Qing Fei Hua Xian Decoction ameliorates bleomycin-induced pulmonary fibrosis by suppressing oxidative stress through balancing ACE-AngII-AT1R/ACE2-Ang-(1-7)-Mas axis

Document Type : Original Article

Authors

1 Department of Integrated Chinese and Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China

2 School of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan 430065, Hubei, China

Abstract

Objective(s): We aimed to investigate the preventative effect of Qing Fei Hua Xian Decoction (QFHXD) against pulmonary fibrosis (PF) and its potential mechanisms. 
Materials and Methods: Bleomycin (BLM)-induced rats were respectively treated with 413.3, 826.6, and 1239.9 mg/kg of QFHXD and prednisone for 28 days. The lung tissues of rats were collected on day 28 for histological and western blotting analysis. 
Results: QFHXD significantly reduced alveolus inflammation, collagen accumulation, and fibrosis deposition in BLM-induced PF rats (P<0.05). Collagen I and III, vimentin, and α-smooth muscle actin(α-SMA) expression levels were likewise decreased in PF rats treated with QFHXD (P<0.05). Additionally, QFHXD increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while decreasing NADPH oxidase 4 (NOX4) expression (P<0.05). Furthermore, QFHXD suppressed the PF progression by down-regulating Angiotensin-Converting Enzyme (ACE) -Angiotensin II (AngII) -Angiotensin II Type 1 Receptor (AT1R) axis (P<0.01) and up-regulating Angiotensin-Converting Enzyme 2 (ACE2) -Angiotensin-(1-7) (Ang-(1-7)) -Mas axis (P<0.05). 
Conclusion: QFHXD suppressed inflammatory infiltration and PF brought on by BLM in lung tissues through reducing oxidative stress by maintaining the equilibrium of ACE-AngII-AT1R and ACE2-Ang-(1-7) -Mas axes. This study may provide a novel clinical therapy option for PF.

