Proliferative response in necrotising enterocolitis is insufficient to prevent disease progression

Abstract

Necrotising enterocolitis (NEC) is characterised by severe mucosal loss and therefore gastrointestinal (GI) cell proliferation is essential for survival, epithelial repair and recovery of function. Trefoil peptides play a key role in epithelial restitution and repair, and we previously reported a down-regulation of these peptides in NEC. Oral administration of epidermal growth factor has a protective effect in a rat model of colitis. These observations raised the question of a link between the pathogenesis of NEC and decreased mucosal cell proliferation. This study investigates the pattern of mucosal cell proliferation in the GI tract of fetuses, normal neonatal controls, infants with NEC and those recovering from NEC. Parents of neonates up to 44 weeks' gestation undergoing laparotomy and bowel resection were approached for consent. Bowel samples from resection specimens, and GI tract extractions from products of conception at termination of pregnancy, were fixed in formalin and then embedded in paraffin blocks. Patterns of small and large bowel mucosal proliferation were assessed by immunohistochemical staining for Ki67. Seventeen foetal and 58 postnatal bowel samples [34 with NEC (22 acute, 12 recovery) and 24 controls] were analysed. The pattern of proliferation seen in the fetus and normal neonate was identical to that in mature bowel. In NEC severe mucosal necrosis was observed, but in viable crypts remaining, there was crypt hyperplasia and a relative increase in the proportion of cells staining positive for Ki67. In those patients recovering from NEC the pattern of proliferation was returning towards the normal range. In those patients with post-NEC strictures the recovery of normal bowel morphology was delayed. In NEC there is massive loss of potential proliferative tissue. The remaining viable tissue shows an increase in proliferative activity in the small and large bowel. Failure of rapid regeneration of functional mucosa may therefore be related to an inability of increased proliferative activity to match the losses from the surface; alternatively there may be rapid production of immature, short-lived cells. This study shows that the proliferative response, although present, is insufficient to rapidly reverse the mucosal insult observed in NEC.

Neonatal necrotizing enterocolitis rat model attenuated by a remote ischemic preconditioning in the pregnant

“…Vieten et al 16 observed that in NEC there is a deficiency of the proliferative activity, incapacitating the neutralization of the rapid epithelium destruction, also associated with the intestinal immaturity of the preterm infants. Corroborating these findings, it was observed a deficiency of the proliferative activity in the intestinal mucosa of the H/R group.…”

“…The inability of mucosal regeneration in preterm infants may be related to the deficiency of the expression of the peptide trefoil factor, present in mucus and released together with mucin by goblet cells, contributing to the etiopathogenesis of NEC. Trefoil factor plays an important role in the intestinal epithelium, participating in its protection, its restitution and its regeneration 16 .…”

“…The villi size was determined by measuring from the crypt base to the villus surface, based on the histological description of the mucosal components. The counting was performed on the labeled slides, analyzing 5 to 10 crypts in each slide, in a field of magnification of 20x, modified from Vieten et al 16 . …”

“…The inability of mucosal regeneration in preterm infants may be related to the deficiency of the expression of the peptide trefoil factor, present in mucus and released together with mucin by goblet cells, contributing to the etiopathogenesis of NEC. Trefoil factor plays an important role in the intestinal epithelium, participating in its protection, its restitution and its regeneration 16 .In the physiological process of intestinal mucosa renewal, in addition to cell proliferation, the process of apoptosis of epithelial cells also occurs 22 . Jilling et al 22 evaluated apoptosis in Neonatal necrotizing enterocolitis rat model attenuated by a remote ischemic preconditioning in the pregnant Gomes ROL et al Acta Cir Bras.…”

Necrotizing enterocolitis: A multifactorial disease with no cure

“…Intestinal trefoil factor is developmentally regulated and deficient in the premature neonate [20] . Recent studies demonstrated a lack of trefoil factor expression in response to NEC in the premature gut [53] and an insufficient proliferative response to reverse the mucosal insult observed in NEC [54] . Thus, impaired restitution of the mucosa may contribute to the cascade of bowel necrosis and generalized sepsis characteristic of NEC.…”