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

Authors: Zychowski, Katherine E; Lucas, Selita N; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J

Published In Toxicol Appl Pharmacol, (2016 08 15)

Abstract: Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-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 O3 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 O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-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.

PubMed ID: 27286659 Exiting the NIEHS site

MeSH Terms: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives*; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/therapeutic use; Air Pollutants/toxicity*; Animals; Bronchial Hyperreactivity/chemically induced; Bronchial Hyperreactivity/drug therapy; Bronchial Hyperreactivity/pathology; Bronchial Hyperreactivity/physiopathology; Bronchoalveolar Lavage Fluid/cytology; Cell Count; Hypertension, Pulmonary/drug therapy; Hypertension, Pulmonary/etiology; Hypertension, Pulmonary/pathology; Hypertension, Pulmonary/physiopathology; Hypertrophy, Right Ventricular/chemically induced; Hypertrophy, Right Ventricular/drug therapy; Hypertrophy, Right Ventricular/pathology; Hypertrophy, Right Ventricular/physiopathology; Hypoxia/complications; Hypoxia/drug therapy; Hypoxia/pathology; Hypoxia/physiopathology; Lung Injury/chemically induced; Lung Injury/drug therapy*; Lung Injury/pathology; Lung Injury/physiopathology; Lung/drug effects; Lung/pathology; Lung/physiopathology; Male; Mice, Inbred C57BL; Organ Size/drug effects; Ozone/toxicity*; Protein Kinase Inhibitors/pharmacology; Protein Kinase Inhibitors/therapeutic use*; Ventricular Function, Right/drug effects; Ventricular Pressure/drug effects; rho-Associated Kinases/antagonists & inhibitors

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