Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury

Jin,Yanwu; Zhao,Xin; Zhang,He; Li,Qingsong; Lu,Guodong; Zhao,Xiaogang

doi:10.3892/etm.2016.3370

Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury

Authors:
- Yanwu Jin
- Xin Zhao
- He Zhang
- Qingsong Li
- Guodong Lu
- Xiaogang Zhao
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Affiliations: Department of Anesthesiology II, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China, Department of Thoracic Surgery, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
Published online on: May 19, 2016 https://doi.org/10.3892/etm.2016.3370
Pages: 1135-1140

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Abstract

Silymarin is a traditional therapeutic used to protect the liver, acting to oppose lipid peroxidation, to enhance liver regeneration and functioning as an antioxidant. However, the effects of silymarin on pulmonary vascular dysfunction have not been investigated. In the present study, the modulatory effects of silymarin on pulmonary vascular dysfunction and the underlying mechanisms behind this were investigated in a lung ischemia‑reperfusion (I/R) injury rat model. Male Sprague Dawley rats were randomly divided into 3 groups, including: i) A control group (n=10); ii) an I/R group (n=10); and iii) a silymarin‑treated group (n=10). All experimental rats received 250 mg/kg/day of silymarin for 8 days. Silymarin was demonstrated to markedly improve lung I/R‑induced pulmonary vascular dysfunction and lung moisture. Following silymarin treatment, inflammation and oxidative stress in the lung I/R‑injury rats were demonstrably suppressed. Treatment with silymarin also inhibited the activation of caspase‑3 and ‑9, and hypoxia inducible factor‑1α (HIF‑1α) and inducible nitric oxide synthase (iNOS) protein expression in the lung I/R‑injury rats. Silymarin was concluded to impact upon pulmonary vascular dysfunction through the HIF‑1α‑iNOS pathway in the lung I/R injury rat model.

