Baicalin alleviates bleomycin-induced early pulmonary fibrosis in mice via the mitoKATP signaling pathway
Abstract
Bleomycin (BLM), a frequently employed chemotherapeutic agent, exhibits restricted clinical utility owing to its pulmonary toxicity. Meanwhile, baicalin (BA)—an active ingredient extracted from the roots of Scutellaria baicalensis Georgi —has been shown to alleviate BLM-induced pulmonary fibrosis (PF). Hence, the objective of this study was to examine the protective effects of BA in the context of BLM-induced early PF in mice and elucidate the underlying mechanism(s). We established an in vivo BLM (3.5 mg/kg)-induced PF murine model and in vitro BLM (35 μM)-damaged MLE-12 cell model. On Day 14 of treatment, the levels of fibrosis and apoptosis were evaluated in mouse lungs via hydroxyproline analysis, western blotting (COL1A1, TGF-β, Bax, Bcl-2, cleaved caspase-3), and Masson, immunohistochemical (α-SMA, AIF, Cyto C), and TUNEL staining. Additionally, in vitro, apoptosis was assessed in MLE-12 cells exposed to BLM for 24 h using the Annexin V/PI assay and western blotting (Bax, Bcl-2, cleaved caspase-3, AIF, Cyto C). To elucidate the role of the mitochondrial ATP-sensitive potassium channel (mitoKATP) in the protective effect of BA, we utilised diazoxide (DZX)—a mitoKATP agonist—and 5-hydroxydecanoate sodium (5-HD)—a mitoKATP inhibitor. Results revealed the involvement of mitoKATP in the protective effect of BA in BLM-induced PF. More specifically, mitoKATP activation can attenuate BLM-induced PF progression and mitigate alveolar epithelial type II cell death by reducing mitochondrial ROS, maintaining the mitochondrial membrane potential, and impeding the mitochondrial apoptotic pathway. Collectively, the findings offer pharmacological support to use BA for the treatment or prevention of BLM-induced PF and suggest that mitoKATP might serve as an effective therapeutic target for this condition.
- Publication:
-
Toxicology
- Pub Date:
- October 2023
- DOI:
- 10.1016/j.tox.2023.153638
- Bibcode:
- 2023Toxgy.49753638H
- Keywords:
-
- 5-HD;
- 5-hydroxydecanoate sodium;
- ΔΨm;
- mitochondrial membrane potential;
- AEC;
- alveolar epithelial cell;
- AIF;
- apoptosis-inducing factor;
- BA;
- baicalin;
- BLM;
- bleomycin;
- DZX;
- diazoxide;
- HYP;
- hydroxyproline;
- LTDF;
- leukotriene D4;
- MIM;
- mitochondrial inner membrane;
- mitoKATP;
- mitochondrial ATP-sensitive potassium channel;
- MMP;
- mitochondrial membrane permeability;
- PF;
- pulmonary fibrosis;
- ROS;
- reactive oxygen species;
- Bleomycin;
- Pulmonary fibrosis;
- AECII;
- MitoKATP;
- Mitochondria apoptosis pathway