Angiopoietin-like 4 is a critical regulator of fibroblasts during pulmonary fibrosis development

• Published in: American journal of respiratory cell and molecular biology Vol. 69; no. 3; pp. 328 - 339
• Main Authors: Saito, Shoichiro, Kitabatake, Masahiro, Ouji-Sageshima, Noriko, Ogawa, Tatsuro, Oda, Akihisa, Nishimura, Tomoko, Nishioka, Tatsuki, Fushimi, Satoki, Hara, Atsushi, Shichino, Shigeyuki, Kumamoto, Makiko, Hontsu, Shigeto, Kawaguchi, Takeshi, Ueha, Satoshi, Sawabata, Noriyoshi, Muro, Shigeo, Matsushima, Kouji, Ito, Toshihiro
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01-09-2023
• Subjects: Angiopoietin; Bleomycin; Cell migration; Collagen; Fibroblasts; Fibrosis; Gene expression; Lung diseases; Pathogenesis; Pulmonary fibrosis; Therapeutic targets; TGF-β; Angiopoietin-like 4; scRNA-seq; Pulmonary fibrosis; Myofibroblast
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2022-0304oc

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-smooth muscle actin (α-SMA)-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 IPF patients from both non-fibrotic and fibrotic areas as determined by a lung computed tomography scan, and compared gene expression between these areas by DNA microarray. We found that angiopoietin-like 4 (ANGPTL4) 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 that Angptl4 was 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 in Angptl4-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.