Xanthine oxidase decreases production of gut wall nitric oxide.

Multiorgan failure is often the lethal outcome of intratracheal aspiration of acidic gastric juice. The pathogenesis of multiorgan failure may involve a systemic imbalance between pro-inflammatory and anti-inflammatory factors. In an anesthetized rat model, intratracheal instillation of HCl elicited intestinal inflammation which was exaggerated by xanthine oxidase (XO) and attenuated by nitric oxide (NO). We hypothesized that XO may mediate injury in part by suppression of NO formation. Therefore, we measured intestinal tissue concentrations of the stable NO oxidative metabolites (NO2- and NO3-) following intratracheal (IT) instillation of NaCl or HCl alone or in combination with interventions aimed at increasing or decreasing XO activity. Compared with IT NaCl (control treatment) jejunal tissue NO2- and NO2- + NO3- concentrations were increased by allopurinol pretreatment, which inhibits XO, and were decreased by systemically administered XO, as well as by IT HCl. The decreased NO2- and NO2- + NO3- concentrations found following IT HCl were completely reversed by either allopurinol or by systemically administered L-arginine (the precursor of NO). We conclude that manipulation of the pro-inflammatory XO system has a reciprocal effect on the intestinal anti-inflammatory NO system in either the undamaged or the endobronchially acidified lung model.

Nitric oxide attenuates and xanthine oxidase exaggerates lung damage-induced gut injury.

Aspirated gastric contents can evoke multiorgan failure. We hypothesized that secondary intestinal epithelial dysfunction after lung damage would be mediated by xanthine oxidase (XO) and antagonized by endogenous gut nitric oxide (NO). Isosmotic saline or HCl solutions were instilled intratracheally in anesthetized rats, and intestinal injury was assessed 190 min later by measuring the blood-to-lumen clearance of 51Cr-labeled EDTA (51Cr-EDTA clearance) and gut wall neutrophil population density. Intratracheal HCl increased 51Cr-EDTA clearance, and this transepithelial leak was attenuated by either systemic L-arginine or intraluminal NO and by chronic dietary pretreatment with allopurinol or sodium tungstate. Conversely, lung damage-induced gut leak was exaggerated by NO synthase inhibition or intravenous XO administration. Intratracheal HCl also increased intestinal wall neutrophil density and myeloperoxide activity. We conclude that two enzymatic systems involved in remote gut barrier dysfunction after endobronchial acidification are XO as mediator and NO synthase as antagonist.

Nitric oxide decreases lung injury after intestinal ischemia.

After injury to a primary organ, mediators are released into the circulation and may initiate inflammation of remote organs. We hypothesized that the local production of nitric oxide (NO) may act to limit the spread of inflammation to secondarily targeted organs. In anesthetized rats, 30 min of intestinal ischemia followed by 2 h of reperfusion (I/R) did not increase lung albumin leak. However, after treatment with NG-nitro-L-arginine methyl ester (L-NAME), intestinal I/R led to increased lung leak, suggesting a protective effect of endogenous NO. The site of action of NO appeared to be the lung and not the gut because 1) after treatment with L-NAME, local delivery of NO to the lung by inhalation abolished the increase in intestinal I/R-induced lung leak; 2) L-NAME had no effect on epithelial permeability (51Cr-labeled EDTA clearance) of reperfused small bowel; and 3) after treatment with L-NAME, local delivery of NO to the gut by luminal perfusion did not improve epithelial permeability of reperfused intestines. Furthermore, L-NAME increased, and inhaled NO decreased, the density of lung neutrophils in rats subjected to intestinal I/R, and treatment with the selectin antagonist fucoidan abolished L-NAME-induced lung leak in rats subjected to intestinal I/R. We conclude that endogenous lung NO limits secondary lung injury after intestinal I/R by decreasing pulmonary neutrophil retention.