Research on the protective effect and mechanisms of 4-phenylbutyric acid on bleomycin-induced pulmonary fibrosis in mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

YANG Yun ^1,2 , YANG Chongyu ¹ , WANG Yali ¹ , CUI Deyue ¹ , BI Hui ¹ , HE Qian ¹ , GE Yunqi ¹ , LI Zhiying ¹ , ZHANG Qiudi ¹ , QIU Hui ¹ ,  ZHOU Jun ¹

1. Department of Pulmonary Critical Care Medicine, The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P. R. China;
2. Department of Pulmonary Critical Care Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P. R. China;

Corresponding author：

ZHOU Jun, Email: zhouyfan@126.com

Keywords：

4-phenylbutyric acid; endoplasmic reticulum stress; pulmonary fibrosis; ATF6; CHOP

DOI：

10.7507/1671-6205.202208018

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Objective To explore the effects of 4-phenylbutyric acid (4-PBA) on idiopathic pulmonary fibrosis (IPF) using a murine model of bleomycin (BLM)-induced pulmonary fibrosis. Methods Pulmonary fibrosis was induced in C57BL/6 mice by intratracheal injection of BLM. A total of 120 mice were randomly allocated into three groups: BLM group, BLM+4-PBA group, and control group. Pathology of lung tissue was analyzed to evaluate the degree of pulmonary fibrosis, and the survival of the mice was noted. The expression levels of the endoplasmic reticulum stress markers, activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP), were analyzed in lung tissues from mice. Results BLM induced significant collagen deposition in the lungs of the mice, which was alleviated by 4-PBA. 4-PBA also dramatically improved the pulmonary function and increased the survival rate in the BLM+4-PBA group compared with that in the BLM group. Both the mRNA and protein expression levels of ATF6 and CHOP were significantly reduced in mouse lung tissue after 2 weeks of 4-PBA treatment. Conclusions 4-PBA treatment could alleviate BLM-induced pulmonary fibrosis in mice via the attenuation of endoplasmic reticulum stress.

Citation： YANG Yun, YANG Chongyu, WANG Yali, CUI Deyue, BI Hui, HE Qian, GE Yunqi, LI Zhiying, ZHANG Qiudi, QIU Hui, ZHOU Jun. Research on the protective effect and mechanisms of 4-phenylbutyric acid on bleomycin-induced pulmonary fibrosis in mice. Chinese Journal of Respiratory and Critical Care Medicine, 2022, 21(11): 797-803. doi: 10.7507/1671-6205.202208018 Copy

