Paradoxical roles of different nitric oxide synthase isoforms in colonic injury

Abstract

Nitric oxide (NO) is a free radical that is largely produced by three isoforms of NO synthase (NOS): neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). NO regulates numerous processes in the gastrointestinal tract; however, the overall role that NO plays in intestinal inflammation is unclear. NO is upregulated in both ulcerative colitis and Crohn's disease as well as in animal models of colitis. There have been conflicting reports on whether NO protects or exacerbates injury in colitis or is simply a marker of inflammation. To determine whether the site, timing, and level of NO production modulate the effect on the inflammatory responses, the dextran sodium sulfate model of colitis was assessed in murine lines rendered deficient in iNOS, nNOS, eNOS, or e/nNOS by targeted gene disruption. The loss of nNOS resulted in more severe disease and increased mortality, whereas the loss of eNOS or iNOS was protective. Furthermore, concomitant loss of eNOS reversed the susceptibility found in nNOS-/- mice. Deficiencies in specific NOS isoforms led to distinctive alterations of inflammatory responses, including changes in leukocyte recruitment and alterations in colonic lymphocyte populations. The present studies indicate that NO produced by individual NOS isoforms plays different roles in modulating an inflammatory process.

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

“…The protective mechanisms exerted by nNOS in that study were not defined, and in contrast, our study indicates that nNOS does not play a significant role in the generation of the inflammatory response induced by TNBS in the mouse. The divergent results between this study and the work by Beck et al (2) likely reflect the different colitis models used.…”

“…These observations suggest colitis affects both NO-based neurotransmission and gastrointestinal motility (39,53). Beck et al (2) using the DSS colitis model, recently identified nNOS as playing an important role in that model, with the loss of nNOS expression resulting in more severe disease and increased mortality. The protective mechanisms exerted by nNOS in that study were not defined, and in contrast, our study indicates that nNOS does not play a significant role in the generation of the inflammatory response induced by TNBS in the mouse.…”

“…Beck et al (2) found that mice deficient in eNOS or iNOS suffered less tissue damage and inflammation than wild-type mice during DSS- induced colitis. In contrast, Sasaki et al, (48) showed that eNOS was protective using the same model.…”

“…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).…”

Altered cGMP Dynamics at the Plasma Membrane Contribute to Diarrhea in Ulcerative 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. 37 A study documented the curative effects of iNOS inhibition with the use of L-NIL on smoke-induced pulmonary emphysema and reversal of the deterioration associated with emphysema in the presence of the drug.…”