [5-ASA]), a common anti-inflammatory treatment for patients with inflammatory bowel disease, reduces intestinal inflammation and maintains normal barrier integrity after burn injury. Male C57BL/6 mice were administered an approximately 20% TBSA dorsal scald burn and resuscitated with either 1 ml normal saline or 100 mg/kg of 5-ASA dissolved in saline. The authors examined intestinal transit and permeability along with the levels of small intestine epithelial cell proinflammatory cytokines and tight junction protein expression 1 day after burn injury in the presence or absence of 5-ASA. A significant decrease in intestinal transit was observed 1 day after burn injury, which accompanied a significant increase in gut permeability. The authors found a substantial increase in the levels of interleukin (IL)-6 (by ~1.5-fold) and IL-18 (by ~2.5-fold) in the small intestine epithelial cells 1 day after injury. Furthermore, burn injury decreases the expression of the tight junction proteins claudin-4, claudin-8, and occludin. Treatment with 5-ASA after burn injury prevented the burn-induced increase in permeability, partially restored normal intestinal transit, normalized the levels of the proinflammatory cytokines IL-6 and IL-18, and restored tight junction protein expression of claudin-4 and occludin compared with that of sham levels. Together these findings suggest that 5-ASA can potentially be used as treatment to decrease intestinal inflammation and normalize intestinal function after burn injury.

[1]  B. Feagan,et al.  Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. , 2016, The Cochrane database of systematic reviews.

[2]  R. Gamelli,et al.  Burn Injury Alters the Intestinal Microbiome and Increases Gut Permeability and Bacterial Translocation , 2015, PloS one.

[3]  M. Icaza-Chávez,et al.  Microbiota intestinal en la salud y la enfermedad , 2013 .

[4]  V. Tremaroli,et al.  Functional interactions between the gut microbiota and host metabolism , 2012, Nature.

[5]  M. Choudhry,et al.  Alteration in intestine tight junction protein phosphorylation and apoptosis is associated with increase in IL-18 levels following alcohol intoxication and burn injury. , 2012, Biochimica et biophysica acta.

[6]  P. Moughan,et al.  Regulation of tight junction permeability by intestinal bacteria and dietary components. , 2011, The Journal of nutrition.

[7]  E. Deitch,et al.  Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction , 2010, Annals of the New York Academy of Sciences.

[8]  D. Chinkes,et al.  The leading causes of death after burn injury in a single pediatric burn center , 2009, Critical care.

[9]  D. Hatef,et al.  Pathophysiologic Response to Severe Burn Injury , 2009 .

[10]  G. Jacobsen,et al.  Thermal injury induces impaired function in polymorphonuclear neutrophil granulocytes and reduced control of burn wound infection , 2009, Clinical and experimental immunology.

[11]  M. Fromm,et al.  Claudin Tight Junction Proteins: Novel Aspects in Paracellular Transport , 2008, Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis.

[12]  D. Herndon,et al.  Gender Differences in Pediatric Burn Patients: Does It Make a Difference? , 2008, Annals of surgery.

[13]  S. Mazmanian,et al.  A microbial symbiosis factor prevents intestinal inflammatory disease , 2008, Nature.

[14]  C. V. Van Itallie,et al.  The density of small tight junction pores varies among cell types and is increased by expression of claudin-2 , 2008, Journal of Cell Science.

[15]  S. Hanauer,et al.  Treatment of inflammatory bowel disease: a review of medical therapy. , 2008, World journal of gastroenterology.

[16]  M. Neurath,et al.  Isolation and subsequent analysis of murine lamina propria mononuclear cells from colonic tissue , 2007, Nature Protocols.

[17]  M. Jäättelä,et al.  The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions , 2007, FEBS letters.

[18]  R. Gamelli,et al.  Inflammation and Sepsis: Past, Present, and the Future , 2007, Journal of burn care & research : official publication of the American Burn Association.

[19]  Hong-pyo Kim,et al.  Heat-shock proteins: new keys to the development of cytoprotective therapies , 2006, Expert opinion on therapeutic targets.

[20]  L. Magnotti,et al.  Burns, bacterial translocation, gut barrier function, and failure. , 2005, The Journal of burn care & rehabilitation.

