Alveolar macrophages inhibit emphysematous pathology via expression of carbonic anhydrase 4.

Chronic obstructive pulmonary disease (CODP) including emphysema affects approximately 400 million individuals worldwide. Therapies to treat COPD remain limited and fail to prevent disease progression. Alveolar macrophages (AMs) reside in the alveoli of the lung and are ideally positioned to encounter inhaled particles and pathogens. Despite exposure to these stimuli, AMs exhibit specialized phenotypes that restrict inflammation to prevent alveolar damage. Here we demonstrate that AMs express high levels of the surface bound enzyme carbonic anhydrase 4 (Car4). Deletion of Car4 on AMs results in increased susceptibility to emphysematous pathology and therapeutic treatment with Car4 is sufficient to prevent emphysema-like disease. Consistent with our murine studies, reduced levels of Carbonic anhydrase 4 (CAIV) distinguishes COPD patients with emphysema from those without emphysema. Mechanistically, murine and human Car4 directly inhibit elastase that promotes destruction of alveolar walls. Collectively, these studies reveal an underappreciated function for Car4 in preventing lung pathology.