GHK-Cu Protects Against Bleomycin-Induced Pulmonary Fibrosis by Reducing Inflammation and Oxidative Stress

Idiopathic pulmonary fibrosis (IPF) is a severe, progressive lung disease characterized by advancing and diffusive fibrosis. The key drivers of its pathogenesis are oxidative stress and inflammation. Current therapeutic options are limited, highlighting the need for novel treatments. The tripeptide Glycyl-L-histidyl-l-lysine (GHK) is known for its role in wound healing and tissue regeneration. The copper-complexed form, GHK-Cu, enhances its bioavailability, making it a promising candidate for intervention. This study investigates whether GHK-Cu can mitigate the pathological processes in a well-established animal model of pulmonary fibrosis, focusing on its potential to modulate key fibrotic and inflammatory pathways like TGFβ1/Smad2/3, NF-κB, and Nrf2.

Researchers induced pulmonary fibrosis in C57BL/6j mice via tracheal instillation of bleomycin (BLM) at a dose of 3 mg/kg. After the BLM challenge, mice were treated with GHK-Cu via intraperitoneal (i.p.) injection every other day for 21 days. Three different GHK-Cu dosages were tested: 0.2 µg/g/day, 2 µg/g/day, and 20 µg/g/day, all administered in 0.5 ml of PBS. The study evaluated histological changes, inflammation in bronchoalveolar lavage fluid (BALF), collagen deposition, and epithelial-mesenchymal transition (EMT) by measuring ɑ-SMA and fibronectin expression. Key signaling pathways were analyzed using immunoblotting.

GHK-Cu treatment significantly inhibited BLM-induced inflammatory and fibrotic pathological changes in the lung tissue. It markedly reduced collagen deposition and alleviated the inflammatory response, evidenced by lower levels of the pro-inflammatory cytokines TNF-ɑ and IL-6 in the BALF. The activity of myeloperoxidase (MPO), an inflammation marker, was also reduced.

GHK-Cu also addressed tissue remodeling by significantly reversing the imbalance between matrix metalloproteinase-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Furthermore, GHK-Cu treatment partially prevented epithelial-mesenchymal transition (EMT), a key process in fibrosis development. Mechanistically, these protective effects were linked to the modulation of several key signaling pathways; GHK-Cu suppressed the TGFβ1 pathway, as indicated by reduced Smad2/3 phosphorylation, and also acted via the Nrf2 and NF-κB pathways to exert its anti-oxidative and anti-inflammatory effects.

Written by TitrateLab, separately from the study summarized above.