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1	Mansour Z, Charles AL, Kindo M, Pottecher J, Chamaraux-Tran TN, Lejay A, Zoll J, Mazzucotelli JP and Geny B: Remote effects of lower limb ischemia-reperfusion: Impaired lung, unchanged liver, and stimulated kidney oxidative capacities. BioMed Res Int. 2014:3923902014. View Article : Google Scholar : PubMed/NCBI
2	Diao TJ, Chen X, Deng LH, Chen HX, Liang Y, Zhao XD, Wang QH, Yuan WS, Gao BC and Ye Y: Protective effect of nitric oxide on hepatopulmonary syndrome from ischemia-reperfusion injury. World J Gastroenterol. 18:3310–3316. 2012.PubMed/NCBI
3	Lv X, Tan J, Liu D, Wu P and Cui X: Intratracheal administration of p38α short-hairpin RNA plasmid ameliorates lung ischemia-reperfusion injury in rats. J Heart Lung Transplant. 31:655–662. 2012. View Article : Google Scholar : PubMed/NCBI
4	Zhao X, Jin Y, Li H, Wang Z, Zhang W and Feng C: Hypoxia-inducible factor 1alpha contributes to pulmonary vascular dysfunction in lung ischemia-reperfusion injury. Int J Clin Exp Pathol. 7:3081–3088. 2014.PubMed/NCBI
5	Natarajan R, Jones DG, Fisher BJ, Wallace TJ, Ghosh S and Fowler AA III: Hypoxia inducible factor-1: Regulation by nitric oxide in posthypoxic microvascular endothelium. Biochem Cell Biol. 83:597–607. 2005. View Article : Google Scholar : PubMed/NCBI
6	Malekinejad H, Sheikhzadeh S and Hobbenaghi R: Silymarin attenuates mycophenolate mofetil-induced duodenal disorders in rats. Avicenna J Phytomed. 4:170–181. 2014.PubMed/NCBI
7	Bonifaz V, Shan Y, Lambrecht RW, Donohue SE, Moschenross D and Bonkovsky HL: Effects of silymarin on hepatitis C virus and haem oxygenase-1 gene expression in human hepatoma cells. Liver Int. 29:366–373. 2009. View Article : Google Scholar : PubMed/NCBI
8	Rao PR and Viswanath RK: Cardioprotective activity of silymarin in ischemia-reperfusion-induced myocardial infarction in albino rats. Exp Clin Cardiol. 12:179–187. 2007.PubMed/NCBI
9	Moral-Sanz J, Menendez C, Moreno L, Moreno E, Cogolludo A and Perez-Vizcaino F: Pulmonary arterial dysfunction in insulin resistant obese Zucker rats. Respir Res. 12:512011. View Article : Google Scholar : PubMed/NCBI
10	Luo C, Yuan D, Zhao W, Chen H, Luo G, Su G and Hei Z: Sevoflurane ameliorates intestinal ischemia-reperfusion-induced lung injury by inhibiting the synergistic action between mast cell activation and oxidative stress. Mol Med Rep. 12:1082–1090. 2015.PubMed/NCBI
11	Shoji T, Omasa M, Nakamura T, Yoshimura T, Yoshida H, Ikeyama K, Fukuse T and Wada H: Mild hypothermia ameliorates lung ischemia reperfusion injury in an ex vivo rat lung model. Eur Surg Res. 37:348–353. 2005. View Article : Google Scholar : PubMed/NCBI
12	Demir M, Amanvermez R, Polat Kamalı A, Karabıçak I, Cınar H, Kesicioğlu T and Polat C: The effect of silymarin on mesenteric ischemia-reperfusion injury. Med Princ Pract. 23:140–144. 2014.PubMed/NCBI
13	Turgut F, Bayrak O, Catal F, Bayrak R, Atmaca AF, Koc A, Akbas A, Akcay A and Unal D: Antioxidant and protective effects of silymarin on ischemia and reperfusion injury in the kidney tissues of rats. Int Urol Nephrol. 40:453–460. 2008. View Article : Google Scholar : PubMed/NCBI
14	Yousefi H, Ahmadiasl N, Alihemmati A and Habibi P: Effect of renal ischemia-reperfusion on lung injury and inflammatory responses in male rat. Iran J Basic Med Sci. 17:802–807. 2014.PubMed/NCBI
15	Chen LF, Tian YF, Lin CH, Huang LY, Niu KC and Lin MT: Repetitive hyperbaric oxygen therapy provides better effects on brain inflammation and oxidative damage in rats with focal cerebral ischemia. J Formos Med Assoc. 113:620–628. 2014. View Article : Google Scholar : PubMed/NCBI
16	Zhang F, Lu M, Wang H and Ren T: Aspirin attenuates angiotensin II-induced inflammation in bone marrow mesenchymal stem cells via the inhibition of ERK1/2 and NF-κB activation. Biomed Rep. 1:930–934. 2013.PubMed/NCBI
17	Jin LY, Li CF, Zhu GF, Wu CT, Wang J and Yan SF: Effect of siRNA against NF-κB on sepsis-induced acute lung injury in a mouse model. Mol Med Rep. 10:631–637. 2014.PubMed/NCBI
18	Amoruso A, Bardelli C, Cattaneo CI, Fresu LG, Manzetti E and Brunelleschi S: Neurokinin (NK)-1 receptor expression in monocytes from bipolar disorder patients: A pilot study. J Affect Disord. 178:188–192. 2015. View Article : Google Scholar : PubMed/NCBI
19	Gupta OP, Sing S, Bani S, Sharma N, Malhotra S, Gupta BD, Banerjee SK and Handa SS: Anti-inflammatory and anti-arthritic activities of silymarin acting through inhibition of 5-lipoxygenase. Phytomedicine. 7:21–24. 2000. View Article : Google Scholar : PubMed/NCBI
20	Zhao J, Lahiri-Chatterjee M, Sharma Y and Agarwal R: Inhibitory effect of a flavonoid antioxidant silymarin on benzoyl peroxide-induced tumor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis. 21:811–816. 2000. View Article : Google Scholar : PubMed/NCBI
21	Yao R, Zhou Y, He Y, Jiang Y, Liu P, Ye L, Zheng Z, Lau WB, Cao Y and Zeng Z: Adiponectin protects against paraquat-induced lung injury by attenuating oxidative/nitrative stress. Exp Ther Med. 9:131–136. 2015.PubMed/NCBI
22	Sulkowska M and Sulkowski S: The effect of pentoxifylline on ultrastructural picture of type II alveolar epithelial cells and generation of reactive oxygen species during cyclophosphamide-induced lung injury. J Submicrosc Cytol Pathol. 29:487–496. 1997.PubMed/NCBI
23	Fu Z, Liu X, Geng B, Fang L and Tang C: Hydrogen sulfide protects rat lung from ischemia-reperfusion injury. Life Sci. 82:1196–1202. 2008. View Article : Google Scholar : PubMed/NCBI
24	Clichici S, Olteanu D, Nagy AL, Oros A, Filip A and Mircea PA: Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl₄-treated rats. J Med Food. 18:290–298. 2015. View Article : Google Scholar : PubMed/NCBI
25	Moshtaghion SM, Malekinejad H, Razi M and Shafie-Irannejad V: Silymarin protects from varicocele-induced damages in testis and improves sperm quality: Evidence for E2f1 involvement. Syst Biol Reprod Med. 59:270–280. 2013. View Article : Google Scholar : PubMed/NCBI
26	Prangsaengtong O, Park JY, Inujima A, Igarashi Y, Shibahara N and Koizumi K: Enhancement of lymphangiogenesis in vitro via the regulations of HIF-1α expression and nuclear translocation by deoxyshikonin. Evid Based Complement Alternat Med. 2013:1482972013. View Article : Google Scholar : PubMed/NCBI
27	Kannan KB, Colorado I, Reino D, Palange D, Lu Q, Qin X, Abungu B, Watkins A, Caputo FJ, Xu DZ, et al: Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 300:G853–G861. 2011. View Article : Google Scholar : PubMed/NCBI
28	Haddad JJ: Science review: Redox and oxygen-sensitive transcription factors in the regulation of oxidant-mediated lung injury: Role for hypoxia-inducible factor-1 alpha. Crit Care. 7:47–54. 2003. View Article : Google Scholar : PubMed/NCBI
29	Jiang H, Huang Y, Xu H, Hu R and Li QF: Inhibition of hypoxia inducible factor-1α ameliorates lung injury induced by trauma and hemorrhagic shock in rats. Acta Pharmacol Sin. 33:635–643. 2012. View Article : Google Scholar : PubMed/NCBI
30	Li LH, Wu LJ, Zhou B, Wu Z, Tashiro S, Onodera S, Uchiumi F and Ikejima T: Silymarin prevents UV irradiation-induced A375-S2 cell apoptosis. Biol Pharm Bull. 27:1031–1036. 2004. View Article : Google Scholar : PubMed/NCBI
31	Atawia RT, Mosli HH, Tadros MG, Khalifa AE, Mosli HA and Abdel-Naim AB: Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia: Emphasis on PTEN, HIF-1α, and NF-κB. Naunyn Schmiedebergs Arch Pharmacol. 387:1131–1140. 2014. View Article : Google Scholar : PubMed/NCBI
32	Kim EJ, Kim J, Lee MY, Sudhanva MS, Devakumar S and Jeon YJ: Silymarin inhibits cytokine-stimulated pancreatic beta cells by blocking the ERK1/2 pathway. Biomol Ther (Seoul). 22:282–287. 2014. View Article : Google Scholar : PubMed/NCBI