Role of inducible nitric oxide synthase in trinitrobenzene sulphonic acid induced colitis in mice

McCafferty, Donna–Marie; Miampamba, Marcel; Sihota, Elaine; Sharkey, Keith A.; Kubes, Paul

doi:10.1136/gut.45.6.864

Cited by 126 publications

(130 citation statements)

References 42 publications

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“…Our findings are similar to those seen in collagenous colitis (41), where high iNOS expression by intestinal epithelial cells is not associated with overt mucosal tissue damage. In fact, like McCafferty et al (34,35) we found that iNOS KO mice exhibited a more severe and protracted colitis, suggesting that rather than acting as a noxious substance during inflammation, NO may have beneficial actions. The absence of iNOS expression under control conditions suggests that iNOS plays its beneficial role after the induction of colitis.…”

Section: Discussionmentioning

confidence: 61%

“…These limitations have encouraged the study of colitis in mice genetically deficient in iNOS. Unfortunately, these studies (34,35,62) have utilized different protocols and yielded conflicting results. Moreover, the few studies that have examined the roles of the other NOS isoforms in experimental colitis have also been conflicting; such that it remains unclear whether the eNOS and nNOS isoforms contribute to intestinal inflammation (2,16) or whether they instead maintain intestinal homeostasis and mucosal integrity (5,48).…”

mentioning

confidence: 99%

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Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Vallance¹,

Dijkstra²,

Qiu³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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The role of nitric oxide (NO) in inflammatory bowel diseases has traditionally focused on the inducible form of NO synthase (iNOS). However, the constitutive endothelial (eNOS) and neuronal (nNOS) isoforms may also impact on colitis, either by contributing to the inflammation or by regulating mucosal integrity in response to noxious stimuli. To date, studies examining the roles of the NOS isoforms in experimental colitis have been conflicting, and the mechanisms by which these enzymes exert their effects remain unclear. To investigate and clarify the roles of the NOS isoforms in gut inflammation, we induced trinitrobenzenesulfonic acid colitis in eNOS, nNOS, and iNOS knockout (KO) mice, assessing the course of colitis at early and late times. Both eNOS and iNOS KO mice developed a more severe colitis compared with wild-type mice. During colitis, iNOS expression dramatically increased on epithelial and lamina propria mononuclear cells, whereas eNOS expression remained localized to endothelial cells. Electron and fluorescence microscopy identified bacteria in the ulcerated colonic mucosa of eNOS KO mice, but not in wild-type, iNOS, or nNOS KO mice. Furthermore, eNOS KO mice had fewer colonic goblet cells, impaired mucin production, and exhibited increased susceptibility to an inflammatory stimulus that was subthreshold to other mice. This susceptibility was reversible, because the NO donor isosorbide dinitrate normalized goblet cell numbers and ameliorated subsequent colitis in eNOS KO mice. These results identify a protective role for both iNOS and eNOS during colitis, with eNOS deficiency resulting in impaired intestinal defense against lumenal bacteria and increased susceptibility to colitis. mucus; bacteria; inflammatory bowel diseases; goblet cells SEVERAL FACTORS HAVE BEEN implicated in the pathogenesis of human inflammatory bowel diseases (IBD) including an immunological intolerance to enteric microflora (10 -12, 43), as well as defects in mucosal barrier function (47). Recently, attention has been focused on the overproduction of nitric oxide (NO) in IBD (7,31,46,58). Several studies have identified increased levels of NO in the rectal dialysates (46), in the inflamed mucosa of patients with ulcerative colitis (UC) (3), and in animal models of colitis (26,37,60). The increased NO synthase (NOS) activity was identified predominantly as the inducible form of NOS (iNOS) (23). Whereas the two constitutive isoforms, neuronal (nNOS) and endothelial-derived (eNOS), modulate several aspects of intestinal physiology (6, 53), their contribution to the inflammatory response has received less attention.Despite considerable evidence that iNOS-derived NO contributes to tissue destruction in colitis and other inflammatory states (27), conflicting results have been obtained by using pharmacological inhibitors of NOS in animal models of IBD. Several studies have found that the nonspecific NOS inhibitor N G -nitro-L-arginine methyl ester reduced intestinal inflammation (17, 37, 45); other studies found little benefit (20) o...

