Developmental delay in hypoxia-induced HO-1 expression predisposes to gut injury.
OBJECTIVE
Necrotizing enterocolitis (NEC) is an often fatal disease that affects 5-8% of preterm newborn infants but does not occur in older infants and children. As carbon monoxide (CO) may exert protective effects against NEC, we assessed patterns of intestinal injury and investigated the expression of the CO-producing enzyme heme oxygenase-1 (HO-1) in mature and immature rat guts in response to hypercapnia and reoxygenation (H/R).


METHODS
Gut barrier failure (increased permeability for dextran) was assessed in immature (newborn rats) and mature rats (weanling rats) subjected to H/R. Their guts were assayed for apoptosis (caspase-3 activity), expression of inducible NO synthase (iNOS) and HO-1 [quantitative polymerase chain reaction (PCR) and immunoblot]. The role of HO-1 was investigated in experiments involving HO-1 induction by hemin or HO-1 inhibition by tin protoporphyrin IX.


RESULTS
In the mature gut, H/R induced the expression of intestinal HO-1 within 48 h, whereas in the immature gut HO-1 up-regulation was delayed by 48 h. Immature, but not mature, rats exhibited gut barrier failure, apoptosis and increased iNOS expression upon H/R. After the induction of HO-1 by hemin, gut barrier failure and apoptosis were abrogated in the immature gut, while the inhibition of HO-1 by tin protoporphyrin IX significantly aggravated gut injury.


CONCLUSIONS
These experiments point to an immaturity-dependent lag in HO-1 expression upon H/R in the immature gut and link low HO-1 to gut barrier failure induced by H/R in a non-infectious dam-fed animal model of gut injury.
Department of Neonatology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Judith
J
Pietzcker
Christof
C
Kluthea
Konrad
K
Klinghammer
Christoph
C
Bührer
Bernd
B
Rüstow
Florian
F
Guthmann
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002463:Cell Membrane Permeability; D002658:Developmental Disabilities; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D006427:Hemin / Q000494:pharmacology; D000860:Hypoxia; D007410:Intestinal Diseases / Q000209:etiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000254:growth & development*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D006427:Hemin; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D053148:Caspase 3