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Nuclear Factor-B Activation in Neonatal Mouse Lung Protects against Lipopolysaccharide-induced Inflammation

¹ Department of Pediatrics, Stanford University School of Medicine, Stanford, California; and ² Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Dr. Marlene Rabinovitch, M.D., The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, CCSR Bldg, Room 2245a, 269 Campus Drive, Stanford, CA 94305-5162. E-mail: marlener{at}stanford.edu

Rationale: Injurious agents often cause less severe injury in neonates as compared with adults.

Objective: We hypothesized that maturational differences in lung inflammation induced by lipopolysaccharide (LPS) may be related to the nature of the nuclear factor (NF)-B complex activated, and the profile of target genes expressed.

Methods: Neonatal and adult mice were injected with intraperitoneal LPS. Lung inflammation was assessed by histology, and apoptosis was determined by TUNEL (terminal deoxynucleotidyl transferase UTP nick-end labeling). The expression of candidate inflammatory and apoptotic mediators was evaluated by quantitative real-time polymerase chain reaction and Western immunoblot.

Results: Neonates demonstrated reduced inflammation and apoptosis, 24 hours after LPS exposure, as compared with adults. This difference was associated with persistent activation of NF-B p65p50 heterodimers in the neonates in contrast to early, transient activation of p65p50 followed by sustained activation of p50p50 in the adults. Adults had increased expression of a panel of inflammatory and proapoptotic genes, and repression of antiapoptotic targets, whereas no significant changes in these mediators were observed in the neonates. Inhibition of NF-B activity in the neonates decreased apoptosis, but heightened inflammation, with increased expression of the same inflammatory genes elevated in the adults. In contrast, inhibition of NF-B in the adults resulted in partial suppression of the inflammatory response.

Conclusions: NF-B activation in the neonatal lung is antiinflammatory, protecting against LPS-mediated lung inflammation by repressing similar inflammatory genes induced in the adult.

Key Words: acute lung injury • apoptosis • gene expression regulation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Pediatric patients demonstrate decreased lung injury in response to injurious agents as compared with adults. However, the molecular mechanisms responsible for this protection are not well defined. What This Study Adds to the Field We demonstrate developmental differences in nuclear factor-B activation in a murine model of LPS-induced acute lung injury, producing antiinflammatory effects in neonatal mice and proinflammatory effects in adult mice.

 

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