Regulation of cigarette smoke-induced lung injury by nerve growth factor, sensory nerves, and substance P
Description
Nerve growth factor (NGF) is a polypeptide that controls the development and function of selected populations of neurons and also regulates inflammatory processes. The respiratory tract is innervated by irritant-responsive sensory nerves that contain neuropeptides called tachykinins, which are released in response to the inhalation of irritants. Inhalation of cigarette smoke causes lung injury and inflammation, which is characterized by the migration of neutrophils and macrophages into the lung. The studies presented in this work tested the hypothesis that NGF regulates cigarette smoke-induced lung injury and inflammation through effects on sensory nerves or by direct effects on inflammatory cells A murine cigarette smoke exposure model was developed in which mice were exposed to smoke from ten cigarettes per day for three consecutive days, resulting in decrements in lung function, as measured by barometric plethysmography, impaired epithelial/endothelial barrier function, as indicated by increased lavage fluid protein content, and inflammatory cell influx. This model was used to examine the effects of manipulating NGF and sensory innervation on the response to cigarette smoke exposure. Mice deficient in the low affinity NGF receptor (NGFR KO), transgenic mice that overexpress NGF in the lungs (CCSP-NGF), mice that overexpress the substance P receptor TacR1 in the lungs (CCSP-TacR1), and mice treated with substance P were exposed to cigarette smoke. NGFR KO and CCSP-NGF mice had more pronounced decrements in lung function, and NGFR KO mice had more inflammation and increased lung lavage fluid protein content following acute smoke exposure when compared to wild-type mice. Tacr1 expression and substance P treatment did not affect responses to cigarette smoke To determine if sensory neuropeptides inhibit cytotoxic effects of cigarette smoke, A549 human lung epithelial cells were treated with cigarette smoke conditioned medium in the presence of substance P, vasoactive intestinal peptide (VIP), or pituitary adenylate cyclase activating peptide (PACAP). No cytoprotective effects of the peptides were observed, and substance P and VIP exhibited small cytotoxic effects. The overall results indicated that NGFR has protective effects against lung injury and inflammation following acute cigarette smoke exposure, and these effects are not mediated by neuropeptides released from sensory nerves