Nano-designed CO donor ameliorates bleomycin-induced pulmonary fibrosis via macrophage manipulation

Chunyu Guo; Cheng Zhang; Zhengmei Xia; Bingdong Song; Weirong Hu; Yingying Cui; Yanni Xue; Mizhen Xia; Dexiang Xu; Shichen Zhang; Jun Fang

doi:10.1016/j.jconrel.2021.11.047

Nano-designed CO donor ameliorates bleomycin-induced pulmonary fibrosis via macrophage manipulation

J Control Release. 2022 Jan:341:566-577. doi: 10.1016/j.jconrel.2021.11.047. Epub 2021 Dec 2.

Authors

Chunyu Guo¹, Cheng Zhang¹, Zhengmei Xia¹, Bingdong Song¹, Weirong Hu¹, Yingying Cui¹, Yanni Xue², Mizhen Xia³, Dexiang Xu¹, Shichen Zhang⁴, Jun Fang⁵

Affiliations

¹ Department of Toxicology, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, School of Public Health, Anhui Medical University, Hefei 230022, China.
² Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei 230022, China; MOE Key Laboratory of Population Health Across Life Cycle, Anhui Provincial Key Laboratory of Population Health and Aristogenics, No. 81 Meishan Road, Hefei 230032, China.
³ School of Life Science, Anhui Medical University, No. 81 Meishan Road, Hefei 230032, China.
⁴ Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei 230022, China; MOE Key Laboratory of Population Health Across Life Cycle, Anhui Provincial Key Laboratory of Population Health and Aristogenics, No. 81 Meishan Road, Hefei 230032, China; School of Public Health and Health Management, Anhui Medical College, No. 632 Furong Road, Hefei 230601, China. Electronic address: zhangshichen@ahmu.edu.cn.
⁵ Department of Toxicology, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, School of Public Health, Anhui Medical University, Hefei 230022, China; Faculty of Pharmaceutical Science, Sojo University, Ikeda 4-22-1, Kumamoto 860-0082, Japan. Electronic address: fangjun@ph.sojo-u.ac.jp.

PMID: 34864115
DOI: 10.1016/j.jconrel.2021.11.047

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease due to chronic inflammatory responses. The prognosis of IPF is very poor, however, the therapeutic options are very limited. Previously we developed a polymeric micellar drug delivery system of carbon monoxide (CO) that is a pivotal anti-inflammatory gaseous molecule, i.e., SMA/CORM2, which exhibited therapeutic potentials against dextran sulfate sodium (DSS)-induced mouse colitis and acetaminophen (APAP) induced liver injury. Along this line, here we investigate the applicability of SMA/CORM2 on IPF using a bleomycin (BLM)-induced pulmonary fibrosis model. Severe inflammation and the consequent pulmonary fibrosis were triggered by BLM, whereas SMA/CORM2 treatment remarkably suppressed the inflammation progression and ameliorated the formation of fibrosis. CO is the effector molecule of SMA/CORM2, which exerted the therapeutic/protective effect mostly through suppressing the reprogramming of anti-inflammatory macrophages as revealed by the decreased expressions of CD206 and arginase-1 that were remarkably upregulated by BLM exposure. The suppression of macrophage polarization accompanied the downregulated hypoxia-inducible factor-1α (HIF-1α) and its target molecule heme oxygenase-1 (HO-1), suggesting a HIF-1α/HO-1 pathway for modulating macrophage reprogramming. As the downstream event of anti-inflammatory macrophage polarization, the alveolar epithelial to mesenchymal transition that is the major source of myofibroblast, the hallmark of IPF, was significantly suppressed by SMA/CORM2 via a TGF-β/Smad2/3 pathway. Compared to native CORM2 of equivalent dose, SMA/CROM2 exhibited a much better protective effect indicating its superior bioavailability as an enhanced permeability and retention (EPR) effect-based nanomedicine. We thus anticipate the application of SMA/CORM2 as a therapeutic candidate for IPF as well as other inflammatory diseases and disorders.

Keywords: Bleomycin; Carbon monoxide; Hypoxia-inducible factor-1α; Idiopathic pulmonary fibrosis; Macrophage reprogramming.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bleomycin / therapeutic use
Colitis* / drug therapy
Epithelial-Mesenchymal Transition
Idiopathic Pulmonary Fibrosis* / chemically induced
Idiopathic Pulmonary Fibrosis* / drug therapy
Macrophages
Mice

Substances

Bleomycin