ENTERIC DEFENSIN EXPRESSION IN NECROTIZING ENTEROCOLITIS

Immaturity of local innate defenses has been suggested as a factor inv olved in the pathophysiology of necrotizing enterocolitis (NEC). The m RNA of enteric human defensins 5 (HD5) and 6 (HD6), antibiotic peptide s expressed in Paneth cells of the small intestine, have significantly lower levels of expression in fetal life compared with the term newbo rn and adult. In the current study, intracellular HD5 was demonstrated by immunohistochemistry at 24 wk of gestation, but at low levels, con sistent with findings at the mRNA level. These data suggest that the l ow level enteric defensin expression, characteristic of normal intesti nal development, may contribute to the immaturity of local defense, wh ich predisposes the premature infant to NEC. To test if levels of defe nsin expression are altered in NEC, specimens from six cases of patien ts with NEC and five control subjects (four patients with atresia and one with meconium ileus) were analyzed to determine HD5 and HD6 mRNA l evels by in situ hybridization. Compared with the control group, the l evel of enteric defensin expression per Paneth cell assessed by image analysis was increased 3-fold in cases of NEC (p = 0.02, analysis of v ariance and covariance). In addition, the number of Paneth cells was i ncreased 2-fold in the small intestinal crypts of NEC specimens compar ed with those of control subjects (p < 0.01, covariance analysis). In healthy tissue, peptide levels within Paneth cells paralleled mRNA lev els through development. In tissue from infants with NEC, the steady s tate level of intracellular peptide was not increased in conjunction w ith the observed rise in defensin mRNA. A straightforward interpretati on of this finding is that HD5 is actively secreted in this setting an d the Paneth cells maintain a constant steady state level of intracell ular peptide, but the possibility of translational regulation of pepti de expression is also consistent with these data. The associations bet ween NEC and enteric defensin expression reported here offer support f or future studies to address the role of these endogenous host defense factors in the pathophysiology of this disease.