A novel two-hit murine model of inhaled occupational exposure-induced lung disease

The lungs are continuously exposed to environmental insults, rendering the lung epithelium vulnerable to damage and persistent inflammation. Such epithelial damage and prolonged inflammation are hallmark features of various lung diseases, including chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), and lung cancer. Organic dust exposure (ODE), prevalent among workers in livestock and agricultural sectors, is associated with significantly increased risk of these respiratory diseases, yet the underlying mechanisms relating these phenomena remain poorly understood. Here, we have generated a novel murine model of inhaled occupational exposure-induced lung disease using a two-hit approach combining exposure to inhaled organic dust and an established murine model of bleomycin-induced PF to interrogate the signatures of lung damage onset and progression. Following the two-hit treatment in C57Bl/6J mice, we identified a distinct immune cell profile in the bronchoalveolar lavage fluid (BALF), dominated by macrophages and lymphocytes. This response was accompanied by unique inflammatory and injury-related histopathological changes in the lung that have not been observed in models using organic dust or bleomycin alone. These data, combined with additional physiological and cytokine findings, highlight the importance of applying multihit modeling in future work seeking to elucidate the cellular and molecular mechanisms associated with lung disease onset and progression.