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.
Highlights
Tropospheric ozone (O3) is a gaseous air pollutant and a powerful oxidant generated from photochemical reactions involving nitrogen oxides and volatile organic compounds (Finlayson-Pitts and Pitts 1997)
Pulmonary inflammation induced by exposure to O3 is typified by increased expression of inflammatory cytokines [interleukin (IL)-1a, IL-1b, IL-6, IL-17A, keratinocyte chemoattractant (KC), macrophage inflammatory protein (MIP)-2, osteopontin, and tumor necrosis factor (TNF)] in lung tissue and/or bronchoalveolar lavage fluid (BALF) and by migration of macrophages and neutrophils to air spaces (Park et al 2004; Johnston et al 2005a,b; Barreno et al 2013; Kasahara et al 2015; Razvi et al 2015)
We measured the amount of active plasminogen activator inhibitor (PAI)-1 in BALF obtained from wild-type and PAI-1-deficient mice exposed to air or O3 (Fig. 1B), and the results were qualitatively similar to those obtained for total PAI-1
Summary
Tropospheric ozone (O3) is a gaseous air pollutant and a powerful oxidant generated from photochemical reactions involving nitrogen oxides and volatile organic compounds (Finlayson-Pitts and Pitts 1997). O3 disproportionally increases mortality among the elderly and among people with respiratory disease (Bell et al 2014; Hao et al 2015) Because these vulnerable subpopulations continue to increase in the United States (U.S.) and because 51% of the U.S population lives in areas with unhealthy levels of O3 in ambient air (Administration on Aging; Wroe et al.2012; Zhang et al 2013; American Lung Association, 2016), a significant number of individuals within these subpopulations are susceptible to the harmful effects of O3. To mitigate or prevent O3-induced lung dysfunction and even possible death in vulnerable individuals, it is imperative to understand the molecular mechanisms underlying O3-induced pulmonary pathology
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