Keywords

References

1. Parimon T, Hohmann MS, Yao C. Cellular Senescence: Pathogenic mechanisms in lung fibrosis. Int J Mol Sci 2021; 22.
2. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183:788-824.
3. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med 2018; 378:1811-1823.
4. Wang D, Yan Z, Bu L, An C, Deng B, Zhang J, et al. Protective effect of peptide DR8 on bleomycin-induced pulmonary fibrosis by regulating the TGF-beta/MAPK signaling pathway and oxidative stress. Toxicol Appl Pharmacol 2019; 382:114703.
5. Kato K, Hecker L. NADPH oxidases: Pathophysiology and therapeutic potential in age-associated pulmonary fibrosis. Redox Biol 2020; 33:101541.
6. Hecker L, Cheng J, Thannickal VJ. Targeting NOX enzymes in pulmonary fibrosis. Cell Mol Life Sci 2012; 69:2365-2371.
7. Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, et al. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 2009; 15:1077-1081.
8. Cheresh P, Kim SJ, Tulasiram S, Kamp DW. Oxidative stress and pulmonary fibrosis. Biochim Biophys Acta 2013; 1832:1028-1040.
9. Zhang Z, Qu J, Zheng C, Zhang P, Zhou W, Cui W, et al. Nrf2 anti-oxidant pathway suppresses Numb-mediated epithelial-mesenchymal transition during pulmonary fibrosis. Cell Death Dis 2018; 9:83-93.
10. Peng LY, An L, Sun NY, Ma Y, Zhang XW, Liu WH, et al. Salvia miltiorrhiza Restrains Reactive Oxygen Species-Associated Pulmonary Fibrosis via Targeting Nrf2-Nox4 Redox Balance. Am J Chin Med 2019; 47:1113-1131.
11. Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Diez-Freire C, Dooies A, et al. The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2010; 182:1065-1072.
12. Meng Y, Yu CH, Li W, Li T, Luo W, Huang S, et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-kappaB pathway. Am J Respir Cell Mol Biol 2014; 50:723-736.
13. Meng Y, Li T, Zhou GS, Chen Y, Yu CH, Pang MX, et al. The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway. Anti-oxid Redox Signal 2015; 22:241-258.
14. Qian W, Cai X, Qian Q, Wang D, Zhang L. Angelica Sinensis Polysaccharide Suppresses Epithelial-Mesenchymal Transition and Pulmonary Fibrosis via a DANCR/AUF-1/FOXO3 Regulatory Axis. Aging Dis 2020; 11:17-30.
15. Wang Z, Fang K, Wang G, Guan X, Pang Z, Guo Y, et al. Protective effect of amygdalin on epithelial-mesenchymal transformation in experimental chronic obstructive pulmonary disease mice. Phytother Res 2019; 33:808-817.
16. Shi W, Hao J, Wu Y, Liu C, Shimizu K, Li R, et al. Protective effects of heterophyllin B against bleomycin-induced pulmonary fibrosis in mice via AMPK activation. Eur J Pharmacol 2022; 921:174825.
17. Luo C, Wang H, Chen X, Cui Y, Li H, Long J, et al. Protection of H9c2 rat cardiomyoblasts against oxidative insults by total paeony glucosides from Radix Paeoniae Rubrae. Phytomedicine 2013; 21:20-24.
18. Szapiel SV, Elson NA, Fulmer JD, Hunninghake GW, Crystal RG. Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse. Am Rev Respir Dis 1979; 120:893-899.
19. Xu Y, Hang WL, Zhou XM, Wu Q. Exploring the mechanism whereby sinensetin delays the progression of pulmonary fibrosis based on network pharmacology and pulmonary fibrosis models. Front Pharmacol 2021; 12:693061.
20. Li X, Zhuang J, Rayford H, Zhang H, Shu R, Uhal BD. Attenuation of bleomycin-induced pulmonary fibrosis by intratracheal administration of antisense oligonucleotides against angiotensinogen mRNA. Curr Pharm Des 2007; 13:1257-1268.
21. Zhang Y, Lu P, Qin H, Zhang Y, Sun X, Song X, et al. Traditional Chinese medicine combined with pulmonary drug delivery system and idiopathic pulmonary fibrosis: Rationale and therapeutic potential. Biomed Pharmacother 2021; 133:111072.
22. Bai Y, Li J, Zhao P, Li Y, Li M, Feng S, et al. A chinese herbal formula ameliorates pulmonary fibrosis by inhibiting oxidative stress via upregulating Nrf2. Front Pharmacol 2018; 9:628-641.
23. McKleroy W, Lee TH, Atabai K. Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis. Am J Physiol Lung Cell Mol Physiol 2013; 304:L709-721.
24. Øya E, Becher R, Ekeren L, Afanou AKJ, Øvrevik J, Holme JA. Pro-inflammatory responses in human bronchial epithelial cells induced by spores and hyphal fragments of common damp indoor molds. Int J Environ Res Public Health 2019; 16:1085.
25. Hewlett JC, Kropski JA, Blackwell TS. Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets. Matrix Biol 2018; 71-72:112-127.
26. Chanda D, Otoupalova E, Smith SR, Volckaert T, De Langhe SP, Thannickal VJ. Developmental pathways in the pathogenesis of lung fibrosis. Mol Aspects Med 2019; 65:56-69.
27. Hansen NU, Karsdal MA, Brockbank S, Cruwys S, Rønnow S, Leeming DJ. Tissue turnover of collagen type I, III and elastin is elevated in the PCLS model of IPF and can be restored back to vehicle levels using a phosphodiesterase inhibitor. Respir Res 2016; 17:76-85.
28. Liu G, Philp AM, Corte T, Travis MA, Schilter H, Hansbro NG, et al. Therapeutic targets in lung tissue remodelling and fibrosis. Pharmacol Ther 2021; 225:107839.
29. Aboonabi A, Singh I. Chemopreventive role of anthocyanins in atherosclerosis via activation of Nrf2-ARE as an indicator and modulator of redox. Biomed Pharmacother 2015; 72:30-36.
30. Cheng F, Shen Y, Mohanasundaram P, Lindstrom M, Ivaska J, Ny T, et al. Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-Slug signaling. Proc Natl Acad Sci U S A 2016; 113:E4320-4327.
31. Parimon T, Yao C, Stripp BR, Noble PW, Chen P. Alveolar epithelial type II cells as drivers of lung fibrosis in idiopathic pulmonary fibrosis. Int J Mol Sci 2020; 21: 2269.
32. Selman M, Pardo A. The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis. Cell Signal 2020; 66:109482.
33. Marshall RP, McAnulty RJ, Laurent GJ. Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. Am J Respir Crit Care Med 2000; 161:1999-2004.
34. Wu CH, Wang Y, Ma M, Mullick AE, Crooke RM, Graham MJ, et al. Antisense oligonucleotides targeting angiotensinogen: Insights from animal studies. Biosci Rep 2019; 39: BSR20180201.
35. Crystal RG, Bitterman PB, Rennard SI, Hance AJ, Keogh BA. Interstitial lung diseases of unknown cause. Disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med 1984; 310:235-244.
36. Serrano-Mollar A, Closa D, Prats N, Blesa S, Martinez-Losa M, Cortijo J, et al. In vivo anti-oxidant treatment protects against bleomycin-induced lung damage in rats. Br J Pharmacol 2003; 138:1037-1048.
37. Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, et al. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 2014; 6:231ra247.
38. Stock CJW, Michaeloudes C, Leoni P, Durham AL, Mumby S, Wells AU, et al. Bromodomain and extraterminal (BET) protein inhibition restores redox balance and inhibits myofibroblast activation. Biomed Res Int 2019; 2019:1484736.
39. Walters DM, Cho HY, Kleeberger SR. Oxidative stress and anti-oxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2. Anti-oxid Redox Signal 2008; 10:321-332.
40. Jarman ER, Khambata VS, Cope C, Jones P, Roger J, Ye LY, et al. An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model. Am J Respir Cell Mol Biol 2014; 50:158-169.
41. Artaud-Macari E, Goven D, Brayer S, Hamimi A, Besnard V, Marchal-Somme J, et al. Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis. Anti-oxid Redox Signal 2013; 18:66-79.
42. Yang J, Tan Y, Zhao F, Ma Z, Wang Y, Zheng S, et al. Angiotensin II plays a critical role in diabetic pulmonary fibrosis most likely via activation of NADPH oxidase-mediated nitrosative damage. Am J Physiol Endocrinol Metab 2011; 301:E132-144.
43. Fang Y, Gao F, Liu Z. Angiotensin-converting enzyme 2 attenuates inflammatory response and oxidative stress in hyperoxic lung injury by regulating NF-kappaB and Nrf2 pathways. QJM 2019; 112:914-924.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 1
January 2023
Pages 107-113

Files

Share

How to cite

Statistics