PDF(Pubmed)
Abstract：
We previously found IQ motif containing GTPase activating protein (IQGAP1) to be consistently elevated in lung fibroblasts (LF) isolated from patients with scleroderma (systemic sclerosis, SSc)-associated interstitial lung disease (ILD) and reported that IQGAP1 contributed to SSc by regulating expression and organization of α-smooth muscle actin (SMA) in LF. The aim of this study was to compare the development of ILD in the presence and absence of IQGAP1. Pulmonary fibrosis was induced in IQGAP1 knockout (KO) and wild-type (WT) mice by a single-intratracheal instillation of bleomycin. Two and three weeks later, mice were euthanized and investigated. We observed that the IQGAP1 KO mouse was characterized by a reduced rate of actin polymerization with reduced accumulation of actin in the lung compared to the WT mouse. After exposure to bleomycin, the IQGAP1 KO mouse demonstrated decreased contractile activity of LF, reduced expression of SMA, TGFβ, and collagen, and lowered overall fibrosis scores compared to the WT mouse. The numbers of inflammatory cells and expression of pro-inflammatory cytokines in lung tissue were not significantly different between IQGAP1 KO and WT mice. We conclude that IQGAP1 plays an important role in the development of lung fibrosis induced by bleomycin, and the absence of IQGAP1 reduces the contractile activity of lung fibroblast and bleomycin-induced pulmonary fibrosis. Thus, IQGAP1 may be a potential target for novel anti-fibrotic therapies for lung fibrosis.
摘要：
我们以前发现，在从硬皮病患者（系统性硬化症，SSc）相关的间质性肺病（ILD），并报道IQGAP1通过调节LF中α-平滑肌肌动蛋白（SMA）的表达和组织来促进SSc。这项研究的目的是比较IQGAP1存在和不存在下ILD的发展。通过单次气管内滴注博来霉素在IQGAP1敲除（KO）和野生型（WT）小鼠中诱导肺纤维化。两三周后,对小鼠实施安乐死并进行研究。我们观察到,与WT小鼠相比,IQGAP1KO小鼠的特征在于肌动蛋白聚合速率降低,并且肌动蛋白在肺中的积累减少。接触博来霉素后,IQGAP1KO小鼠表现出LF的收缩活动减少，减少SMA的表达，TGFβ,和胶原蛋白，并且与WT小鼠相比降低了总体纤维化评分。IQGAP1KO和WT小鼠肺组织中炎症细胞的数量和促炎细胞因子的表达没有显着差异。我们得出结论，IQGAP1在博来霉素诱导的肺纤维化的发展中起重要作用，IQGAP1的缺失降低了肺成纤维细胞和博莱霉素诱导的肺纤维化的收缩活性。因此，IQGAP1可能是针对肺纤维化的新型抗纤维化疗法的潜在靶标。
