The KCa3.1 blocker TRAM-34 inhibits proliferation of fibroblasts in paraquat-induced pulmonary fibrosis

Abstract

KCa3.1, a Ca2+-activated K+ channel, plays an important role in modulating calcium signaling and maintaining membrane potential during cell activation. It has been reported to promote fibroblast function in many fibrotic diseases. However, the role of KCa3.1 in the pathophysiology of pulmonary fibrosis after paraquat (PQ) poisoning has not been studied. A rat model of PQ poisoning was used. After treatment with TRAM-34, which is a highly selective KCa3.1 blocker, the expression of KCa3.1, TGF-β1 and α-SMA were evaluated via Western blot, histology and other assays. Bromodeoxyuridine (BrdU) marking and MTT assay were used to measure primary rat pulmonary fibroblast proliferation. The results showed that KCa3.1 expression was elevated after PQ poisoning. Blockade of KCa3.1 alleviated PQ-induced pulmonary inflammation and fibrosis. Blockade of KCa3.1 also attenuated the level of collagen I and α-SMA and the proliferation of fibroblasts. However, TGF-β1 expression remained unaffected by blockade of KCa3.1 in rat lung tissues after PQ poisoning. The present study suggests that KCa3.1 expression increased and might promote pulmonary fibroblast proliferation in PQ-induced pulmonary fibrosis. In addition, we confirmed that TRAM-34 attenuates proliferation and collagen secretion of fibroblasts. Our findings indicated that TRAM-34 might inhibit PQ-induced proliferation of pulmonary fibroblasts and prevent progression of lung fibrosis.