title: Heme oxygenase-1 deficiency promotes the development of necrotizing enterocolitis-like intestinal injury in a newborn mouse model.
abstract: Necrotizing enterocolitis (NEC) is typified by mucosal destruction, which subsequently can lead to intestinal necrosis. Prematurity, enteral feeding, and bacterial colonization are the main risk factors and, combined with other stressors, can cause increased intestinal permeability, injury, and an exaggerated inflammatory response. Heme oxygenase-1 (HO-1) mediates intestinal protection due to anti-inflammatory, antioxidative, and antiapoptotic effects of its products carbon monoxide, biliverdin, and bilirubin. This study investigates a possible role of HO-1 in the pathogenesis of NEC using a newborn mouse model. We induced NEC-like intestinal injury in 7-day-old HO-1 heterozygous (HO-1 Het, Hmox1(+/-)) and wild-type (Wt, Hmox1(+/+)) mice by gavage feeding and hypoxic exposures. Control (Con) pups of both genotypes were dam-fed. Intestines of HO-1 Het Con pups appeared predisposed to injury, with higher histological damage scores, more TUNEL-positive cells, and a significant reduction in muscularis externa thickness compared with Wt Con pups. The increase in HO activity after HO-1 induction by the substrate heme or by hypoxic stress was significantly impaired in HO-1 Het pups. After induction of intestinal injury, HO-1 Het pups displayed significantly higher NEC incidence (78 vs. 43%), mortality (83 vs. 54%), and median scores (2.5 vs. 1.5) than Wt NEC pups. PCR array analyses revealed increased expressions of IL-1β, P-selectin, matrix metallopeptidase 2, collagen type XVIII-α1, serpine 1, and others in NEC-induced HO-1 Het ileal and jejunal tissues. We conclude that a partial HO-1 deficiency promotes experimental NEC-like intestinal injury, possibly mediated by exaggerated inflammation and disruption in tissue repair.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schulz
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wong
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.forename: Flora
authors.initials: F
authors.lastname: Kalish
authors.forename: Karen M
authors.initials: KM
authors.lastname: Chisholm
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Hendrik J
authors.initials: HJ
authors.lastname: Vreman
authors.forename: Karl G
authors.initials: KG
authors.lastname: Sylvester
authors.forename: David K
authors.initials: DK
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D043170:Collagen Type XVIII / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006418:Heme / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000860:Hypoxia; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D015601:Injury Severity Score; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007583:Jejunum / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000473:pathology; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D043170:Collagen Type XVIII; D053583:Interleukin-1beta; D008565:Membrane Proteins; D019007:P-Selectin; D006418:Heme; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: apoptosis; bilirubin/biliverdin; carbon monoxide; intestinal inflammation; necrotizing enterocolitis