1.	Loomis-King H, Flaherty KR, Moore BB. Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis. Curr Opin Pharmacol, 2013, 13(3): 377-385.
2.	Lawson WE, Cheng DS, Degryse AL, et al. Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc Natl Acad Sci U S A, 2011, 108(26): 10562-10567.
3.	Korfei M, Ruppert C, Mahavadi P, et al. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2008, 178(8): 838-846.
4.	Qiu H, Weng D, Chen T, et al. Stimulator of interferon genes deficiency in acute exacerbation of idiopathic pulmonary fibrosis. Front Immunol, 2017, 8: 1756.
5.	Chen T, Qiu H, Zhao MM, et al. IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis. J Cell Mol Med, 2019, 23(2): 908-919.
6.	Lichter-Konecki U, Diaz GA, Merritt JL 2nd, et al. Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Mol Genet Metab, 2011, 103(4): 323-329.
7.	Ricobaraza A, Cuadrado-Tejedor M, Garcia-Osta A. Long-term phenylbutyrate administration prevents memory deficits in Tg2576 mice by decreasing Aβ. Front Biosci (Elite Ed), 2011, 3(4): 1375-1384.
8.	Carlisle RE, Brimble E, Werner KE, et al. 4 phenylbutyrate inhibits tunicamycin induced acute kidney injury via CHOP/GADD153 repression. PLoS One, 2014, 9(1): e84663.
9.	Luo T, Chen BH, Wang XB. 4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress. Chem Biol Interact, 2015, 242: 99-106.
10.	Koyama M, Furuhashi M, Ishimura S, et al. Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol, 2014, 306(9): H1314-H1323.
11.	Ayala P, Montenegro J, Vivar R, et al. Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol. Exp Mol Pathol, 2012, 92(1): 97-104.
12.	Liu SH, Yang CC, Chan DC, et al. Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro. Oncotarget, 2016, 7(16): 22116-22127.
13.	Durante W. Targeting endoplasmic reticulum stress in hypoxia-induced cardiac injury. Vascul Pharmacol, 2016, 83: 1-3.
14.	王国辽, 张洁, 饶家榕, 等. 博来霉素致小鼠肺纤维化模型的建立及生物标志物的筛选. 畜牧兽医学报, 2021, 52(4): 1134-1140.
15.	Lee HY, Marahatta A, Bhandary B, et al. 4-Phenylbutyric acid regulates CCl₄-induced acute hepatic dyslipidemia in a mouse model: a mechanism-based PK/PD study. Eur J Pharmacol, 2016, 777: 104-112.
16.	Sisson TH, Hansen JM, Shah M, et al. Expression of the reverse tetracycline-transactivator gene causes emphysema-like changes in mice. Am J Respir Cell Mol Biol, 2006, 34(5): 552-560.
17.	Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary. J Clin Pathol, 1988, 41(4): 467-470.
18.	Snyder L, Neely ML, Hellkamp AS, et al. Predictors of death or lung transplant after a diagnosis of idiopathic pulmonary fibrosis: insights from the IPF-PRO Registry. Respir Res, 2019, 20(1): 105.
19.	Williamson JD, Sadofsky LR, Hart SP. The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis. Exp Lung Res, 2015, 41(2): 57-73.
20.	Della Latta V, Cecchettini A, Del Ry S, et al. Bleomycin in the setting of lung fibrosis induction: from biological mechanisms to counteractions. Pharmacol Res, 2015, 97: 122-130.
21.	Grootjans J, Kaser A, Kaufman RJ, et al. The unfolded protein response in immunity and inflammation. Nat Rev Immunol, 2016, 16(8): 469-484.
22.	Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2012, 302(8): L721-L729.
23.	Nogee LM, Dunbar AE 3rd, Wert SE, et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med, 2001, 344(8): 573-579.
24.	Xu PF, Yao YK, Zhou JY. Particulate matter with a diameter of ≤2.5 μm induces and enhances bleomycin-induced pulmonary fibrosis by stimulating endoplasmic reticulum stress in rat. Biochem Cell Biol, 2019, 97(4): 357-363.
25.	Thomas AQ, Lane K, Phillips J 3rd, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med, 2002, 165(9): 1322-1328.
26.	Lawson WE, Crossno PF, Polosukhin VV, et al. Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1119-L1126.
27.	Baek HA, Kim DS, Park HS, et al. Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts. Am J Respir Cell Mol Biol, 2012, 46(6): 731-739.
28.	王艳勋, 徐作军. 内质网应激与特发性肺纤维化. 中华医学杂志, 2013, 93(44): 3563-3565.
29.	Zhao H, Qin HY, Cao LF, et al. Phenylbutyric acid inhibits epithelial-mesenchymal transition during bleomycin-induced lung fibrosis. Toxicol Lett, 2015, 232(1): 213-220.
30.	McMillan TR, Moore BB, Weinberg JB, et al. Exacerbation of established pulmonary fibrosis in a murine model by gammaherpesvirus. Am J Respir Crit Care Med, 2008, 177(7): 771-780.

