Introduction: Lung adaptation from pulmonary insults is an essential requirement for host fitness and survival. Lung epithelial injury and inflammation trigger oxidative stress which further damages the tracheobronchial tree. Failure… Click to show full abstract
Introduction: Lung adaptation from pulmonary insults is an essential requirement for host fitness and survival. Lung epithelial injury and inflammation trigger oxidative stress which further damages the tracheobronchial tree. Failure or incomplete adaptation to oxidative injury favours the development of severe airway disease. Objectives: Establish a new model to explore airway adaptation to oxidative injury in order to elucidate key mechanisms for preserving lung function. Methods: To establish a model for the study of adaptation to oxidative stress induced-lung injury, we exposed mice to repeated chlorine gas exposures. Outcome measures were assessed 24h after the last chlorine exposure. Lung function mechanics were explored using FlexiVent. Inflammation and anti-oxidant responses were assessed in both bronchoalveolar lavage and lung tissue. Knock-out mice, depletion, adoptive transfer and gene array approaches were used to further explore the mechanistic. Results: Here we report a striking respiratory airway adaptation in mice after repeated chlorine exposures. Mice rapidly adapt by controlling the neutrophilic inflammation and airway hyperresponsiveness. After excluding antioxidant mechanisms and regulatory T cells, we found that adaptation was mediated by resident alveolar macrophages, programmed with a potent pro-phagocytic capacity. Notably, 5% of alveolar macrophages expressed Foxp3 and depletion of these cells abolished adaptation. Conclusions: This new model of adaptation to oxidative stress-induced lung injury lead us to discover a subset of alveolar macrophages Foxp3 + , which may provide new cellular mechanism in resolving inflammation leading to airway adaptation and host fitness. CIHR MOP-126131.
               
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