[21]  J. Auwerx,et al.  Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator–activated receptor-γ , 2005, The Journal of experimental medicine.

[22]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[23]  R. Gamelli,et al.  Impaired intestinal immunity and barrier function: a cause for enhanced bacterial translocation in alcohol intoxication and burn injury. , 2004, Alcohol.

[24]  J. Lederer,et al.  Injury, sepsis, and the regulation of Toll‐like receptor responses , 2004, Journal of leukocyte biology.

[25]  E. Ulvestad,et al.  Concentrations of cytokines in plasma of patients with large burns: their relation to time after injury, burn size, inflammatory variables, infection, and outcome. , 2003, The European journal of surgery = Acta chirurgica.

[26]  H. Allgayer.  Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease , 2003, Alimentary pharmacology & therapeutics.

[27]  G. Barbara,et al.  A role for inflammation in irritable bowel syndrome? , 2002, Gut.

[28]  R. Gamelli,et al.  Gut-associated lymphoid T cell suppression enhances bacterial translocation in alcohol and burn injury. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[29]  J. Gordon,et al.  Commensal Host-Bacterial Relationships in the Gut , 2001, Science.

[30]  A. Sjöqvist,et al.  Permeability of the rat small intestinal epithelium along the villus-crypt axis: effects of glucose transport. , 2000, Gastroenterology.

[31]  D. McMillan,et al.  HSF1 is required for extra‐embryonic development, postnatal growth and protection during inflammatory responses in mice , 1999, The EMBO journal.

[32]  W. Sandborn,et al.  Inhibition of Interleukin-1-stimulated NF-κB RelA/p65 Phosphorylation by Mesalamine Is Accompanied by Decreased Transcriptional Activity* , 1999, The Journal of Biological Chemistry.

[33]  D. Polk,et al.  Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor kappaB activation in mouse colonocytes. , 1999, Gastroenterology.

[34]  W. L. Lin,et al.  Changes in circulating levels of interleukin 6 in burned patients. , 1999, Burns : journal of the International Society for Burn Injuries.

[35]  E. Faist,et al.  SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS), MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS), MULTIPLE ORGAN FAILURE (MOF): ARE WE WINNING THE BATTLE? , 1998, Shock.

[36]  Bernd Bukau,et al.  The Hsp70 and Hsp60 Chaperone Machines , 1998, Cell.

[37]  G. Struhl,et al.  Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb , 1998, Nature.

[38]  E. Chang,et al.  Effects of mesalamine on the hsp72 stress response in rat IEC-18 intestinal epithelial cells. , 1997, Gastroenterology.

[39]  W. L. Lin,et al.  Changes in serum tumour necrosis factor-α in burned patients , 1997 .

[40]  R. Berg,et al.  The indigenous gastrointestinal microflora. , 1996, Trends in microbiology.

[41]  I. Chaudry,et al.  THE GUT: A CYTOKINE‐GENERATING ORGAN IN SYSTEMIC INFLAMMATION? , 1995, Shock.

[42]  E. Deitch.  Intestinal permeability is increased in burn patients shortly after injury , 1990, Surgery.

[43]  E. Deitch,et al.  The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. , 1990, Archives of surgery.

[44]  A. Mason,et al.  A standard animal burn. , 1968, The Journal of trauma.

[45]  E. Deitch,et al.  Role of the gut in the development of injury- and shock induced SIRS and MODS: the gut-lymph hypothesis, a review. , 2006, Frontiers in bioscience : a journal and virtual library.

[46]  J. Mate,et al.  Role of 5-aminosalicylic acid (5-ASA) in treatment of inflammatory bowel disease: a systematic review. , 2002, Digestive diseases and sciences.

[47]  M. Feder,et al.  Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. , 1999, Annual review of physiology.

[48]  B. Seed,et al.  PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. , 1998, Nature.

[49]  W. L. Lin,et al.  Changes in serum tumour necrosis factor-alpha in burned patients. , 1997, Burns : journal of the International Society for Burn Injuries.

[50]  Z. Ba,et al.  Differential alterations in plasma IL-6 and TNF levels after trauma and hemorrhage. , 1991, The American journal of physiology.

[51]  W. Boron,et al.  Effect of diabetes on Na(+)-H+ exchange by single isolated hepatocytes. , 1991, The American journal of physiology.