1. Loomis-King H, Flaherty KR, Moore BB. Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis. Curr Opin Pharmacol, 2013, 13(3): 377-385.
2. Lawson WE, Cheng DS, Degryse AL, et al. Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc Natl Acad Sci U S A, 2011, 108(26): 10562-10567.
3. Korfei M, Ruppert C, Mahavadi P, et al. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2008, 178(8): 838-846.
4. Qiu H, Weng D, Chen T, et al. Stimulator of interferon genes deficiency in acute exacerbation of idiopathic pulmonary fibrosis. Front Immunol, 2017, 8: 1756.
5. Chen T, Qiu H, Zhao MM, et al. IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis. J Cell Mol Med, 2019, 23(2): 908-919.
6. Lichter-Konecki U, Diaz GA, Merritt JL 2nd, et al. Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate. Mol Genet Metab, 2011, 103(4): 323-329.
7. Ricobaraza A, Cuadrado-Tejedor M, Garcia-Osta A. Long-term phenylbutyrate administration prevents memory deficits in Tg2576 mice by decreasing Aβ. Front Biosci (Elite Ed), 2011, 3(4): 1375-1384.
8. Carlisle RE, Brimble E, Werner KE, et al. 4 phenylbutyrate inhibits tunicamycin induced acute kidney injury via CHOP/GADD153 repression. PLoS One, 2014, 9(1): e84663.
9. Luo T, Chen BH, Wang XB. 4-PBA prevents pressure overload-induced myocardial hypertrophy and interstitial fibrosis by attenuating endoplasmic reticulum stress. Chem Biol Interact, 2015, 242: 99-106.
10. Koyama M, Furuhashi M, Ishimura S, et al. Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol, 2014, 306(9): H1314-H1323.
11. Ayala P, Montenegro J, Vivar R, et al. Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol. Exp Mol Pathol, 2012, 92(1): 97-104.
12. Liu SH, Yang CC, Chan DC, et al. Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro. Oncotarget, 2016, 7(16): 22116-22127.
13. Durante W. Targeting endoplasmic reticulum stress in hypoxia-induced cardiac injury. Vascul Pharmacol, 2016, 83: 1-3.
14. 王国辽, 张洁, 饶家榕, 等. 博来霉素致小鼠肺纤维化模型的建立及生物标志物的筛选. 畜牧兽医学报, 2021, 52(4): 1134-1140.
15. Lee HY, Marahatta A, Bhandary B, et al. 4-Phenylbutyric acid regulates CCl₄-induced acute hepatic dyslipidemia in a mouse model: a mechanism-based PK/PD study. Eur J Pharmacol, 2016, 777: 104-112.
16. Sisson TH, Hansen JM, Shah M, et al. Expression of the reverse tetracycline-transactivator gene causes emphysema-like changes in mice. Am J Respir Cell Mol Biol, 2006, 34(5): 552-560.
17. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary. J Clin Pathol, 1988, 41(4): 467-470.
18. Snyder L, Neely ML, Hellkamp AS, et al. Predictors of death or lung transplant after a diagnosis of idiopathic pulmonary fibrosis: insights from the IPF-PRO Registry. Respir Res, 2019, 20(1): 105.
19. Williamson JD, Sadofsky LR, Hart SP. The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis. Exp Lung Res, 2015, 41(2): 57-73.
20. Della Latta V, Cecchettini A, Del Ry S, et al. Bleomycin in the setting of lung fibrosis induction: from biological mechanisms to counteractions. Pharmacol Res, 2015, 97: 122-130.
21. Grootjans J, Kaser A, Kaufman RJ, et al. The unfolded protein response in immunity and inflammation. Nat Rev Immunol, 2016, 16(8): 469-484.
22. Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2012, 302(8): L721-L729.
23. Nogee LM, Dunbar AE 3rd, Wert SE, et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med, 2001, 344(8): 573-579.
24. Xu PF, Yao YK, Zhou JY. Particulate matter with a diameter of ≤2.5 μm induces and enhances bleomycin-induced pulmonary fibrosis by stimulating endoplasmic reticulum stress in rat. Biochem Cell Biol, 2019, 97(4): 357-363.
25. Thomas AQ, Lane K, Phillips J 3rd, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med, 2002, 165(9): 1322-1328.
26. Lawson WE, Crossno PF, Polosukhin VV, et al. Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1119-L1126.
27. Baek HA, Kim DS, Park HS, et al. Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts. Am J Respir Cell Mol Biol, 2012, 46(6): 731-739.
28. 王艳勋, 徐作军. 内质网应激与特发性肺纤维化. 中华医学杂志, 2013, 93(44): 3563-3565.
29. Zhao H, Qin HY, Cao LF, et al. Phenylbutyric acid inhibits epithelial-mesenchymal transition during bleomycin-induced lung fibrosis. Toxicol Lett, 2015, 232(1): 213-220.
30. McMillan TR, Moore BB, Weinberg JB, et al. Exacerbation of established pulmonary fibrosis in a murine model by gammaherpesvirus. Am J Respir Crit Care Med, 2008, 177(7): 771-780.

Chinese Journal of Respiratory and Critical Care Medicine

Research on the protective effect and mechanisms of 4-phenylbutyric acid on bleomycin-induced pulmonary fibrosis in mice

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