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

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.

Mitochondrial toxicity of tobacco smoke and air pollution

“…Treatment of these ozone-exposed mice with MitoQ (5mg/kg intraperitoneally), an antioxidant that targets the mitochondrion, significantly increased mitochondrial membrane potential and decreased the following: ozone-induced airway hyper-responsiveness, bronchoalveolar lavage total cell counts, keratinocyte-derived cytokine levels, mitochondrial ROS levels and cellular ROS levels 226 . In contrast, a similar study with a slightly lower ozone exposure of 2.5 parts per million showed that N-acetylcysteine treatment did not attenuate ozone-induced lung injury in the same mouse model of COPD 235 235. .…”

“…. The improvement observed in pulmonary function with MitoQ but not N-acetylcysteine suggests that mitochondrially targeted therapies to be more efficacious and that mitochondrial oxidants play a pivotal role in ozone-induced lung injury 235 .…”

“…The increasing prevalence of acute respiratory diseases has also been linked to climate change and alterations in ground level ozone pollution distribution 228, 229 . Mice exposed to ozone (3 parts per million, 3 hours/day, twice a week for 1 or 6 weeks) exhibit phenotypes similar to human patients with COPD including lung inflammation and airway hyper-responsiveness 226, 235 . Mitochondria isolated from the lungs of ozone-exposed mice have increased levels of mitochondrial ROS at both the 1-week and 6-week time points, decreased ATP content, decreased mitochondrial electron transport chain complex I enzyme activity and decreased protein levels of complexes I, III and V compared to control air-exposed mice 226 .…”

Translational models of lung disease

“…Exposure to ozone and particulates, as well as the use of lung proteases have also been used as models of COPD. Chronic (6 week) ozone exposure in mice causes significant lung injury with some features related to inflammatory and emphysematous changes occurring in human COPD as well as changes in lung function and AHR [20,32,33]. Exposure to ultrafine particles, silica, coal dust and diesel exhaust particles (DEP) has been used which all cause significant levels of oxidative stress, inflammation and emphysema [20].…”

“…In future, bioinformatic comparisons of signature genes or pathways from clinical specimens from patients with different sub-phenotypes of COPD need to be integrated with clinical observations and similar phenotypic end points as clinical studies and related back to in vivo models in order to further understand, define and treat COPD (Figure 3, [19,39,40]). Only then can animal models be tailored precisely to the specific physiological and pharmacological features of human COPD which each model possesses [6,[17][18][19][20][22][23][24][25]32,33].…”