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Section: Discussionmentioning

confidence: 61%

mentioning

confidence: 99%

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Vallance¹,

Dijkstra²,

Qiu³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Previous studies have consistently found that the loss of iNOS causes reduced severity of DSS-induced colitis. 13,35,36 However, studies that involve the use of iNOS inhibitors have generated mixed information, with the inconsistencies largely stemming from the narrow window of selectivity and specificity toward iNOS of these inhibitors. 14,15 Exogenous NO-donors stimulate electrolyte secretion in guinea pig mucosa, but with the role of endogenous NO largely undetermined.…”

Section: Inhibition Of Cftr and Inos Activity Attenuates Diarrhea In mentioning

confidence: 99%

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative Colitis

Arora

Sinha

Zhang

et al. 2015

The American Journal of Pathology

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Ulcerative colitis (UC) belongs to inflammatory bowel disorders, a group of gastrointestinal disorders that can produce serious recurring diarrhea in affected patients. The mechanism for UC-and inflammatory bowel disorder-associated diarrhea is not well understood. The cystic fibrosis transmembraneconductance regulator (CFTR) chloride channel plays an important role in fluid and water transport across the intestinal mucosa. CFTR channel function is regulated in a compartmentalized manner through the formation of CFTR-containing macromolecular complexes at the plasma membrane. In this study, we demonstrate the involvement of a novel macromolecular signaling pathway that causes diarrhea in UC. We found that a nitric oxide-producing enzyme, inducible nitric oxide synthase (iNOS), is overexpressed under the plasma membrane and generates compartmentalized cGMP in gut epithelia in UC. The scaffolding protein Na þ /H þ exchanger regulatory factor 2 (NHERF2) bridges iNOS with CFTR, forming CFTR-NHERF2-iNOS macromolecular complexes that potentiate CFTR channel function via the nitric oxide-cGMP pathway under inflammatory conditions both in vitro and in vivo. Potential disruption of these complexes in Nherf2 À/À mice may render them more resistant to CFTR-mediated secretory diarrhea than Nherf2 þ/þ mice in murine colitis models. Our study provides insight into the mechanism of pathophysiologic occurrence of diarrhea in UC and suggests that targeting CFTR and CFTR-containing macromolecular complexes will ameliorate diarrheal symptoms and improve conditions associated with inflammatory bowel disorders. (Am J Pathol 2015 http://dx

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“…To induce colitis, 200 mg/kg TNBS (Sigma-Aldrich) dissolved in 30% ethanol was administered intrarectally to lightly anesthetized (ketamine/ xylazine) mice via a catheter (20). Control mice received 30% ethanol.…”

Section: Tnbs-induced Colitismentioning

confidence: 99%

Points of Control Exerted along the Macrophage-Endothelial Cell-Polymorphonuclear Neutrophil Axis by PECAM-1 in the Innate Immune Response of Acute Colonic Inflammation

Sugimoto

Tao

Yang

et al. 2008

The Journal of Immunology

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PECAM-1 is expressed on endothelial cells and leukocytes. Its extracellular domain has been implicated in leukocyte diapedesis. In this study, we used PECAM-1−/− mice and relevant cells derived from them to assess the role of PECAM-1 in an experimental model of acute colonic inflammation with a predominant innate immune response, i.e., 2,4,6-trinitrobenzine sulfonic acid (TNBS). Using chimeric approaches, we addressed the points of control exerted by PECAM-1 along the macrophage-endothelial cell-polymorphonuclear neutrophil (PMN) axis. In vivo, TNBS-induced colitis was ameliorated in PECAM-1−/− mice, an event attributed to PECAM-1 on hematopoietic cells rather than to PECAM-1 on endothelial cells. The in vivo innate immune response was mimicked in vitro by using a construct of the vascular-interstitial interface, i.e., PMN transendothelial migration was induced by colonic lavage fluid (CLF) from TNBS mice or macrophages (MΦ) challenged with CLF. Using the construct, we confirmed that endothelial cell PECAM-1 does not play a role in PMN transendothelial migration. Although MΦ activation (NF-κB nuclear binding) and function (keratinocyte-derived chemokine production) induced by CLF was diminished in PECAM-1−/− MΦ, this did not affect their ability to promote PMN transendothelial migration. By contrast, PECAM-1−/− PMN did not adhere to or migrate across endothelial cell monolayers in response to CLF. Further, as compared with PECAM-1+/+ PMN, PECAM-1−/− PMN were less effective in orientating their CXCR2 receptors (polarization) in the direction of a chemotactic gradient. Collectively, our findings indicate that PECAM-1 modulation of PMN function (at a step before diapedesis) most likely contributes to the inflammation in a colitis model with a strong innate immune component.

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Role of inducible nitric oxide synthase in trinitrobenzene sulphonic acid induced colitis in mice

Cited by 126 publications

References 42 publications

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative Colitis

Points of Control Exerted along the Macrophage-Endothelial Cell-Polymorphonuclear Neutrophil Axis by PECAM-1 in the Innate Immune Response of Acute Colonic Inflammation

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