title: Kallistatin protects against bleomycin-induced idiopathic pulmonary fibrosis by inhibiting angiogenesis and inflammation.
abstract: Aberrant angiogenesis and vascular remodeling are the main features of idiopathic pulmonary fibrosis. Kallistatin is an anti-angiogenic peptide with known effects on endothelial cells. This study aimed to demonstrate that kallistatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in a rat model by inhibiting angiogenesis. Twenty-five rats were randomly divided into five experimental groups: (A) Saline only (SA)-as the negative control, (B) BLM only (BLM)-as the model group, (C) BLM and 0.1 mg/kg kallistatin (L-Kal), (D) BLM and 0.5 mg/kg kallistatin (M-Kal), and (E) BLM and 2.5 mg/kg kallistatin (H-Kal). Fibrillar collagen was quantified by Masson's trichrome and hematoxylin-eosin staining. Transforming growth factor-β1 (TGF-β1), α-smooth-muscle-actin (α-SMA) and microvascular density (MVD) were measured by immunohistochemistry. Vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), and tumor necrosis factor-α (TNF-α) were assayed by Western immunoblotting or ELISA. Daily administration of kallistatin attenuated fibrosis in BLM-induced pulmonary fibrosis, as shown by histology. During inflammation from BLM-induced pulmonary fibrosis, kallistatin reduced the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid. Kallistatin also inhibited VEGF expression and phosphorylation of VEGFR2 (Flk-1). In vitro, kallistatin blocked tube formation by inhibiting Flk-1 and GSK-3β phosphorylation. The results demonstrated that continuous administration of kallistatin attenuated BLM-induced pulmonary fibrosis and improved survival of BLM rats. Reducing pulmonary fibrosis was achieved by partial inhibition of pulmonary inflammation and angiogenesis.
authors.affiliation: Institute of Molecular Medicine, Huaqiao UniversityQuanzhou 362021, China; College of Chemical Engineering and Materials Sciences, Quanzhou Normal UniversityQuanzhou 326000, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Huang
authors.affiliation: Institute of Molecular Medicine, Huaqiao University Quanzhou 362021, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: College of Chemical Engineering and Materials Sciences, Quanzhou Normal University Quanzhou 326000, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Xie
authors.affiliation: School of Chemistry & Chemical Engineering of Guangxi Normal University Guilin 541004, China.
authors.forename: Shulan
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Institute of Molecular Medicine, Huaqiao University Quanzhou 362021, China.
authors.forename: Zhaofa
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Molecular Medicine, Huaqiao University Quanzhou 362021, China.
authors.forename: Xianxiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute of Molecular Medicine, Huaqiao University Quanzhou 362021, China.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Institute of Molecular Medicine, Huaqiao University Quanzhou 362021, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Institute of Molecular Medicine, Huaqiao University Quanzhou 362021, China.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Lin
authors.affiliation: Institute of Molecular Medicine, Huaqiao University Quanzhou 362021, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Diao
keywords: Kallistatin; angiogenesis; bleomycin; pulmonary fibrosis