Carbonic anhydrase IX promotes acute lung injury and mortality in females during metabolic acidosis and pneumonia.

Carbonic anhydrase IX (CA IX) is a unique transmembrane CA isoform that is associated with chronic pulmonary vascular diseases and is upregulated in the lungs during infection. Whether CA IX contributes to alveolar-capillary dysfunction in the acute respiratory distress syndrome (ARDS) is unknown. Here, we tested the hypothesis that CA IX promotes acute lung injury during metabolic acidosis and pneumonia. Wild-type (WT) and CA IX knockout (KO) mice were fed 0.5% sucrose water (control) or 0.28 M NH₄Cl + 0.5% sucrose water for 7 days to induce metabolic acidosis, followed by intratracheal instillation of bacteria. Metabolic acidosis by itself did not cause pulmonary edema but modestly increased the lung wet-to-dry ratio in WT mice during pneumonia. A major sex difference in outcome was seen, where WT females had a higher filtration coefficient (K_f) in the isolated perfused lung and increased mortality compared with KO females. The K_f of WT and KO males did not differ; however, WT males had a 20% lower survival rate than KO males. In vitro expression of CA IX in pulmonary microvascular endothelial cells increased gap formation in the cell monolayer compared with KO cells during infection. No difference in lung bacterial clearance and plasma cytokines were seen between WT and KO mice regardless of sex. Thus, we report that CA IX promotes lung permeability and mortality but does not affect lung bacterial clearance, suggesting that CA IX may facilitate lung injury by directly affecting alveolar-capillary permeability and may serve as a therapeutic target in ARDS.NEW & NOTEWORTHY Acidosis is prevalent in patients with ARDS, yet the mechanisms involved in alveolar-capillary dysfunction during metabolic acidosis and lung injury remain poorly defined. Here, we report that carbonic anhydrase IX, a unique pH regulatory protein, promotes pulmonary edema and mortality but does not affect lung bacterial clearance during metabolic acidosis and pneumonia. Our findings suggest that carbonic anhydrase IX may serve as a therapeutic target to alleviate lung injury in patients with acidosis and ARDS.