Protective effects of GHK-Cu in bleomycin-induced pulmonary fibrosis via anti-oxidative stress and anti-inflammation pathways

• Published in: Life sciences (1973) Vol. 241; p. 117139
• Main Authors: Ma, Wen-hui, Li, Meng, Ma, Hai-feng, Li, Wei, Liu, Li, Yin, Yan, Zhou, Xiao-ming, Hou, Gang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.01.2020
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Antibiotics, Antineoplastic - toxicity; Antioxidants - pharmacology; Bleomycin - toxicity; Collagen - metabolism; Copper - administration & dosage; Copper - chemistry; Cytokines - metabolism; Disease Models, Animal; Epithelial-mesenchymal transition; Epithelial-Mesenchymal Transition - drug effects; GHK-Cu; Inflammation - drug therapy; Inflammation - immunology; Inflammation - pathology; Male; Mice; Mice, Inbred C57BL; Nuclear factor (NF)-κB; Nuclear factor erythroid-related factor 2; Oligopeptides - administration & dosage; Oligopeptides - chemistry; Oxidative Stress - drug effects; Pulmonary fibrosis; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - prevention & control; Signal Transduction - drug effects; Smad; Transforming growth factor beta1; Epithelial-mesenchymal transition; Transforming growth factor beta1; Pulmonary fibrosis; GHK-Cu; Nuclear factor erythroid-related factor 2; Smad; Nuclear factor (NF)-κB
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.117139

Idiopathic pulmonary fibrosis (IPF) is a serious lung problem with advancing and diffusive pulmonary fibrosis as the pathologic basis, and with oxidative stress and inflammation as the key pathogenesis. Glycyl-L-histidyl-l-lysine (GHK) is a tripeptide participating into wound healing and regeneration. GHK-Cu complexes improve GHK bioavailability. Thus, the current study aimed to explore the therapeutic role of GHK-Cu on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model. BLM (3 mg/kg) was administered via tracheal instillation (TI) to induce a pulmonary fibrosis model in C57BL/6j mice 21 days after the challenge of BLM. GHK-Cu was injected intraperitoneally (i.p.) at different dosage of 0.2, 2 and 20 μg/g/day in 0.5 ml PBS on alternate day. The histological changes, inflammation response, the collagen deposition and epithelial-mesenchymal transition (EMT) was evaluated in the lung tissue. EMT was evaluated by ɑ-SMA and fibronectin expression in the lung tissue. NF-κB p65, Nrf2 and TGFβ1/Smad2/3 signalling pathways were detected by immunoblotting analysis. GHK-Cu complex inhibited BLM-induced inflammatory and fibrotic pathological changes, alleviated the inflammatory response in the BALF by reducing the levels of the inflammatory cytokines, TNF-ɑ and IL-6 and the activity of MPO as well as reduced collagen deposition. In addition, the GHK-Cu treatment significantly reversed the MMP-9/TIMP-1 imbalance and partially prevented EMT via Nrf2, NF-κB and TGFβ1 pathways, as well as Smad2/3 phosphorylation. GHK-Cu presented a protective effect in BLM-induced inflammation and oxidative stress by inhibiting EMT progression and suppressing TGFβ1/Smad2/3 signalling in pulmonary fibrosis.