TGFß1 induces resistance of human lung myofibroblasts to cell death via down-regulation of TRPA1 channels.
TGFß1 induces resistance of human lung myofibroblasts to cell death via down-regulation of TRPA1 channels.
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TGFα1 通过下调 TRPA1 通道诱导人肺肌成纤维细胞对细胞死亡的抵抗力。
DOI：
10.1111/bph.15467
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发表时间：
2021
影响因子：
7.3
通讯作者：
Virk HS
中科院分区：
文献类型：
--
作者：
Virk HS
背景和目的gf β1介导的肌成纤维细胞活化有助于许多疾病的病理性纤维化，包括特发性肺纤维化（IPF），其中肌成纤维细胞对氧化介导的细胞凋亡的抵抗也很明显。因此，我们研究了氧化还原敏感TRPA1离子通道在人肺肌成纤维细胞（HLMFs）细胞死亡和TGFβ1介导的促纤维化反应中的作用。实验方法研究了tgf - β1刺激对IPF患者和非纤维化患者的HLMFs中TRPA1表达和细胞活力的影响。我们还研究了人肺中TGFβ1依赖性纤维化的模型。我们使用了qRT - PCR、免疫荧光检测、慢病毒载体过表达和电生理方法。关键结果strpa1 mRNA、蛋白和离子流在非纤维化患者和IPF患者的HLMFs中均有表达，TGFβ1可降低其表达。在人肺纤维化模型中，TRPA1 mRNA也被tgf - β1下调。TRPA1过表达或激活诱导HLMF凋亡，以及h2o2诱导坏死激活TRPA1通道。tgf - β1下调或药物抑制后TRPA1抑制可保护HLMFs免于凋亡和坏死。在TRPA1阴性的HEK293T细胞系中，慢病毒载体介导的TRPA1表达也可诱导对h2o2诱导的细胞死亡的敏感性。结论和意义stgf β1通过下调TRPA1通道诱导HLMFs对TRPA1激动剂和H2O2介导的细胞死亡产生抗性。我们的数据表明，阻止TGFβ1依赖性TRPA1下调的治疗策略可能会降低IPF中肌成纤维细胞的存活率，从而改善临床结果。
Background and PurposeTGFβ1‐mediated myofibroblast activation contributes to pathological fibrosis in many diseases including idiopathic pulmonary fibrosis (IPF), where myofibroblast resistance to oxidant‐mediated apoptosis is also evident. We therefore investigated the involvement of redox‐sensitive TRPA1 ion channels on human lung myofibroblasts (HLMFs) cell death and TGFβ1‐mediated pro‐fibrotic responses.Experimental approachThe effects of TGFβ1 stimulation on TRPA1 expression and cell viability was studied in HLMFs derived from IPF patients and non‐fibrotic patients. We also examined a model of TGFβ1‐dependent fibrogenesis in human lung. We used qRT‐PCR, immunofluorescent assays, overexpression with lentiviral vectors and electrophysiological methods.Key ResultsTRPA1 mRNA, protein and ion currents were expressed in HLMFs derived from both non‐fibrotic patient controls and IPF patients, and expression was reduced by TGFβ1. TRPA1 mRNA was also down‐regulated by TGFβ1 in a model of lung fibrogenesis in human lung. TRPA1 over‐expression or activation induced HLMF apoptosis, and activation of TRPA1 channel activation by H2O2induced necrosis. TRPA1 inhibition following TGFβ1 down‐regulation or pharmacological inhibition, protected HLMFs from both apoptosis and necrosis. Lentiviral vector mediated TRPA1 expression was also found to induce sensitivity to H2O2induced cell death in a TRPA1‐negative HEK293T cell line.Conclusion and ImplicationsTGFβ1 induces resistance of HLMFs to TRPA1 agonist‐ and H2O2‐mediated cell death via down‐regulation of TRPA1 channels. Our data suggest that therapeutic strategies which prevent TGFβ1‐dependent down‐regulation of TRPA1 may reduce myofibroblast survival in IPF and therefore improve clinical outcomes.