Therapeutic effects of MEL-dKLA by targeting M2 macrophages in pulmonary fibrosis

• Published in: Biomedicine & pharmacotherapy 2024-09, Vol.178, p.117246, Article 117246
• Main Authors: Choi, Ilseob, Han, Ik-Hwan, Cha, Nari, Kim, Hye Yeon, Bae, Hyunsu
• Format: Article
• Language: English
• Subjects: Animals; Bleomycin; Coculture Techniques; Disease Models, Animal; Epithelial-Mesenchymal Transition - drug effects; Epithelial-to-mesenchymal transition; Extracellular Matrix - metabolism; Fibroblast-to-myofibroblast transition; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Idiopathic pulmonary fibrosis; Idiopathic Pulmonary Fibrosis - chemically induced; Idiopathic Pulmonary Fibrosis - drug therapy; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Lung - drug effects; Lung - metabolism; Lung - pathology; M2 macrophage; Macrophages - drug effects; Macrophages - metabolism; Male; MEL-dKLA; Mice; Mice, Inbred C57BL; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Myofibroblasts - pathology; Peptide; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - pathology; RAW 264.7 Cells
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117246

Idiopathic pulmonary fibrosis is a progressive lung disease characterized by excessive extracellular matrix accumulation and myofibroblast proliferation with limited treatment options available. M2 macrophages are pivotal in pulmonary fibrosis, where they induce the epithelial-to-mesenchymal and fibroblast-to-myofibroblast transitions. In this study, we evaluated whether MEL-dKLA, a hybrid peptide that can eliminate M2 macrophages, could attenuate pulmonary fibrosis in a cell co-culture system and in a bleomycin-induced mouse model. Our findings demonstrated that the removal of M2 macrophages using MEL-dKLA stimulated reprogramming to an antifibrotic environment, which effectively suppressed epithelial-to-mesenchymal and fibroblast-to-myofibroblast transition responses in lung epithelial and fibroblast cells and reduced extracellular matrix accumulation both in vivo and in vitro. Moreover, MEL-dKLA exhibited antifibrotic efficacy without damaging tissue-resident macrophages in the bleomycin-induced mouse model. Collectively, our findings suggest that MEL-dKLA may be a new therapeutic option for the treatment of idiopathic pulmonary fibrosis. [Display omitted] •MEL-dKLA alleviates pulmonary fibrosis by targeting Fra-2+ M2 macrophages in a mouse model.•MEL-dKLA inhibits epithelial-mesenchymal and fibroblast-myofibroblast transitions.•MEL-dKLA reprograms the microenvironment into an anti-fibrotic state by eliminating M2 macrophages.