Update in pathogenesis and prospective in treatment of necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is among the most common and devastating diseases in neonates and, despite the significant advances in neonatal clinical and basic science investigations, its etiology is largely understood, specific treatment strategies are lacking, and morbidity and mortality remain high. Improvements in the understanding of pathogenesis of NEC may have therapeutic consequences. Pharmacologic inhibition of toll-like receptor signaling, the use of novel nutritional strategies, and microflora modulation may represent novel promising approaches to the prevention and treatment of NEC. This review, starting from the recent acquisitions in the pathogenic mechanisms of NEC, focuses on current and possible therapeutic perspectives.

Figure 1

The role of TLR4 in epithelium injury and repair mechanisms. Many factors typical of prenatal birth such as infections, inappropriate enteral nutrition, antibiotics use, microcirculatory dysfunction, and hypoxia induce epithelial injury. Hyperactivation of TLR4 signaling affects the healing process favoring pathological bacteria translocation across epithelial barrier.

Figure 2

Possible therapeutic interventions on molecular mechanism inducing necrotizing enterocolitis. (1) TLR4 induces proinflammatory cytokine via the NFκB pathway. (2) Proinflammatory cytokine promotes epithelial injury. (3) NFκB signal increases expression of TLR4. (4) TLR signal may be induced directly by bacterial products (i.e., LPS), HMGB1, and via NFκB by PAF activated receptor (PAF-R). (5) TRL4 is autoregulated by hsp70 proteins. (6) PPAR, blocking NFκB pathway, is a potent inhibitor of TRL4 signal. (7) Nitric oxide (NO), produced by NO-synthetase, protects epithelium from injury. Evidenced in black-block we have reported molecules that may have potential therapeutic role in necrotizing enterocolitis, interfering with TRL4 signaling (i.e., inhibition of HMGB1 by 2-P-glycyrrhizate; induction of PPAR by probiotics, fatty acids, and EGF; PAF hydrolysis by PAF-acetylhydrolase; induction of Hsp70 by Celastrol; blocking proinflammatory cytokine by monoclonal antibodies), or maintaining epithelial barrier integrity (i.e., fatty acids, EGF, zinc, and glutamine) or protecting against epithelial injury (i.e., NO, probiotics). Please note that this is a simplified cartoon; thus reported molecules may play many other functions at mucosal and systemic level that may interfere with the development of necrotizing enterocolitis (see the text). Direct effects of TLR4 on epithelium are reported in Figure 1.