Intestinal O2 Consumption in Necrotizing Enterocolitis: Role of Nitric Oxide

Abstract

ABSTRACT:We tested the hypothesis that inducible isoform of nitric oxide synthase (iNOS)-derived nitric oxide (NO) inhibits oxygen consumption (VO 2 ) in human intestine resected for necrotizing enterocolitis (NEC). Each NEC resection specimen was divided into two sections based on histologic appearance: healthy or diseased. Intestine removed from infants for reasons other than NEC was used as control. The tissue injury score (0 -6, with 6 indicating complete necrosis) was 0.4 Ϯ 0.2 in control tissue, 1.2 Ϯ 0.4 in NEC-healthy tissue, and 4.6 Ϯ 0.5 in NEC-diseased tissue. Prominent iNOS staining was present in villus enterocytes in NEC-healthy tissue but not in the other tissue types. Intestinal VO 2 (per direct oximetry, in nM O 2 /min/g) was significantly greater in control tissue than in NEC-healthy or NEC-diseased tissues. Accumulation of NO into buffer bathing intestinal slices (in nM NO/L/g) was greater in NEC-healthy tissue than control or NEC-diseased tissues. The specific iNOS antagonist L-N -(1-iminoethyl)-lysine (L-NIL) reduced buffer NO concentration 76% and increased VO 2 by 90% in NEChealthy tissue; however, L-NIL had no effect on NO or VO 2 in control or NEC-diseased tissue. Addition of exogenous NO via S-nitroso-Nacetylpenicillamine depressed VO 2 in NEC-healthy and control tissues but not NEC-diseased tissue. A significant correlation was present between buffer NO concentration and VO 2 in NEC-healthy tissue. We conclude that iNOS-derived NO suppresses VO 2 in intestine resected for NEC that demonstrates a relatively normal histology on light microscopy. (Pediatr Res 59: 500-505, 2006) T he inducible isoform of nitric oxide synthase (iNOS) has been demonstrated in human intestine resected for NEC and hence implicated in disease pathogenesis (1,2). iNOSderived nitric oxide (NO) has also been proposed as relevant in the etiology of intestinal damage following hypotension (3), lipopolysaccharide administration (4), ischemia-reperfusion (5), sustained use of hyperalimentation (6), and inflammatory bowel disease (7). Many mechanisms have been proposed to explain the intestinal damage generated by iNOS-derived NO. NO can react with superoxide anion to form peroxynitrite, a highly cytotoxic radical; indeed, nitrotyrosine, the footprint of peroxynitrite, has been identified in intestine resected for inflammatory bowel disease or NEC (1,7). iNOS also activates proinflammatory cytokines and hence generates an inflammatory response, whereas iNOS-derived NO causes enterocyte apoptosis (7,8).Yet another putative mechanism by which NO might affect tissue viability is via its direct effect on cellular respiration. NO reversibly inactivates cytochrome c within the mitochondrial electron transport chain (9) and depresses tissue VO 2 in heart, kidney, and skeletal muscle tissues (10 -12). Accordingly, we hypothesized that iNOS-derived NO suppresses VO 2 in human preterm intestine resected for NEC. To test this hypothesis, intestinal VO 2 and NO production were measured under in vitro conditions in human intestine ...

Enteral Feeding Reduces Endothelial Nitric Oxide Synthase in the Caudal Intestinal Microvasculature of Preterm Piglets

“…On the other hand, the lack of a direct relationship indicates that additional stress factors have been involved (15,16). A direct association between NEC lesions and low eNOS expression was detected, similar to human NEC (33) where hypoxia is known to be a contributing factor (6). Therefore, we speculate that a low eNOS density increases the risk for NEC by increasing the hypoxia sensitivity of the intestine.…”

Enteral Feeding Interventions in the Prevention of Necrotizing Enterocolitis: A Systematic Review of Experimental and Clinical Studies

“…iNOS has been observed to be upregulated in the enterocytes of infants with NEC [181]. NO or reactive species derived from NO have been implied to suppress intestinal oxygen consumption [182] and inhibit enterocyte proliferation and migration [177,180]. Moreover, they increase gut barrier permeability by affecting TJ and gap junctions or inducing enterocyte apoptosis and necrosis [177,180,183].…”

Recent advances in understanding necrotizing enterocolitis

“…The pathogenesis of NEC is likely initiated by postnatal insults on the immature intestine in the presence of some of the previously mentioned risk factors. These factors lead to the initial epithelial injury, which causes an intestinal inflammatory response and release of inflammatory mediators 31 . Ford et al .…”