Melittin Alleviates Bleomycin-induced Pulmonary Fibrosis Through Regulating TGF-β1/Smad2/3 and AMPK/SIRT1/PGC-1α Signaling Pathways

Overview

Journal Iran J Basic Med Sci

Publisher Mashhad University of Medical Sciences

Specialty General Medicine

Date 2025 Feb 19

PMID 39968084

Authors

Jia-Wang Yu

Wei-Hua Lu

Affiliations

Soon will be listed here.

Abstract

Objectives: The present study investigated the protective effect of melittin (MEL) against bleomycin (BLM)- induced pulmonary fibrosis (PF) in mice and the mechanism underlying this effect.

Materials And Methods: A mouse model of PF was established by intratracheal injection of 3.5 mg/kg BLM. Twenty-four hours after the model was established, the mice in the treatment groups were intraperitoneally injected with MEL, and specimens were collected 28 days later. The body weight, survival rate, and pulmonary index (PI) of the mice were determined. Haematoxylin and eosin (HE) staining, Masson's trichrome staining, immunohistochemical staining, kit assays, and Western blot (WB) analysis were performed.

Results: Our study indicated that MEL significantly increased the body weight and survival rate, reduced PI, and improved lung histopathology in mice. In addition, MEL inhibited epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Attenuated mitochondrial damage and reduced oxidative stress (OS) were also observed in MEL-treated mice. We further showed that MEL inhibited the TGF-β1/Smad2/3 pathway and activated the AMPK/SIRT1/PGC-1α pathway.

Conclusion: MEL is a promising future therapeutic agent for PF. Its multifaceted and complex mechanism of action inhibits both EMT and ECM production by modulating the TGF-β1/Smad2/3 pathway. It also improves mitochondrial function and reduces OS at least partially through the activation of the AMPK/SIRT1/PGC-1α signaling pathway.

References

Qian W, Cai X, Qian Q, Zhang W, Wang D . Astragaloside IV modulates TGF-β1-dependent epithelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. J Cell Mol Med. 2018; 22(9):4354-4365. PMC: 6111865. DOI: 10.1111/jcmm.13725. View

Mansour H, Omran M, Hasan H, El Kiki S . Modulation of bleomycin-induced oxidative stress and pulmonary fibrosis by N-acetylcysteine in rats via AMPK/SIRT1/NF-κβ. Clin Exp Pharmacol Physiol. 2020; 47(12):1943-1952. DOI: 10.1111/1440-1681.13378. View

Otoupalova E, Smith S, Cheng G, Thannickal V . Oxidative Stress in Pulmonary Fibrosis. Compr Physiol. 2020; 10(2):509-547. DOI: 10.1002/cphy.c190017. View

Tian L, Cao W, Yue R, Yuan Y, Guo X, Qin D . Pretreatment with Tilianin improves mitochondrial energy metabolism and oxidative stress in rats with myocardial ischemia/reperfusion injury via AMPK/SIRT1/PGC-1 alpha signaling pathway. J Pharmacol Sci. 2019; 139(4):352-360. DOI: 10.1016/j.jphs.2019.02.008. View

Andugulapati S, Gourishetti K, Tirunavalli S, Shaikh T, Sistla R . Biochanin-A ameliorates pulmonary fibrosis by suppressing the TGF-β mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems. Phytomedicine. 2020; 78:153298. PMC: 7395646. DOI: 10.1016/j.phymed.2020.153298. View

Ju N, Hayashi H, Shimamura M, Baba S, Yoshida S, Morishita R . Prevention of bleomycin-induced pulmonary fibrosis by a RANKL peptide in mice. Sci Rep. 2022; 12(1):12474. PMC: 9304352. DOI: 10.1038/s41598-022-16843-7. View

Li Z, Jiao Y, Wu Z, Liu H, Li Y, Cai Y . The role of quercetin in ameliorating bleomycin-induced pulmonary fibrosis: insights into autophagy and the SIRT1/AMPK signaling pathway. Mol Biol Rep. 2024; 51(1):795. DOI: 10.1007/s11033-024-09752-7. View

Ma W, Li M, Ma H, Li W, Liu L, Yin Y . Protective effects of GHK-Cu in bleomycin-induced pulmonary fibrosis via anti-oxidative stress and anti-inflammation pathways. Life Sci. 2019; 241:117139. DOI: 10.1016/j.lfs.2019.117139. View

Rangarajan S, Bone N, Zmijewska A, Jiang S, Park D, Bernard K . Metformin reverses established lung fibrosis in a bleomycin model. Nat Med. 2018; 24(8):1121-1127. PMC: 6081262. DOI: 10.1038/s41591-018-0087-6. View

10.

Siekacz K, Piotrowski W, Iwanski M, Gorski P, Bialas A . The Role of Interaction between Mitochondria and the Extracellular Matrix in the Development of Idiopathic Pulmonary Fibrosis. Oxid Med Cell Longev. 2021; 2021:9932442. PMC: 8545566. DOI: 10.1155/2021/9932442. View

11.

Nguyen C, Lee G . Neuroprotective Activity of Melittin-The Main Component of Bee Venom-Against Oxidative Stress Induced by Aβ in In Vitro and In Vivo Models. Antioxidants (Basel). 2021; 10(11). PMC: 8614890. DOI: 10.3390/antiox10111654. View

12.

Yu G, Tzouvelekis A, Wang R, Herazo-Maya J, Ibarra G, Srivastava A . Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med. 2017; 24(1):39-49. PMC: 5760280. DOI: 10.1038/nm.4447. View

13.

Gazdhar A, Lebrecht D, Roth M, Tamm M, Venhoff N, Foocharoen C . Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis. Sci Rep. 2014; 4:5336. PMC: 4061543. DOI: 10.1038/srep05336. View

14.

Savin I, Zenkova M, Senkova A . Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches. Int J Mol Sci. 2022; 23(23). PMC: 9735580. DOI: 10.3390/ijms232314959. View

15.

Park J, Park B, Park K . Suppression of Hepatic Epithelial-to-Mesenchymal Transition by Melittin via Blocking of TGFβ/Smad and MAPK-JNK Signaling Pathways. Toxins (Basel). 2017; 9(4). PMC: 5408212. DOI: 10.3390/toxins9040138. View

16.

Lv Q, Wang J, Xu C, Huang X, Ruan Z, Dai Y . Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways. Mol Med. 2020; 26(1):49. PMC: 7245944. DOI: 10.1186/s10020-020-00173-3. View

17.

Guha S, Ferrie R, Ghimire J, Ventura C, Wu E, Sun L . Applications and evolution of melittin, the quintessential membrane active peptide. Biochem Pharmacol. 2021; 193:114769. PMC: 9235364. DOI: 10.1016/j.bcp.2021.114769. View

18.

Salton F, Volpe M, Confalonieri M . Epithelial⁻Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis. Medicina (Kaunas). 2019; 55(4). PMC: 6524028. DOI: 10.3390/medicina55040083. View

19.

Li S, Yang Q, Chen F, Tian L, Huo J, Meng Y . The antifibrotic effect of pheretima protein is mediated by the TGF-β1/Smad2/3 pathway and attenuates inflammation in bleomycin-induced idiopathic pulmonary fibrosis. J Ethnopharmacol. 2021; 286:114901. DOI: 10.1016/j.jep.2021.114901. View

20.

Yaghoubi A, Jamehdar S, Akbari Eidgahi M, Ghazvini K . Evaluation of the therapeutic effect of melittin peptide on the ulcerative colitis mouse model. Int Immunopharmacol. 2022; 108:108810. DOI: 10.1016/j.intimp.2022.108810. View