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Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

¹ Divisions of Pulmonary and Critical Care Medicine and ³ Cardiopulmonary Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; and ² Division of Toxicology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Patrice M. Becker, M.D., Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Room 4B74, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: pbecker1{at}jhmi.edu

Rationale: Cigarette smoke (CS) exposure is an important risk factor for chronic obstructive pulmonary disease; however, not all smokers develop disease, suggesting that other factors influence disease development.

Objectives: We sought to determine whether neuropilin-1 (Nrp1), an integral component of receptor complexes mediating alveolar septation and vascular development, was involved in maintenance of normal alveolar structure, and/or altered susceptibility to the effects of CS.

Methods: Transgenic mice were generated to achieve inducible lung-specific deletion of epithelial Nrp1. We determined whether conditional Nrp1 deletion altered airspace size, then compared the effects of chronic CS or filtered air exposure on airspace size, inflammation, and the balance between cell death and proliferation in conditionally Nrp1–deficient adult mice and littermate controls. Finally, we evaluated the effects of Nrp1 silencing on cell death after acute exposure of A549 cells to cigarette smoke extract or short chain ceramides.

Measurements and Main Results: Genetic deletion of epithelial Nrp1 in either postnatal or adult lungs resulted in a small increase in airspace size. More notably, both airspace enlargement and apoptosis of type I and type II alveolar epithelial cells were significantly enhanced following chronic CS exposure in conditionally Nrp1-deficient adult mice. Silencing of Nrp1 in A549 cells did not alter cell survival after vehicle treatment but significantly augmented apoptosis after exposure to cigarette smoke extract or ceramide.

Conclusions: These data support a role for epithelial Nrp1 in the maintenance of normal alveolar structure and suggest that dysregulation of Nrp1 expression may promote epithelial cell death in response to CS exposure, thereby enhancing emphysema development.

Key Words: chronic obstructive pulmonary disease • genetically modified mice • apoptosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject An imbalance between pathways mediating alveolar cell proliferation and death may lead to airspace destruction and the generation of emphysema. Disruption of growth factor signaling cascades critical for lung development and postnatal homeostasis may promote the development of emphysema in response to cigarette smoke exposure. What This Study Adds to the Field This study suggests that loss of pulmonary epithelial Nrp1 enhances apoptosis of Type I and II epithelial cells and airspace enlargement in response to chronic cigarette smoke exposure.