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The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus

Jonas Van Dingenen (UGent) , Leen Pieters (UGent) , Anne Vral (UGent) and Romain Lefebvre (UGent)
Author
Abstract
Objective: Intestinal inflammation triggers postoperative ileus (POI), commonly seen after abdominal surgery and characterized by impaired gastrointestinal transit; when prolonged, this leads to increased morbidity. Hydrogen sulfide (H2S) is recognized as an important mediator of many (patho) physiological processes, including inflammation, and is now investigated for anti-inflammatory application. Therefore, the aim of this study was to investigate the effect of the H2S-releasing naproxen derivative ATB-346, developed to reduce gastrointestinal injury by naproxen, and the slow-release H2S donor GYY4137 on intestinal inflammation and delayed gastrointestinal transit in murine POI. Methods: C57BI6J mice were fasted for 6 h,anesthetized and after laparotomy, POI was induced by compressing the small intestine with two cotton applicators for 5 min (intestinal manipulation; IM). GYY4137 (50 mg/kg, intraperitoneally), ATB-346 (16 mg/kg, intragastrically) or naproxen (10 mg/kg, intragastrically) were administered 1 h before IM. At 24 h postoperatively, gastrointestinal transit was assessed via fluorescent imaging, and mucosa-free muscularis segments were prepared for later analysis. Inflammatory parameters and activity of inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2 were measured. Histological examination of whole tissue sections was done on hematoxylin-eosin stained slides. Results: Pre-treatment with GYY4137 (geometric center; GC: 7.6 +/- 0.5) and ATB-346 (GC: 8.4 +/- 0.3) prevented the delayed transit induced by IM (GC: 3.6 +/- 0.5 vs. 9.0 +/- 0.4 in non-operated controls) while naproxen only partially did (GC: 5.9 +/- 0.5; n = 8 for all groups). GYY4137 and ATB-346 significantly reduced the IM-induced increase in muscular myeloperoxidase (MPO) activity and protein levels of interleukin (IL)-6, IL-1 beta and monocyte chemotactic protein 1; the reduction by naproxen was less pronounced and only reached significance for MPO activity and IL-6 levels. All treatments significantly reduced the increase in COX-2 activity caused by IM, whereas only GYY4137 significantly reduced the increase in iNOS activity. Naproxen treatment caused significant histological damage of intestinal villi. Conclusion: The study shows that naproxen partially prevents POI, probably through its inhibitory effect on COX-2 activity. Both ATB-346 and GYY4137 were more effective, the result with GYY4137 showing that H2S per se can prevent POI.
Keywords
ATB-346, GYY4137, hydrogen sulfide, naproxen, postoperative ileus, HYDROGEN-SULFIDE DONOR, ANTIINFLAMMATORY DRUG, REPERFUSION INJURY, MOUSE, MODEL, CELLS, ISCHEMIA, PROTECTS, DYSFUNCTION, SUPPRESSES, EXPRESSION, ATB-346, GYY4137, hydrogen sulfide, naproxen, postoperative ileus

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MLA
Van Dingenen, Jonas et al. “The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus.” FRONTIERS IN PHARMACOLOGY 10 (2019): n. pag. Print.
APA
Van Dingenen, Jonas, Pieters, L., Vral, A., & Lefebvre, R. (2019). The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus. FRONTIERS IN PHARMACOLOGY, 10.
Chicago author-date
Van Dingenen, Jonas, Leen Pieters, Anne Vral, and Romain Lefebvre. 2019. “The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus.” Frontiers in Pharmacology 10.
Chicago author-date (all authors)
Van Dingenen, Jonas, Leen Pieters, Anne Vral, and Romain Lefebvre. 2019. “The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus.” Frontiers in Pharmacology 10.
Vancouver
1.
Van Dingenen J, Pieters L, Vral A, Lefebvre R. The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus. FRONTIERS IN PHARMACOLOGY. Lausanne: Frontiers Media Sa; 2019;10.
IEEE
[1]
J. Van Dingenen, L. Pieters, A. Vral, and R. Lefebvre, “The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus,” FRONTIERS IN PHARMACOLOGY, vol. 10, 2019.
@article{8627556,
  abstract     = {Objective: Intestinal inflammation triggers postoperative ileus (POI), commonly seen after abdominal surgery and characterized by impaired gastrointestinal transit; when prolonged, this leads to increased morbidity. Hydrogen sulfide (H2S) is recognized as an important mediator of many (patho) physiological processes, including inflammation, and is now investigated for anti-inflammatory application. Therefore, the aim of this study was to investigate the effect of the H2S-releasing naproxen derivative ATB-346, developed to reduce gastrointestinal injury by naproxen, and the slow-release H2S donor GYY4137 on intestinal inflammation and delayed gastrointestinal transit in murine POI. Methods: C57BI6J mice were fasted for 6 h,anesthetized and after laparotomy, POI was induced by compressing the small intestine with two cotton applicators for 5 min (intestinal manipulation; IM). GYY4137 (50 mg/kg, intraperitoneally), ATB-346 (16 mg/kg, intragastrically) or naproxen (10 mg/kg, intragastrically) were administered 1 h before IM. At 24 h postoperatively, gastrointestinal transit was assessed via fluorescent imaging, and mucosa-free muscularis segments were prepared for later analysis. Inflammatory parameters and activity of inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2 were measured. Histological examination of whole tissue sections was done on hematoxylin-eosin stained slides. Results: Pre-treatment with GYY4137 (geometric center; GC: 7.6 +/- 0.5) and ATB-346 (GC: 8.4 +/- 0.3) prevented the delayed transit induced by IM (GC: 3.6 +/- 0.5 vs. 9.0 +/- 0.4 in non-operated controls) while naproxen only partially did (GC: 5.9 +/- 0.5; n = 8 for all groups). GYY4137 and ATB-346 significantly reduced the IM-induced increase in muscular myeloperoxidase (MPO) activity and protein levels of interleukin (IL)-6, IL-1 beta and monocyte chemotactic protein 1; the reduction by naproxen was less pronounced and only reached significance for MPO activity and IL-6 levels. All treatments significantly reduced the increase in COX-2 activity caused by IM, whereas only GYY4137 significantly reduced the increase in iNOS activity. Naproxen treatment caused significant histological damage of intestinal villi. Conclusion: The study shows that naproxen partially prevents POI, probably through its inhibitory effect on COX-2 activity. Both ATB-346 and GYY4137 were more effective, the result with GYY4137 showing that H2S per se can prevent POI.},
  articleno    = {116},
  author       = {Van Dingenen, Jonas and Pieters, Leen and Vral, Anne and Lefebvre, Romain},
  issn         = {1663-9812},
  journal      = {FRONTIERS IN PHARMACOLOGY},
  keywords     = {ATB-346,GYY4137,hydrogen sulfide,naproxen,postoperative ileus,HYDROGEN-SULFIDE DONOR,ANTIINFLAMMATORY DRUG,REPERFUSION INJURY,MOUSE,MODEL,CELLS,ISCHEMIA,PROTECTS,DYSFUNCTION,SUPPRESSES,EXPRESSION,ATB-346,GYY4137,hydrogen sulfide,naproxen,postoperative ileus},
  language     = {eng},
  pages        = {11},
  publisher    = {Frontiers Media Sa},
  title        = {The H2S-Releasing Naproxen Derivative ATB-346 and the Slow-Release H2S Donor GYY4137 Reduce Intestinal Inflammation and Restore Transit in Postoperative Ileus},
  url          = {http://dx.doi.org/10.3389/fphar.2019.00116},
  volume       = {10},
  year         = {2019},
}

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