Article

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

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 07/2009; 180(5):396-406. DOI: 10.1164/rccm.200809-1483OC
Source: PubMed

ABSTRACT

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.
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.
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.
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.
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.

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    • "Maintenance of airway homeostasis provoked by lung injuries can be another explanation. A recent report demonstrating that cigarette smoke induced airspace enlargement and alveolar epithelial cell death was potentiated by conditional deletion of pulmonary epithelial NP1 in the lungs of adult animals led us to hypothesize that Sema3A might be an essential mediator of distal airspace homeostasis (29). As well known, structural damages are frequently encountered in the lung of asthmatics (30). "
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    • "The role of class 3 Sema has also been explored in other lung disease models associated with distal airspace enlargement. Mice with lung-specific deletion of epithelial Nrp1 are more susceptible to cigarette smoke-induced lung injury [24]. Genetic deletion of epithelial Nrp1 in either postnatal or adult lungs resulted in a small increase in airspace size, but when challenged with cigarette smoke, both airspace enlargement and apoptosis of type I and type II alveolar epithelial cells were significantly enhanced in conditionally Nrp1-deficient adult mice. "
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    • "In the present study, we also observed profound alveolar cell apoptosis. This is in keeping with a number of other reports based on the examination of human emphysema tissue or various animal models (4,17,20,21,23,32,57). One potential limitation of our study results is that 12-wk-old Smad3 / mice showed a less pronounced alveolar cell apoptosis than 8-or 20-wk-old Smad3 / mice. "
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