The role of nitric oxide in intestinal epithelial injury and restitution in neonatal necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal disease encountered in the premature infant. Although the inciting events leading to NEC remain elusive, various risk factors, including prematurity, hypoxemia, formula feeding, and intestinal ischemia, have been implicated in the pathogenesis of NEC. Data from our laboratory and others suggest that NEC evolves from disruption of the intestinal epithelial barrier, as a result of a combination of local and systemic insults. We postulate that nitric oxide (NO), an important second messenger and inflammatory mediator, plays a key role in intestinal barrier failure seen in NEC. Nitric oxide and its reactive nitrogen derivative, peroxynitrite, may affect gut barrier permeability by inducing enterocyte apoptosis (programmed cell death) and necrosis, or by altering tight junctions or gap junctions that normally play a key role in maintaining epithelial monolayer integrity. Intrinsic mechanisms that serve to restore monolayer integrity following epithelial injury include enterocyte proliferation, epithelial restitution via enterocyte migration, and re-establishment of cell contacts. This review focuses on the biology of NO and the mechanisms by which it promotes epithelial injury while concurrently disrupting the intrinsic repair mechanisms.

Figure 1. NO Production

Nitric oxide synthase (NOS) catalyzes the reaction between arginine and oxygen, with the consumption of 1.5 moles of NADPH per mole of NO produced. Citrulline and water are also produced during the reaction.

Figure 2. Effects of NO on the intestinal barrier

Perinatal insults and hypoxia lead to mucosal damage. NO and its reactive intermediary, peroxynitrite (ONOO⁻), are produced. This leads to a cascade of events, including apoptosis at the villus tip, bacterial translocation, and immunocyte activation. Activated immunocytes and inflamed enterocytes continue to produce cytokines and inflammatory mediators such as NO. Unchecked, this cycle will continue and lead to systemic sepsis, and can eventually lead to death in the most severe cases.