Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure

Ozone (O-3)-related cardiorespiratory effects are a growing public health concern. Ground level O-3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O-3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O-3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O-3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O-2) or hypoxia (10.0% O-2), followed by a 4-h exposure to either 1 ppm O-3 or filtered air (FA). As an additional experimental intervention fasudil (20 mg/kg) was administered intraperitoneally prior to and after O-3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O-3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O-3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O-3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. (C) 2016 Elsevier Inc. All rights reserved.