title: 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.
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of Illinois at Chicago, 840 S Wood St., Chicago, IL 60612, USA.
authors.forename: Krishnan
authors.initials: K
authors.lastname: MohanKumar
authors.forename: Niroop
authors.initials: N
authors.lastname: Kaza
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Jagadeeswaran
authors.forename: Steven A
authors.initials: SA
authors.lastname: Garzon
authors.forename: Anchal
authors.initials: A
authors.lastname: Bansal
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kurundkar
authors.forename: Kopperuncholan
authors.initials: K
authors.lastname: Namachivayam
authors.forename: Juan I
authors.initials: JI
authors.lastname: Remon
authors.forename: C Rekha
authors.initials: CR
authors.lastname: Bandepalli
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.forename: Joern-Hendrik
authors.initials: JH
authors.lastname: Weitkamp
authors.forename: Akhil
authors.initials: A
authors.lastname: Maheshwari
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D054365:Chemokine CXCL5 / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D058645:Denaturing Gradient Gel Electrophoresis; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007234:Infant, Premature; D007249:Inflammation / Q000473:pathology; D007410:Intestinal Diseases / Q000139:chemically induced / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D020556:Neutrophil Infiltration / Q000502:physiology; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D054365:Chemokine CXCL5; D014302:Trinitrobenzenesulfonic Acid