6-desulfated heparin inhibits heparan sulfate shedding and epithelial cell damage during bleomycin induced pulmonary injury

Jing Yang; Xiao-ni Liu; Qing-qing WU; Yan-duo Zhai; Jing-hua Chen; Yi-shu Yan; Shan-shan DU; Yang JI; Xin-hui Xing

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6-desulfated heparin inhibits heparan sulfate shedding and epithelial cell damage during bleomycin induced pulmonary injury

Author: Jing YANG ¹ ; Xiao-Ni LIU ¹ ; Qing-Qing WU ¹ ; Yan-Duo ZHAI ¹ ; Jing-Hua CHEN ¹ ; Yi-Shu YAN ¹ ; Shan-Shan DU ² ; Yang JI ² ; Xin-Hui XING ²
Author Information

1. Dept of Pharmaceutics .School of Life Sciences and Health Engineering Jiangnan University
2. Institute of Biochemical Engineering, Tsinghua University, Moe Key Laboratory of Industrial Biocatalysis, Dept of Chemical Engineering
Publication Type:Journal Article
Keywords: c-Met/Akt sig¬naling pathway; epithelial cell harrier; hepa¬rin; lung injury; selective desulfation; Syndecan-1
From: Chinese Pharmacological Bulletin 2022;38(8):1147-1155
CountryChina
Language:Chinese
Abstract: Aim To study the effect of different hepa- ry.Methods First, heparin derivatives with different rin sulfation patterns on bleomycin induced lung inju- sulfation patterns,6-desulfated heparin (6-DeH) and N-acetvlated heparin ( N-AcH ) , were synthesized.Secondly, the effect of these compounds on BLM-in¬duced bronchial epithelial cell ( BEARS-2B) injury was evaluated via lactate dehydrogenase activity, MTT experiment, Annexin V/ PI staining and Hoechst 33258 staining.Then , immunofluorescence staining and West¬ern blotting were used to investigate the shedding of Svndecan-1 and the activation of c-Met by 6-DeH/Akt j j signaling pathway.Finally, a BLM-induced lung injury mouse model was used to further verify the protective effect of 6-DeH by HE staining, Svndecan-1 immunos- taining,bodv weight change,and survival rate.Results In the BLM-induced BEARS-2B injury model, 6- DeH was selected as the best candidate, which exerted their effect by competitively binding to BLM, thereby reducing the damage of heparan sulfate barrier (Svnde- can-1 ) on cell surface, and improving cell survival by activating the downstream c-Met/Akt pathway.In the BLM-induced lung injury mouse model, it was further confirmed that 6-DeH reduced the shedding of Svnde- can-1 in the early stage, and delayed the lung injury and fibrosis process.Conclusions 6-DeH protects the bronchial epithelial cells against BLM-induced lung in¬jur)' through inhibiting the shedding of Svndecan-1 and activating the c-Met/Akt signaling pathway.