Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease, characterized by progressive damage to the lung tissues. Apoptosis and endoplasmic reticulum stress (ER stress) in type II alveolar epithelial cells (AECs) and lung macrophages have been linked with the development of IPF. Therefore, apoptosis- and ER stress-targeted therapies have drawn attention as potential avenues for treatment of IPF. The calcium-activated potassium ion channel KCa3.1 has been proposed as a potential therapeutic target for fibrotic diseases including IPF. While KCa3.1 is expressed in AECs and macrophages, its influence on ER stress and apoptosis during the disease process is unclear. We utilized a novel sheep model of pulmonary fibrosis to demonstrate that apoptosis and ER stress occur in type II AECs and macrophages in sheep with bleomycin-induced lung fibrosis. Apoptosis in type II AEC and macrophages was identified using the TUNEL method of tagging fragmented nuclear DNA, while ER stress was characterized by increased expression of GRP-78 ER chaperone proteins. We demonstrated that apoptosis and ER stress in type II AECs and macrophages increased significantly 2 weeks after the final bleomycin infusion and remained high for up to 7 weeks post-bleomycin injury. Senicapoc treatment significantly reduced the rates of ER stress in type II AECs and macrophages that were resident in bleomycin-infused lung segments. There were also significant reductions in the rates of apoptosis of type II AECs and macrophages in the lung segments of senicapoc-treated sheep. In vivo blockade of the KCa3.1 ion channel alleviates the ER stress and apoptosis in type II AECs and macrophages, and this effect potentially contributes to the anti-fibrotic effects of senicapoc.

中文翻译：

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体内阻断 KCa3.1 离子通道可减轻肺纤维化绵羊模型中 ER 应激和细胞凋亡水平的升高

特发性肺纤维化 (IPF) 是一种致命的间质性肺病，其特征是肺组织进行性损伤。II 型肺泡上皮细胞 (AEC) 和肺巨噬细胞的凋亡和内质网应激 (ER 应激) 与 IPF 的发展有关。因此，细胞凋亡和 ER 应激靶向疗法作为 IPF 治疗的潜在途径引起了人们的关注。钙激活的钾离子通道 KCa3.1 已被提议作为包括 IPF 在内的纤维化疾病的潜在治疗靶点。虽然 KCa3.1 在 AEC 和巨噬细胞中表达，但其在疾病过程中对 ER 应激和细胞凋亡的影响尚不清楚。我们利用一种新型的绵羊肺纤维化模型来证明博莱霉素诱导的肺纤维化绵羊的 II 型 AEC 和巨噬细胞中发生细胞凋亡和 ER 应激。使用标记片段化核 DNA 的 TUNEL 方法鉴定了 II 型 AEC 和巨噬细胞的凋亡，而 ER 应激的特征在于 GRP-78 ER 伴侣蛋白的表达增加。我们证明了在最后一次输注博莱霉素后 2 周，II 型 AEC 和巨噬细胞中的细胞凋亡和 ER 应激显着增加，并且在博莱霉素损伤后长达 7 周内保持高水平。Senicapoc 治疗显着降低了位于博来霉素肺段中的 II 型 AEC 和巨噬细胞的 ER 应激率。senicapoc 处理的绵羊肺段中 II 型 AEC 和巨噬细胞的凋亡率也显着降低。体内阻断 KCa3.1 离子通道可减轻 II 型 AEC 和巨噬细胞中的 ER 应激和细胞凋亡，这种作用可能有助于 senicapoc 的抗纤维化作用。