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The Fas System Confers Protection against Alveolar Disruption in Hyperoxia-Exposed Newborn Mice

¹ Department of Pathology, Women and Infants Hospital, Providence, Rhode Island; ² Division of Pediatric Surgery, Rhode Island Hospital, Providence, Rhode Island; and Departments of ³ Pathology and Laboratory Medicine, ⁴ Pediatrics, and ⁵ Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island

Correspondence and requests for reprints should be addressed to Monique E. De Paepe, M.D., Women and Infants Hospital, Dept. of Pathology, 101 Dudley Street, Providence, RI 02905. E-mail: mdepaepe{at}wihri.org

The functional significance of the Fas/Fas-ligand (FasL) system in hyperoxia-induced lung injury and alveolar disruption in newborn lungs in vivo remains undetermined. To assess the role of the Fas/FasL system, we compared the effects of hyperoxia (95% O₂ from birth to Postnatal Day [P]7) in Fas-deficient lpr mice and wild-type mice. Alveolar disruption was more severe in hyperoxic lpr mice than in wild-type mice. In addition, a transient alveolarization defect was noted in normoxic lpr mice. Hyperoxia induced marked up-regulation of pulmonary Fas expression in wild-type mice, as well as elevated mRNA levels of pro-apoptotic Bax, Bad, and Bak. Pulmonary apoptotic activity was similar in hyperoxic wild-type and lpr mice. In contrast, lung growth and proliferation, assessed by stereologic volumetry and Ki67 proliferation studies, were significantly higher in hyperoxic wild-type mice compared with lpr mice, suggesting the Fas/FasL system has a pro-proliferative role in hyperoxic conditions. Levels of the prosurvival MAPkinase, pERK1/2, were significantly higher in hyperoxic wild-type mice compared with lpr mice, while pAkt levels were similar. These data suggest that the primary role of the Fas/FasL system in hyperoxic newborn lungs is pro-proliferative, rather than pro-apoptotic, and likely mediated through a Fas-ERK1/2 pathway. Fas-induced proliferation and lung growth in hyperoxic newborn lungs may counteract, in part, the detrimental effects of apoptosis mediated by non-Fas pathways, such as pro-apoptotic Bax/Bcl-2 family members. The capacity of the Fas/FasL signaling pathway to mediate protective rather than destructive functions in hyperoxic newborn lungs highlights the versatility of this complex pathway.

Key Words: CD95 • oxygen toxicity • apoptosis • programmed cell death • bronchopulmonary dysplasia

CLINICAL RELEVANCE This study suggests that the main function of the Fas/FasL signaling system in hyperoxic lungs is pro-proliferative, rather than pro-apoptotic. These data may prompt reappraisal of the functions of the Fas system in the lung.