Angiopoietin-like 4 is a critical regulator of fibroblasts during pulmonary fibrosis development
Angiopoietin-like 4 is a critical regulator of fibroblasts during pulmonary fibrosis development
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血管生成素样 4 是肺纤维化发展过程中成纤维细胞的关键调节因子
DOI：
10.1165/rcmb.2022-0304oc
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发表时间：
2023
影响因子：
6.4
通讯作者：
Noriyoshi Sawa
中科院分区：
文献类型：
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作者：
Shoichiro Saito;Masahiro Kitabatake;Noriko Ouji-Sageshima;Tatsuro Ogawa;Akihisa Oda;Tomoko Nishimura;Tatsuki Nishioka;Satoki Fushimi;Atsushi Hara;Shigeyuki Shichino;Makiko Kumamoto;Shigeto Hontsu;Takeshi Kawaguchi;Satoshi Ueha;Noriyoshi Sawa
特发性肺纤维化（IPF）是一种慢性、进行性和不可逆的间质性肺炎，由细胞外基质成分（包括I型胶原）的过度产生和沉积引起。活化的成纤维细胞，称为表达α-SMA（α-平滑肌肌动蛋白）的肌成纤维细胞，是肺纤维化（PF）中I型胶原的主要来源，但疾病进展的潜在机制尚未完全阐明。在这里，我们从IPF患者的非纤维化和纤维化区域获得肺成纤维细胞，通过肺部计算机断层扫描确定，并通过DNA微阵列比较这些区域之间的基因表达。我们发现ANGPTL 4（angiopoietin-like 4）仅在纤维化区域的成纤维细胞中高表达。ANGPTL 4在IPF肺的成纤维细胞区域选择性表达，其中肌成纤维细胞标志物α-SMA也表达。ANGPTL 4还调节纤维化相关标志物的基因表达、细胞迁移和增殖。此外，在由博来霉素治疗诱导的PF的鼠模型中，ANGPTL 4表达在从急性期到慢性期的肺中被显著诱导。博来霉素诱导PF过程中的单细胞转录组分析显示Angptl 4主要在活化的成纤维细胞和肌成纤维细胞中表达。此外，在博来霉素诱导的纤维化模型中给予重组ANGPTL 4显著增加胶原沉积并加重PF。相反，在Angptl 4缺陷小鼠中PF的发病机制得到改善。这些结果表明，ANGPTL 4对PF的进展至关重要，可能是IPF的早期诊断标志物和治疗靶点。
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial pneumonia caused by the excessive production and deposition of extracellular matrix components, including type I collagen. Activated fibroblasts, called α-SMA (α-smooth muscle actin)-expressing myofibroblasts, are the major source of type I collagen in pulmonary fibrosis (PF), but the mechanisms underlying disease progression have not been fully elucidated. Here, we obtained lung fibroblasts from patients with IPF from both nonfibrotic and fibrotic areas as determined by a lung computed tomography scan and compared gene expression between these areas by DNA microarray. We found thatANGPTL4(angiopoietin-like 4) was highly expressed only in fibroblasts from the fibrotic area. ANGPTL4 was selectively expressed in the fibroblastic area of IPF lungs, where the myofibroblast marker α-SMA was also expressed. ANGPTL4 also regulates the gene expression of fibrosis-related markers, cell migration, and proliferation. In addition, ANGPTL4 expression in a murine model of PF induced by treatment with bleomycin was significantly induced in the lungs from the acute to the chronic phase. Single-cell transcriptome analysis during the course of bleomycin-induced PF revealed thatAngptl4was predominantly expressed in the activated fibroblasts and myofibroblasts. Moreover, the administration of recombinant ANGPTL4 to the bleomycin-induced fibrosis model significantly increased collagen deposition and exacerbated the PF. In contrast, the pathogenesis of PF inAngptl4-deficient mice was improved. These results indicate that ANGPTL4 is critical for the progression of PF and might be an early diagnostic marker and therapeutic target for IPF.