Carbonic Anhydrase Inhibition Ameliorates Inflammation and Experimental Pulmonary Hypertension.

RATIONALE: Inflammation and vascular smooth muscle cell (VSMC) phenotypic switching are causally linked to pulmonary arterial hypertension (PAH) pathogenesis. Carbonic anhydrase inhibition (CAI) induces mild metabolic acidosis and exerts protective effects in hypoxic pulmonary hypertension (PH). Carbonic anhydrases and metabolic acidosis are further known to modulate immune cell activation.

OBJECTIVE: To evaluate if CAI modulates macrophage activation, inflammation, and VSMC phenotypic switching in severe experimental PH.

METHODS: PH was assessed in Sugen 5416/hypoxia (SU/Hx) rats after treatment with acetazolamide or ammonium chloride (NH4Cl). We evaluated pulmonary and systemic inflammation and characterized the effect of CAI and metabolic acidosis in alveolar and bone marrow-derived macrophages (BMDM). We further evaluated the treatment effects on VSMC phenotypic switching in pulmonary arteries (PAs) and pulmonary artery smooth muscle cells (PASMC) and corroborated some of our findings in lungs and PAs of PAH patients.

MEASUREMENTS AND MAIN RESULTS: Both idiopathic PAH patients and SU/Hx rats had increased expression of lung inflammatory markers and signs of PASMC de-differentiation in PAs. Acetazolamide and NH4Cl ameliorated SU/Hx-induced PH and blunted pulmonary and systemic inflammation. Expression of CA isoform 2 (Car2, CA2) was increased in alveolar macrophages from SU/Hx animals, classically (M1) and alternatively (M2) activated BMDMs, and PAH patient lungs. CAIs and acidosis had distinct effects on M1 and M2 markers in BMDMs. Inflammatory cytokines drove PASMC de-differentiation and this was inhibited by acetazolamide and acidosis.

CONCLUSION: The protective anti-inflammatory effect of acetazolamide in PH is mediated by a dual mechanism of macrophage CAI and systemic metabolic acidosis.