Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: evidence from an animal model

Abstract

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants. In tissue samples of NEC, we identified numerous macrophages and a few neutrophils but not many lymphocytes. We hypothesized that these pathoanatomic characteristics of NEC represent a common tissue injury response of the gastrointestinal tract to a variety of insults at a specific stage of gut development. To evaluate developmental changes in mucosal inflammatory response, we used trinitrobenzene sulfonic acid (TNBS)-induced inflammation as a nonspecific insult and compared mucosal injury in newborn vs. adult mice. Enterocolitis was induced in 10-day-old pups and adult mice (n = 25 animals per group) by administering TNBS by gavage and enema. Leukocyte populations were enumerated in human NEC and in murine TNBS-enterocolitis using quantitative immunofluorescence. Chemokine expression was measured using quantitative polymerase chain reaction, immunoblots, and immunohistochemistry. Macrophage recruitment was investigated ex vivo using intestinal tissue-conditioned media and bone marrow-derived macrophages in a microchemotaxis assay. Similar to human NEC, TNBS enterocolitis in pups was marked by a macrophage-rich leukocyte infiltrate in affected tissue. In contrast, TNBS-enterocolitis in adult mice was associated with pleomorphic leukocyte infiltrates. Macrophage precursors were recruited to murine neonatal gastrointestinal tract by the chemokine CXCL5, a known chemoattractant for myeloid cells. We also demonstrated increased expression of CXCL5 in surgically resected tissue samples of human NEC, indicating that a similar pathway was active in NEC. We concluded that gut mucosal injury in the murine neonate is marked by a macrophage-rich leukocyte infiltrate, which contrasts with the pleomorphic leukocyte infiltrates in adult mice. In murine neonatal enterocolitis, macrophages were recruited to the inflamed gut mucosa by the chemokine CXCL5, indicating that CXCL5 and its cognate receptor CXCR2 merit further investigation as potential therapeutic targets in NEC.

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

“…This corresponds to other studies showing an increased number of inflammatory monocytes in the small bowel of mice submitted to the NEC protocol as well as in human NEC samples (31,32). Therefore, it has been speculated that infiltrating monocytes/macrophages contribute to NEC through exaggerating the neonatal immune response by releasing proinflammatory cyto-and chemokines (33,34).…”

Smad7 inhibits autocrine expression of TGF-β2in intestinal epithelial cells in baboon necrotizing enterocolitis

“…This reduction in TGF-␤ 2 expression is a unique feature of NEC and contrasts with inflammatory conditions of the gastrointestinal tract in older children/ adults such as ulcerative colitis and Crohn's disease (11,36), celiac disease (29), and shigellosis (39), which are associated with increased TGF-␤ expression. In a recent study, we showed that the inflammatory changes in NEC may be related not to specific etiological factors but may instead represent a generic tissue injury response of the developing gastrointestinal tract (35). We induced nonspecific intestinal injury in neonatal and adult mice by administering 2,4,6-trinitrobenzene sulfonic acid (TNBS); TNBS-enterocolitis increased TGF-␤ 2 expression in adult mice but inhib- ited its expression in pups (unpublished observation, MohanKumar K, Kaza N, Jagadeeswaran R, Garzon SA, Bansal A, Kurundkar AR, Namachivayam K, Remon JI, Bandepalli R, Feng X, Weitkamp J-H, Maheshwari A.).…”

Amniotic fluid-borne hepatocyte growth factor protects rat pups against experimental necrotizing enterocolitis

“…To investigate whether enteral administration of amniotic fluid affected the inflammatory response during NEC, we used RT-qPCR to measure mRNA expression of selected inflammatory mediators associated with NEC (n ϭ 5 animals/group) (24). As shown in Fig.…”