Vitamin D alleviates lipopolysaccharide‑induced acute lung injury via regulation of the renin‑angiotensin system
Jun Xu, Jialai Yang, Jian Chen, Qingli Luo, Qiu Zhang, Hong Zhang, Jun Xu, Jialai Yang, Jian Chen, Qingli Luo, Qiu Zhang, Hong Zhang
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. ALI and ARDS result are associated with high mortality in patients. At present, no effective treatments for ALI and ARDS exist. It is established that vitamin D exhibits anti‑inflammatory effects, however, the specific effect of vitamin D on ALI remains largely unknown. The aim of the present study was to investigate whether, and by which mechanism, vitamin D alleviates lipopolysaccharide (LPS)‑induced ALI. The results demonstrated that a vitamin D agonist, calcitriol, exhibited a beneficial effect on LPS‑induced ALI in rats; calcitriol pretreatment significantly improved LPS‑induced lung permeability, as determined using Evans blue dye. Results from reverse transcription‑quantitative polymerase chain reaction, western blotting and ELISA analysis demonstrated that calcitriol also modulated the expression of members of the renin‑angiotensin system (RAS), including angiotensin (Ang) I‑converting enzymes (ACE and ACE2), renin and Ang II, which indicates that calcitriol may exert protective effects on LPS‑induced lung injury, at least partially, by regulating the balance between the expression of members of the RAS. The results of the present study may provide novel targets for the future treatment of ALI.
Figures
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References
- Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685–1693. doi: 10.1056/NEJMoa050333.
- Phua J, Badia JR, Adhikari NK, Friedrich JO, Fowler RA, Singh JM, Scales DC, Stather DR, Li A, Jones A, et al. Has mortality from acute respiratory distress syndrome decreased over time? A systematic review. Am J Respir Crit Care Med. 2009;179:220–227. doi: 10.1164/rccm.200805-722OC.
- Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2008;295:L379–L399. doi: 10.1152/ajplung.90520.2008.
- Wheeler AP, Bernard GR. Acute lung injury and the acute respiratory distress syndrome: A clinical review. Lancet. 2007;369:1553–1564. doi: 10.1016/S0140-6736(07)60604-7.
- Su X, Wang L, Song Y, Bai C. Inhibition of inflammatory responses by ambroxol, a mucolytic agent, in a murine model of acute lung injury induced by lipopolysaccharide. Intensive Care Med. 2004;30:133–140. doi: 10.1007/s00134-003-2001-y.
- Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, Selznick SH, Dominguez CE, Jurutka PW. The nuclear vitamin D receptor: Biological and molecular regulatory properties revealed. J Bone Miner Res. 1998;13:325–349. doi: 10.1359/jbmr.1998.13.3.325.
- Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW. Respiratory epithelial cells convert inactive vitamin D to its active form: Potential effects on host defense. J Immunol. 2008;181:7090–7099. doi: 10.4049/jimmunol.181.10.7090.
- Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA, Raza K, Sansom DM. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol. 2009;183:5458–5467. doi: 10.4049/jimmunol.0803217.
- D'Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, Pipeling MR, Brower RG, Tuder RM, McDyer JF, King LS. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119:2898–2913. doi: 10.1172/JCI36498.
- Kong J, Zhu X, Shi Y, Liu T, Chen Y, Bhan I, Zhao Q, Thadhani R, Li YC. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol. 2013;27:2116–2125. doi: 10.1210/me.2013-1146.
- Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275:33238–33243. doi: 10.1074/jbc.M002615200.
- Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: New players of the renin-angiotensin system. J Endocrinol. 2013;216:R1–R17. doi: 10.1530/JOE-12-0341.
- Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–116. doi: 10.1038/nature03712.
- Treml B, Neu N, Kleinsasser A, Gritsch C, Finsterwalder T, Geiger R, Schuster M, Janzek E, Loibner H, Penninger J, Loeckinger A. Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med. 2010;38:596–601. doi: 10.1097/CCM.0b013e3181c03009.
- Li Y, Zeng Z, Cao Y, Liu Y, Ping F, Liang M, Xue Y, Xi C, Zhou M, Jiang W. Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways. Sci Rep. 2016;6:27911. doi: 10.1038/srep27911.
- Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J. Vitamin D: A negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol 89–90. 2004:1–392.
- Shi Y, Liu T, Li Y, Xing Y, Zhao X, Fu J, Xue X. Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system. Sci Rep. 2017;7:3312. doi: 10.1038/s41598-017-03474-6.
- Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int. 2008;74:170–179. doi: 10.1038/ki.2008.101.
- Zhang H, Sun GY. Expression and regulation of AT1 receptor in rat lung microvascular endothelial cell. J Surg Res. 2006;134:190–197. doi: 10.1016/j.jss.2006.01.026.
- Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262.
- Yang P, Gu H, Zhao Z, Wang W, Cao B, Lai C, Yang X, Zhang L, Duan Y, Zhang S, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014;4:7027. doi: 10.1038/srep07027.
- Rey-Parra GJ, Vadivel A, Coltan L, Hall A, Eaton F, Schuster M, Loibner H, Penninger JM, Kassiri Z, Oudit GY, Thébaud B. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury. J Mol Med (Berl) 2012;90:637–647. doi: 10.1007/s00109-012-0859-2.
- Borghi C, Boschi S, Ambrosioni E, Melandr G, Branzi A, Magnani B. Evidence of a partial escape of renin-angiotensin-aldosterone blockade in patients with acute myocardial infarction treated with ACE inhibitors. J Clin Pharmacol. 1993;33:40–45. doi: 10.1002/j.1552-4604.1993.tb03901.x.
- Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349. doi: 10.1056/NEJM200005043421806.
- Shi YY, Liu TJ, Fu JH, Xu W, Wu LL, Hou AN, Xue XD. Vitamin D/VDR signaling attenuates lipopolysaccharide-induced acute lung injury by maintaining the integrity of the pulmonary epithelial barrier. Mol Med Rep. 2016;13:1186–1194. doi: 10.3892/mmr.2015.4685.
- Zhang M, Dong M, Liu W, Wang L, Luo Y, Li Z, Jin F. 1α,25-dihydroxyvitamin D3 ameliorates seawater aspiration-induced acute lung injury via NF-κB and RhoA/Rho kinase pathways. PLoS One. 2014;9:e104507. doi: 10.1371/journal.pone.0104507.
- Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110:229–238. doi: 10.1172/JCI0215219.
- Ishii K, Takeuchi H, Fukunaga K, Hirano Y, Suda K, Hagiwara T, Miyasho T, Yamada S, Nakamura R, Takahashi T, et al. Attenuation of lipopolysaccharide-induced acute lung injury after (pro)renin receptor blockade. Exp Lung Res. 2015;41:199–207. doi: 10.3109/01902148.2014.993444.
- Chen LN, Yang XH, Nissen DH, Chen YY, Wang LJ, Wang JH, Gao JL, Zhang LY. Dysregulated renin-angiotensin system contributes to acute lung injury caused by hind-limb ischemia-reperfusion in mice. Shock. 2013;40:420–429. doi: 10.1097/SHK.0b013e3182a6953e.
- Liu L, Qiu HB, Yang Y, Wang L, Ding HM, Li HP. Losartan, an antagonist of AT1 receptor for angiotensin II, attenuates lipopolysaccharide-induced acute lung injury in rat. Arch Biochem Biophys. 2009;481:131–136. doi: 10.1016/j.abb.2008.09.019.
- Wang F, Xia ZF, Chen XL, Jia YT, Wang YJ, Ma B. Angiotensin II type-1 receptor antagonist attenuates LPS-induced acute lung injury. Cytokine. 2009;48:246–253. doi: 10.1016/j.cyto.2009.08.001.
- Burrell LM, Johnston CI, Tikellis C, Cooper ME. ACE2, a new regulator of the renin-angiotensin system. Trends Endocrinol Metab. 2004;15:166–169. doi: 10.1016/j.tem.2004.03.001.
- Shi Y, Zhang B, Chen XJ, Xu DQ, Wang YX, Dong HY, Ma SR, Sun RH, Hui YP, Li ZC. Osthole protects lipopolysaccharide-induced acute lung injury in mice by preventing down-regulation of angiotensin-converting enzyme 2. Eur J Pharm Sci. 2013;48:819–824. doi: 10.1016/j.ejps.2012.12.031.
- Zambelli V, Bellani G, Borsa R, Pozzi F, Grassi A, Scanziani M, Castiglioni V, Masson S, Decio A, Laffey JG, et al. Angiotensin-(1–7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental acute respiratory distress syndrome. Intensive Care Med Exp. 2015;3:44. doi: 10.1186/s40635-015-0044-3.
Source: PubMed