Pulmonary epithelial neuropilin-1 deletion enhances development of cigarette smoke-induced emphysema.
BACKGROUND
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.


OBJECTIVE
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.


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.
Le
Anne
A
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Zielinski
Rachel
R
He
Chaoxia
C
Crow
Michael T
MT
Biswal
Shyam
S
Tuder
Rubin M
RM
Becker
Patrice M
PM
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004646:Emphysema / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D017353:Gene Deletion; D051379:Mice; D008822:Mice, Transgenic; D039942:Neuropilin-1 / Q000235:genetics*; D011650:Pulmonary Alveoli / Q000473:pathology; D011897:Random Allocation; D012016:Reference Values; D020545:Respiratory Mucosa / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1