Department of Pediatric Newborn Medicine and.
Department of Neonatology, Heidelberg University Children's Hospital, Heidelberg, Germany.
Am J Respir Cell Mol Biol. 2019 Oct;61(4):512-524. doi: 10.1165/rcmb.2018-0232OC.
Inflammation and vascular smooth muscle cell (VSMC) phenotypic switching are causally linked to pulmonary arterial hypertension (PAH) pathogenesis. Carbonic anhydrase inhibition induces mild metabolic acidosis and exerts protective effects in hypoxic pulmonary hypertension. Carbonic anhydrases and metabolic acidosis are further known to modulate immune cell activation. To evaluate if carbonic anhydrase inhibition modulates macrophage activation, inflammation, and VSMC phenotypic switching in severe experimental pulmonary hypertension, pulmonary hypertension was assessed in Sugen 5416/hypoxia (SU/Hx) rats after treatment with acetazolamide or ammonium chloride (NHCl). We evaluated pulmonary and systemic inflammation and characterized the effect of carbonic anhydrase inhibition and metabolic acidosis in alveolar macrophages and bone marrow-derived macrophages (BMDMs). We further evaluated the treatment effects on VSMC phenotypic switching in pulmonary arteries and pulmonary artery smooth muscle cells (PASMCs) and corroborated some of our findings in lungs and pulmonary arteries of patients with PAH. Both patients with idiopathic PAH and SU/Hx rats had increased expression of lung inflammatory markers and signs of PASMC dedifferentiation in pulmonary arteries. Acetazolamide and NHCl ameliorated SU/Hx-induced pulmonary hypertension and blunted pulmonary and systemic inflammation. Expression of carbonic anhydrase isoform 2 was increased in alveolar macrophages from SU/Hx animals, classically (M1) and alternatively (M2) activated BMDMs, and lungs of patients with PAH. Carbonic anhydrase inhibition and acidosis had distinct effects on M1 and M2 markers in BMDMs. Inflammatory cytokines drove PASMC dedifferentiation, and this was inhibited by acetazolamide and acidosis. The protective antiinflammatory effect of acetazolamide in pulmonary hypertension is mediated by a dual mechanism of macrophage carbonic anhydrase inhibition and systemic metabolic acidosis.
炎症和血管平滑肌细胞 (VSMC) 表型转换与肺动脉高压 (PAH) 的发病机制密切相关。碳酸酐酶抑制可引起轻度代谢性酸中毒，并在低氧性肺动脉高压中发挥保护作用。碳酸酐酶和代谢性酸中毒进一步调节免疫细胞的激活。为了评估碳酸酐酶抑制是否调节严重实验性肺动脉高压中的巨噬细胞激活、炎症和 VSMC 表型转换，我们在 Sugen 5416/缺氧 (SU/Hx) 大鼠中评估了乙酰唑胺或氯化铵 (NHCl) 治疗后的肺动脉高压。我们评估了肺部和全身炎症，并描述了碳酸酐酶抑制和代谢性酸中毒对肺泡巨噬细胞和骨髓来源的巨噬细胞 (BMDMs) 的影响。我们进一步评估了该治疗对肺动脉和肺动脉平滑肌细胞 (PASMC) 中 VSMC 表型转换的影响，并在 PAH 患者的肺和肺血管中验证了我们的一些发现。特发性 PAH 患者和 SU/Hx 大鼠的肺部炎症标志物表达增加，肺动脉中的 PASMC 去分化迹象明显。乙酰唑胺和 NHCl 改善了 SU/Hx 诱导的肺动脉高压，并减轻了肺部和全身炎症。SU/Hx 动物的肺泡巨噬细胞、经典 (M1) 和替代 (M2) 激活的 BMDMs 以及 PAH 患者的肺中，碳酸酐酶同工酶 2 的表达增加。碳酸酐酶抑制和酸中毒对 BMDMs 中的 M1 和 M2 标志物有不同的影响。炎症细胞因子驱动 PASMC 去分化，而这一过程被乙酰唑胺和酸中毒所抑制。乙酰唑胺在肺动脉高压中的保护抗炎作用是通过巨噬细胞碳酸酐酶抑制和全身代谢性酸中毒的双重机制介导的。
