Alveolar macrophages inhibit emphysematous pathology via expression of carbonic anhydrase 4

Chronic obstructive pulmonary disease (COPD) including emphysema is the fourth leading cause of death 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 lung 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 murine studies, reduced levels of human Car4 (CA4) distinguish COPD patients with emphysema from those without. Mechanistically, murine and human Car4 directly inhibit neutrophil elastase, which promotes destruction of alveolar walls and drives emphysema. Collectively, these studies reveal the existence of a lung-specific elastase inhibitor that protects the elastin-containing walls of the alveoli and provides important therapeutic insight into a disease that affects 300 million individuals globally.