Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms.
Protease-activated receptors (PARs) and tachykinin-immunoreactive fibers are located in the lung as sentries to respond to a variety of pathological stimuli. The effects of PAR activation on the lung have not been adequately studied. We report on the effects of instilling PAR-activating peptides (PAR-APs, including PAR1-, PAR2-, and PAR4-AP) into the lungs of ventilated or spontaneously breathing mice. PAR2-AP, but not PAR1-AP or PAR4-AP, caused a sharp increase in lung endothelial and epithelial permeability to protein, extravascular lung water, and airway tone. No responses to PAR2-AP were detected in PAR2 knockout mice. In bronchoalveolar lavage, PAR2 activation caused 8- and 5-fold increase in MIP-2 and substance P levels, respectively, and a 12-fold increase in the number of neutrophils. Ablation of sensory neurons (by capsaicin) markedly decreased the PAR2-mediated airway constriction, and virtually abolished PAR2-mediated pulmonary inflammation and edema, as did blockade of NK1 or NK2 receptors. Thus, PAR2 activation in the lung induces airway constriction, lung inflammation, and protein-rich pulmonary edema. These effects were either partly or completely neuropeptide dependent, suggesting that PAR2 can cause lung inflammation by a neurogenic mechanism.
Su
Xiao
X
Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
Camerer
Eric
E
Hamilton
Justin R
JR
Coughlin
Shaun R
SR
Matthay
Michael A
MA
D000208:Acute Disease; D000403:Airway Resistance / Q000502:physiology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000502:physiology; D002211:Capsaicin / Q000633:toxicity; D016923:Cell Death / Q000502:physiology; D015633:Extravascular Lung Water / Q000502:physiology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D009475:Neurons, Afferent / Q000473:pathology; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D009195:Peroxidase / Q000096:biosynthesis / Q000378:metabolism; D011175:Positive-Pressure Respiration; D044464:Receptor, PAR-2 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D009479:Neuropeptides; D009842:Oligopeptides; D044464:Receptor, PAR-2; D008315:Malondialdehyde; D009195:Peroxidase; D002211:Capsaicin