The protective role of vitamin D3 in a murine model of asthma via the suppression of TGF-β/Smad signaling and activation of the Nrf2/HO-1 pathway

Wang,Zhihui; Zhang,Haitao; Sun,Xiaohan; Ren,Lihong

doi:10.3892/mmr.2016.5563

The protective role of vitamin D3 in a murine model of asthma via the suppression of TGF-β/Smad signaling and activation of the Nrf2/HO-1 pathway

Authors:
- Zhihui Wang
- Haitao Zhang
- Xiaohan Sun
- Lihong Ren
View Affiliations

Affiliations: Department of Pediatric Internal Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: July 27, 2016 https://doi.org/10.3892/mmr.2016.5563
Pages: 2389-2396
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Asthma is a common worldwide health burden, the prevalence of which is increasing. Recently, the biologically active form of vitamin D3, 1,25-dihydroxyvitamin D3, has been reported to have a protective role in murine asthma; however, the molecular mechanisms by which vitamin D3 attenuates asthma‑associated airway injury remain elusive. In the present study, BALB/c mice were sensitized to ovalbumin (OVA) and were administered 100 ng 1,25-dihydroxyvitamin D3 (intraperitoneal injection) 30 min prior to each airway challenge. The inflammatory responses were measured by ELISA, airway damage was analyzed by hematoxylin and eosin staining, airway remodeling was analyzed by Masson staining and periodic acid‑Schiff staining, markers of oxidative stress were measured by commercial kits, and the expression levels of α‑smooth muscle actin (α-SMA) and the activity of the NF‑E2‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1) and the transforming growth factor‑β (TGF‑β)/Smad signaling pathways were measured by immunohistochemistry and western blotting. The results demonstrated that OVA‑induced airway inflammation and immunoglobulin E overexpression were significantly reduced by vitamin D3 treatment. In addition, treatment with vitamin D3 decreased α‑SMA expression, collagen deposition and goblet cell hyperplasia, and inhibited TGF‑β/Smad signaling in the asthmatic airway. The upregulated levels of malondialdehyde, and the reduced activities of superoxide dismutase and glutathione in OVA‑challenged mice were also markedly restored following vitamin D3 treatment. Furthermore, treatment with vitamin D3 enhanced activation of the Nrf2/HO‑1 pathway in the airways of asthmatic mice. In conclusion, these findings suggest that vitamin D3 may protect airways from asthmatic damage via the suppression of TGF‑β/Smad signaling and activation of the Nrf2/HO‑1 pathway; however, these protective effects were shown to be accompanied by hypercalcemia.

