Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms

J Immunol. 2005 Aug 15;175(4):2598-605. doi: 10.4049/jimmunol.175.4.2598.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Airway Resistance / physiology
  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Capillary Permeability / physiology
  • Capsaicin / toxicity
  • Cell Death / physiology
  • Extravascular Lung Water / physiology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Lung / blood supply
  • Lung / drug effects
  • Lung / metabolism*
  • Lung / pathology*
  • Malondialdehyde / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Fibers, Unmyelinated / drug effects
  • Neurons, Afferent / pathology
  • Neuropeptides / pharmacology
  • Neuropeptides / physiology*
  • Neutrophils / drug effects
  • Neutrophils / physiology
  • Oligopeptides / administration & dosage*
  • Oligopeptides / antagonists & inhibitors
  • Peroxidase / biosynthesis
  • Peroxidase / metabolism
  • Positive-Pressure Respiration
  • Receptor, PAR-2 / administration & dosage*
  • Receptor, PAR-2 / antagonists & inhibitors
  • Receptor, PAR-2 / deficiency
  • Receptor, PAR-2 / metabolism*
  • Up-Regulation / physiology

Substances

  • Neuropeptides
  • Oligopeptides
  • Receptor, PAR-2
  • Malondialdehyde
  • Peroxidase
  • Capsaicin