Clioquinol Attenuates Pulmonary Fibrosis through Inactivation of Fibroblasts via Iron Chelation.

Abstract

Strict control of iron homeostasis is critical for the maintenance of normal lung function. Iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (PF), but the characteristics of iron metabolism in the pathogenesis of PF and related targeting therapeutics are not well studied. In this study, we investigated the cellular and molecular characteristics of iron metabolism in fibrotic lungs and further explored the efficacy of clioquinol (CQ) for the treatment of PF as well as its functional mechanism. Iron aggregates accumulated in the lungs of patients with idiopathic PF, and FTL (ferritin light chain) transcripts were increased in their pulmonary fibroblasts. In the bleomycin (BLM)-induced PF (BLM-PF) mouse model, pulmonary iron accumulation is a very early and concomitant event of PF. Labile iron pool levels in both fibroblasts and macrophages from the BLM-PF model were elevated, and iron metabolism was dysregulated. CQ attenuated PF induced by BLM and FITC, and iron-saturated CQ did not alleviate BLM-PF. Furthermore, CQ inhibited the activation of fibroblasts, including proliferation, fibrotic differentiation, proinflammatory cytokine secretion, and migration. In conclusion, our study demonstrated that CQ, acting as an iron chelator, attenuates experimental PF through inactivation of fibroblasts, providing support for targeting iron metabolism as a basis for PF treatment.

• Authors: Yumeng Zhu, Jing Chang, Ke Tan, Steven K Huang, Xin Liu, Xiaofan Wang, Mengshu Cao, Hongmin Zhang, Shuxin Li, Xianglin Duan, Yanzhong Chang, Yumei Fan, Pengxiu Cao
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 65 Issue 2 Pg. 189-200 (08 2021) ISSN: 1535-4989 [Electronic] United States
• PMID: 33861690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chelating Agents
• Bleomycin
• Clioquinol
• Iron

Topics

• Animals
• Bleomycin (adverse effects, pharmacology)
• Chelating Agents (pharmacology)
• Clioquinol (pharmacology)
• Disease Models, Animal
• Female
• Fibroblasts (metabolism, pathology)
• Humans
• Idiopathic Pulmonary Fibrosis (chemically induced, drug therapy, metabolism, pathology)
• Iron (metabolism)
• Male
• Mice