Effects of N-Acetylcysteine in Ozone-Induced Chronic Obstructive Pulmonary Disease Model

Feng Li,Pank Bhavsar,Ian Adcock,Xin Zhou,Yan Chang,Cornelis Wiegman,Joanna M Seiffert,Kian Fan Chung,Jie Zhu,Colin Clarke,Junfeng Zhang,Mehrdad Arjomandi

doi:10.1371/journal.pone.0080782

Abstract

IntroductionChronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. We determined the recovery from ozone-induced injury and whether an antioxidant, N-acetylcysteine (NAC), could prevent or reverse the lung damage.MethodsMice were exposed to ozone (2.5 ppm, 3 hours/12 exposures, over 6 weeks) and studied 24 hours (24h) or 6 weeks (6W) later. Nac (100 mg/kg, intraperitoneally) was administered either before each exposure (preventive) or after completion of exposure (therapeutic) for 6 weeks.ResultsAfter ozone exposure, there was an increase in functional residual capacity, total lung volume, and lung compliance, and a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Mean linear intercept (Lm) and airway hyperresponsiveness (AHR) to acetylcholine increased, and remained unchanged at 6W after cessation of exposure. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells.ConclusionEmphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The beneficial effects of therapeutic NAC may be restricted to the ASM.

Highlights

Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice
Pulmonary function measurements There were significant increases in lung volume parameters (IC, Functional residual capacity (FRC) and total lung capacity (TLC)) and compliance (Cchord) and decreases in airflow during expiration (FEV25/forced vital capacity (FVC), FEV50/FVC) in PBSpretreated ozone-exposed mice compared to air-exposed group (Figure 1)
We demonstrated that lung inflammation, emphysema, abnormal lung function and airway hyperresponsiveness (AHR) were induced by 6 weeks of ozone exposure and that these persisted up to 6 weeks after cessation of exposure

Summary

Introduction

Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells. Conclusion: Emphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The development of a chronic exposure model to ozone in mice that results in chronic lung inflammation and emphysema provides direct support for an important role for oxidative stress in COPD[5]. Oxidative stress on the lungs may induce airway smooth muscle hyperplasia and dysfunction, and contribute to ensuing bronchial hyperresponsiveness (BHR) (1,4,5)

Methods

Results

Conclusion