Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.
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.
Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131, United States.
Katherine E
KE
Zychowski
Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131, United States.
Selita N
SN
Lucas
Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131, United States.
Bethany
B
Sanchez
Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131, United States.
Guy
G
Herbert
Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, NM 87131, United States. Electronic address: mcampen@salud.unm.edu.
Matthew J
MJ
Campen
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D010126:Ozone / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016278:Ventricular Function, Right / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D000393:Air Pollutants; D047428:Protein Kinase Inhibitors; D010126:Ozone; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil
Chronic obstructive pulmonary disease (COPD); Fasudil; Hypoxia; Inflammation; Ozone; Pulmonary hypertension