Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms

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.

Protease-Activated Receptor 2, Dipeptidyl Peptidase I, and Proteases Mediate Clostridium difficile Toxin A Enteritis

“…In support of this role for PAR 2 , deletion of PAR 2 also protects against colitis induced by Citrobacter rodentium, allergic inflammation of the airways, and arthritis. [33][34][35][36] In contrast, pretreatment with PAR 2 -AP protects against chemically induced colitis due to the release of calcitonin gene-related peptide. 11 Although deletion of PAR 2 significantly diminished MPO, TxA-induced pathologic changes were more completely blocked.…”

CD47 Deficiency Protects Mice from Lipopolysaccharide-Induced Acute Lung Injury and Escherichia coli Pneumonia

“…As previously described (20), the lungs were removed, counted in a gamma counter (Packard), weighed, and homogenized (after addition of 1 ml distilled water). The blood was collected through puncture of the right ventricle.…”

Up-Regulation of Trypsin and Mesenchymal MMP-8 During Development of Hyperoxic Lung Injury in the Rat

“…PAR 2 is markedly up-regulated by inflammatory agents and widely expressed in lungs (11). Activation of PAR 2 increases lung vascular and epithelial permeability to protein and causes pulmonary edema in a dose-dependent manner (10). In preterm infants with RDS, trypsin-2 colocalizes with PAR 2 in airway epithelium (12).…”

“…This lung injury is neutrophil dependent and possibly mediated by the ability of trypsin to up-regulate pulmonary intercellular adhesion molecule-1, a key vascular endothelial adhesion molecule necessary for transport of leukocytes from intravascular space into inflamed tissues (30). The proinflammatory effects of trypsin may also be mediated through activation of PAR 2 , a G protein-coupled receptor that is believed to play an important role in inflammation (10,11). PAR 2 is markedly up-regulated by inflammatory agents and widely expressed in lungs (11).…”

“…Trypsin is a potent activator of proteinase-activated receptor 2 (PAR 2 ), a G protein-coupled receptor that is believed to play an important role in airway inflammation (10,11). In preterm infants, high pulmonary trypsinogen-2 early postnatally is associated with the severity of acute lung injury and with the development of bronchopulmonary dysplasia (BPD) (8).…”