Abstract

Environmental air pollutants including ozone cause severe lung injury and aggravate respiratory diseases such as asthma and COPD. Here we compared the effect of ozone on respiratory epithelium injury, inflammation, hyperreactivity and airway remodeling in mice upon acute (1ppm, 1 h) and chronic exposure (1.5ppm, 2 h, twice weekly for 6 weeks). Acute ozone exposure caused respiratory epithelial disruption with protein leak and neutrophil recruitment in the broncho-alveolar space, leading to lung inflammation and airway hyperresponsiveness (AHR) to methacholine. All these parameters were increased upon chronic ozone exposure, including collagen deposition. The structure of the airways as assessed by automatic numerical image analysis showed significant differences: While acute ozone exposure increased bronchial and lumen circularity but decreased epithelial thickness and area, chronic ozone exposure revealed epithelial injury with reduced height, distended bronchioles, enlarged alveolar space and increased collagen deposition, indicative of peribronchiolar fibrosis and emphysema as characterized by a significant increase in the density and diameter of airspaces with decreased airspace numbers. In conclusion, morphometric numerical analysis enables an automatic and unbiased assessment of small airway remodeling. The structural changes of the small airways correlated with functional changes allowing to follow the progression from acute to chronic ozone induced respiratory pathology.

Highlights

  • Pulmonary tissue damage is inflicted by exposure to different external factors such as air pollution, tobacco smoke, particulate matter and allergens, causing epithelial alteration, inflammation, fibrosis, emphysema and airway hyperresponsiveness (AHR)

  • The effect of acute and chronic ozone exposure was investigated in WT mice (Fig. 1B,C)

  • MMP-9 levels in BAL were increased after acute, but not chronic ozone exposure (Fig. 2C), while TIMP1 levels were higher in BAL after chronic ozone exposure (Fig. 2C)

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Summary

Introduction

Pulmonary tissue damage is inflicted by exposure to different external factors such as air pollution, tobacco smoke, particulate matter and allergens, causing epithelial alteration, inflammation, fibrosis, emphysema and airway hyperresponsiveness (AHR). In order to conduct a more accurate and reliable quantitative evaluation of bronchial structural changes, we developed an automatic numerical analysis which is totally observer-independent. To assess injury which can occur in alveolar parenchyma and lead to emphysema, a new automatic numerical quantification of the density, diameter and number of airspaces was carried out instead of the standard mean linear intercept (Lm) measurement. These combined histological and functional investigations give access to a more thorough analysis of airways remodeling, and represent an efficient and reliable approach to test the efficacy of drug candidates

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