Plasminogen activator inhibitor-1 does not contribute to the pulmonary pathology induced by acute exposure to ozone

Abstract

Expression of plasminogen activator inhibitor (PAI)‐1, the major physiological inhibitor of fibrinolysis, is increased in the lung following inhalation of ozone (O3), a gaseous air pollutant. PAI‐1 regulates expression of interleukin (IL)‐6, keratinocyte chemoattractant (KC), and macrophage inflammatory protein (MIP)‐2, which are cytokines that promote lung injury, pulmonary inflammation, and/or airway hyperresponsiveness following acute exposure to O3. Given these observations, we hypothesized that PAI‐1 contributes to the severity of the aforementioned sequelae by regulating expression of IL‐6, KC, and MIP‐2 following acute exposure to O3. To test our hypothesis, wild‐type mice and mice genetically deficient in PAI‐1 (PAI‐1‐deficient mice) were acutely exposed to either filtered room air or O3 (2 ppm) for 3 h. Four and/or twenty‐four hours following cessation of exposure, indices of lung injury [bronchoalveolar lavage fluid (BALF) protein and epithelial cells], pulmonary inflammation (BALF IL‐6, KC, MIP‐2, macrophages, and neutrophils), and airway responsiveness to aerosolized acetyl‐β‐methylcholine chloride (respiratory system resistance) were measured in wild‐type and PAI‐1‐deficient mice. O3 significantly increased indices of lung injury, pulmonary inflammation, and airway responsiveness in wild‐type and PAI‐1‐deficient mice. With the exception of MIP‐2, which was significantly lower in PAI‐1‐deficient as compared to wild‐type mice 24 h following cessation of exposure to O3, no other genotype‐related differences occurred subsequent to O3 exposure. Thus, following acute exposure to O3, PAI‐1 neither regulates pulmonary expression of IL‐6 and KC nor functionally contributes to any of the pulmonary pathological sequelae that arise from the noxious effects of inhaled O3.

Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone

“…In this instance, baseline R RS is the R RS value obtained following PBS administration. For further details with regard to the generation of methacholine dose-response curves and the calculation of ED 200 R RS , please refer to our laboratory's prior work (Razvi et al 2015;Elkhidir et al 2016).…”

“…Ccrl2 is necessary to produce maximum injury and inflammation in response to certain stimuli (Otero et al 2010;Douglas et al 2013). Consequently, because inhalation of O 3 causes lung injury and lung inflammation (Razvi et al 2015;Elkhidir et al 2016), we examined the potential contribution of Ccrl2 to these sequelae. Lung hyperpermeability and airway epithelial desquamation are two features of O 3 -induced lung injury (Scheel et al 1959;Bhalla et al 1986).…”