Chronic lung exposure to Saccharopolyspora rectivirgula leads to a pulmonary fibrotic pattern in mice 2257218

Abstract Introduction Hypersensitivity pneumonitis (HP) is an immune-mediated pulmonary disorder resulting from repeated exposure to environmental agents, such as Saccharopolyspora rectivirgula (SR) antigens, responsible for Farmer’s lung. This disease progresses from acute alveolar inflammation to a chronic stage characterized by the development of pulmonary fibrosis in humans. The only effective treatment to date is avoidance of antigen exposure, which is difficult to achieve for workers. An acute mouse model of HP in response to SR is already widely used in the field; however, evidences of fibrosis and the development of pulmonary function alterations in a chronic model of HP remain lacking, undermining our ability to develop relevant therapies for patients. The objective of this study is to develop a chronic and fibrotic mouse model of HP induced by SR antigens with better relevance to human HP pathophysiology. Methods Mice were exposed intranasally to SR antigens for three consecutive days per week, followed by a four-day rest period. This cycle was repeated for 6, 8, 10 and 12 weeks. Pulmonary function was analysed with the FlexiVent system, followed by broncho-alveolar lavage (BAL) and lung tissue collection. Samples were analyzed with flow cytometry to characterize inflammatory cell populations. Results Chronic exposure led to increased alveoli and tissue CD4 and CD8 T cells, alveolar macrophages and neutrophils infiltration in time. Functional data analyses revealed decreased inspiratory capacity and static compliance with a tendency towards increased elastance between 8-12 weeks of exposure (compared to unexposed mice), all indicative of a fibrotic respiratory pattern. The presence of fibrosis will be further confirmed via histological and gene expression analyses. Conclusion Chronic exposure to SR leads to chronic inflammation and a fibrotic pulmonary function pattern. This model is of utmost importance for understanding fibrosis-associated mechanisms and evaluating potential therapeutic strategies for HP. Funding Source Canadian Institutes of Health Research (CIHR) Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)