View Figures

View References

1	Hamid Q and Tulic M: Immunobiology of asthma. Ann Rev Physiol. 71:489–507. 2009. View Article : Google Scholar
2	Masoli M, Fabian D, Holt S and Beasley R; Global Initiative for Asthma (GINA) Program: The global burden of asthma: Executive summary of the GINA dissemination committee report. Allergy. 59:469–478. 2004. View Article : Google Scholar : PubMed/NCBI
3	Zhou W and Nie X: Afzelin attenuates asthma phenotypes by downregulation of GATA3 in a murine model of asthma. Mol Med Rep. 12:71–76. 2015.PubMed/NCBI
4	Barnes PJ: Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 131:636–645. 2013. View Article : Google Scholar : PubMed/NCBI
5	Dusso AS, Brown AJ and Slatopolsky E: Vitamin D. Am J Physiol Renal Physiol. 289:F8–F28. 2005. View Article : Google Scholar : PubMed/NCBI
6	Nebel D, Svensson D, Arosenius K, Larsson E, Jönsson D and Nilsson BO: 1α,25-dihydroxyvitamin D3 promotes osteogenic activity and downregulates proinflammatory cytokine expression in human periodontal ligament cells. J Periodontal Res Dec. 12:2014.Epub ahead of print.
7	Kelsey L, Katoch P, Ray A, Mitra S, Chakraborty S, Lin MF and Mehta PP: Vitamin D3 regulates the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells. PloS One. 9:e1064372014. View Article : Google Scholar : PubMed/NCBI
8	Robsahm TE, Tretli S, Dahlback A and Moan J: Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control. 15:149–158. 2004. View Article : Google Scholar : PubMed/NCBI
9	Pálmer HG, González-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M and Muñoz A: Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 154:369–387. 2001. View Article : Google Scholar : PubMed/NCBI
10	Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S and White JH: Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 173:2909–2912. 2004. View Article : Google Scholar : PubMed/NCBI
11	Penna G and Adorini L: 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 164:2405–2411. 2000. View Article : Google Scholar : PubMed/NCBI
12	Chen S, Sims GP, Chen XX, Gu YY, Chen S and Lipsky PE: Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 179:1634–1647. 2007. View Article : Google Scholar : PubMed/NCBI
13	Rigo I, McMahon L, Dhawan P, Christakos S, Yim S, Ryan LK and Diamond G: Induction of triggering receptor expressed on myeloid cells (TREM-1) in airway epithelial cells by 1,25(OH) vitamin D₃. Innate Immun. 18:250–257. 2012. View Article : Google Scholar
14	Gorman S, Tan DH, Lambert MJ, Scott NM, Judge MA and Hart PH: Vitamin D(3) deficiency enhances allergen-induced lymphocyte responses in a mouse model of allergic airway disease. Pediatr Allergy Immunol. 23:83–87. 2012. View Article : Google Scholar : PubMed/NCBI
15	Lai G, Wu C, Hong J and Song Y: 1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) attenuates airway remodeling in a murine model of chronic asthma. J Asthma. 50:133–140. 2013. View Article : Google Scholar
16	Zhou Y, Zhou X and Wang X: 1,25-Dihydroxyvitamin D3 prevented allergic asthma in a rat model by suppressing the expression of inducible nitric oxide synthase. Allergy Asthma Proc. 29:258–267. 2008. View Article : Google Scholar : PubMed/NCBI
17	Terawaki K, Yokomizo T, Nagase T, Toda A, Taniguchi M, Hashizume K, Yagi T and Shimizu T: Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type immune responses. J Immunol. 175:4217–4225. 2005. View Article : Google Scholar : PubMed/NCBI
18	Le AV, Cho JY, Miller M, McElwain S, Golgotiu K and Broide DH: Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice. J Immunol. 178:7310–7316. 2007. View Article : Google Scholar : PubMed/NCBI
19	Yao P, Nussler A, Liu L, Hao L, Song F, Schirmeier A and Nussler N: Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol. 47:253–261. 2007. View Article : Google Scholar : PubMed/NCBI
20	Halwani R, Al-Muhsen S, Al-Jahdali H and Hamid Q: Role of transforming growth factor-β in airway remodeling in asthma. Am J Respir Cell Mol Biol. 44:127–133. 2011. View Article : Google Scholar
21	Li MO, Wan YY, Sanjabi S, Robertson AK and Flavell RA: Transforming growth factor-beta regulation of immune responses. Ann Rev Immunol. 24:99–146. 2006. View Article : Google Scholar
22	Ryter SW, Alam J and Choi AM: Heme oxygenase-1/carbon monoxide: From basic science to therapeutic applications. Physiol Rev. 86:583–650. 2006. View Article : Google Scholar : PubMed/NCBI
23	Kaspar JW, Niture SK and Jaiswal AK: Nrf2: INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 47:1304–1309. 2009. View Article : Google Scholar : PubMed/NCBI
24	Zella JB, McCary LC and DeLuca HF: Oral administration of 1,25-dihydroxyvitamin D3 completely protects NOD mice from insulin-dependent diabetes mellitus. Arch Biochem Biophys. 417:77–80. 2003. View Article : Google Scholar : PubMed/NCBI
25	Litonjua AA and Weiss ST: Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol. 120:1031–1035. 2007. View Article : Google Scholar : PubMed/NCBI
26	Wittke A, Weaver V, Mahon BD, August A and Cantorna MT: Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J Immunol. 173:3432–3436. 2004. View Article : Google Scholar : PubMed/NCBI
27	Rodrigo GJ, Rodrigo C and Hall JB: Acute asthma in adults: A review. Chest. 125:1081–1102. 2004. View Article : Google Scholar : PubMed/NCBI
28	Holgate ST: What does inflammation and airway remodelling mean? Clinical & Experimental Allergy Reviews. 1:59–61. 2001. View Article : Google Scholar
29	Fahy JV: Remodeling of the airway epithelium in asthma. Am J Respir Crit Care Med. 164:S46–S51. 2001. View Article : Google Scholar : PubMed/NCBI
30	Makinde T, Murphy RF and Agrawal DK: The regulatory role of TGF-beta in airway remodeling in asthma. Immunol Cell Biol. 85:348–356. 2007. View Article : Google Scholar : PubMed/NCBI
31	Sagara H, Okada T, Okumura K, Ogawa H, Ra C, Fukuda T and Nakao A: Activation of TGF-beta/Smad2 signaling is associated with airway remodeling in asthma. J Allergy Clin Immunol. 110:249–254. 2002. View Article : Google Scholar : PubMed/NCBI
32	Riedl MA and Nel AE: Importance of oxidative stress in the pathogenesis and treatment of asthma. Curr Opin Allergy Clin Immunol. 8:49–56. 2008. View Article : Google Scholar : PubMed/NCBI
33	Andreadis AA, Hazen SL, Comhair SA and Erzurum SC: Oxidative and nitrosative events in asthma. Free Radic Biol Med. 35:213–225. 2003. View Article : Google Scholar : PubMed/NCBI
34	Bao BY, Ting HJ, Hsu JW and Lee YF: Protective role of 1 alpha, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int J Cancer. 122:2699–2706. 2008. View Article : Google Scholar : PubMed/NCBI
35	Hamden K, Carreau S, Jamoussi K, Miladi S, Lajmi S, Aloulou D, Ayadi F and Elfeki A: 1 Alpha,25 dihydroxyvitamin D3: Therapeutic and preventive effects against oxidative stress, hepatic, pancreatic and renal injury in alloxan-induced diabetes in rats. J Nutr Sci Vitaminol (Tokyo). 55:215–222. 2009. View Article : Google Scholar
36	Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN and Biswal S: Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 202:47–59. 2005. View Article : Google Scholar : PubMed/NCBI
37	Kim J, Cha YN and Surh YJ: A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res. 690:12–23. 2010. View Article : Google Scholar
38	Lim S, Groneberg D, Fischer A, Oates T, Caramori G, Mattos W, Adcock I, Barnes PJ and Chung KF: Expression of heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways: Effect of inhaled corticosteroids. Am J Respir Crit Care Med. 162:1912–1918. 2000. View Article : Google Scholar : PubMed/NCBI