Asiatic acid prevents the development of interstitial lung disease in a hypochlorous acid‑induced mouse model of scleroderma

Xia,Xiaoru; Dai,Caijun; Yu,Hua; Huang,Xiaoying; Chen,Ali; Tan,Yingxia; Wang,Liangxing

doi:10.3892/ol.2018.8412

Asiatic acid prevents the development of interstitial lung disease in a hypochlorous acid‑induced mouse model of scleroderma

Authors:
- Xiaoru Xia
- Caijun Dai
- Hua Yu
- Xiaoying Huang
- Ali Chen
- Yingxia Tan
- Liangxing Wang
View Affiliations

Affiliations: Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Respiratory Medicine, Jinhua Municipal Central Hospital, Zhejiang University Jinhua Hospital, Jinhua, Zhejiang 321000, P.R. China, Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Pulmonary Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: April 2, 2018 https://doi.org/10.3892/ol.2018.8412
Pages: 8711-8716

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

Interstitial lung disease is the most common complication of systemic sclerosis (SSc) and is associated with a high rate of mortality. Due to the complex pathogenesis of SSc, the therapies currently available remain limited. In the present study, the effect of asiatic acid (AA) on SSc‑associated pulmonary fibrosis (PF) and its association with the transforming growth factor‑β1 (TGF‑β1)/Smad2/3 signaling pathway were evaluated. A hypochlorous acid (HOCl)‑induced model of SSc was used to evaluate the therapeutic effect of AA on PF in SSc, where AA was administered to SSc mice by gavage. PF was alleviated in the AA‑treated SSc mice groups when examined under light microscopy. In addition, there was a decrease in histopathological progression and collagen in the lungs. AA significantly reduced expression of type I collagen in the lungs of mice with SSc. It also significantly suppressed α‑smooth muscle actin expression, which attenuated the conversion of fibroblasts into muscle fibroblasts. These AA‑associated antifibrosis and anti‑immune effects were mediated through the significant downregulation of advanced oxidation protein product, E‑selectin, and anti‑DNA topoisomerase‑1 autoantibody levels in the serum. Furthermore, the expression levels of TGF‑β1 and the phosphorylated‑Smad2/3/Smad2/3 ratios in AA‑treated SSc mice were similar to the control. The presence of pulmonary inflammation and fibrosis was confirmed in the HOCl‑induced SSc mice and the results demonstrated that selective inhibition of reactive oxygen species prevented PF. By focusing on the classical TGF‑β1/Smad2/3 signaling pathway, a mechanism of action of AA was identified to be associated with the inhibition of Smad2/3 activation through negative regulation of Smad2/3 phosphorylation.

View Figures

View References

1	Balbir-Gurman A and Braun-Moscovici Y: Scleroderma-new aspects in pathogenesis and treatment. Best Prac Res Clin Rheumatol. 26:13–24. 2012. View Article : Google Scholar
2	Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Müller-Ladner U, Distler O, et al: Causes and risk factors for death in systemic sclerosis: A study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 69:1809–1815. 2010. View Article : Google Scholar : PubMed/NCBI
3	Bourji K, Meyer A, Chatelus E, Pincemail J, Pigatto E, Defraigne JO, Singh F, Charlier C, Geny B, Gottenberg JE, et al: High reactive oxygen species in fibrotic and nonfibrotic skin of patients with diffuse cutaneous systemic sclerosis. Free Radic Biol Med. 87:282–289. 2015. View Article : Google Scholar : PubMed/NCBI
4	Yoshizaki A, Iwata Y, Komura K, Ogawa F, Hara T, Muroi E, Takenaka M, Shimizu K, Hasegawa M, Fujimoto M, et al: CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol. 172:1650–1663. 2008. View Article : Google Scholar : PubMed/NCBI
5	Allanore Y, Borderie D, Lemarechal H, Ekindjian OG and Kahan A: Acute and sustained effects of dihydropyridine-type calcium channel antagonists on oxidative stress in systemic sclerosis. Am J Med. 116:595–600. 2004. View Article : Google Scholar : PubMed/NCBI
6	Sambo P, Baroni SS, Luchetti M, Paroncini P, Dusi S, Orlandini G and Gabrielli A: Oxidative stress in scleroderma: Maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum. 44:2653–2664. 2001. View Article : Google Scholar : PubMed/NCBI
7	Varga J and Abraham D: Systemic sclerosis: A prototypic multisystem fibrotic disorder. J Clin Invest. 117:557–567. 2007. View Article : Google Scholar : PubMed/NCBI
8	Fernandez IE and Eickelberg O: The impact of TGF-β on lung fibrosis: From targeting to biomarkers. Proc Am Thorac Soc. 9:111–116. 2012. View Article : Google Scholar : PubMed/NCBI
9	Liu RM and Desai LP: Reciprocal regulation of TGF-β and reactive oxygen species: A perverse cycle for fibrosis. Redox Biol. 6:565–577. 2015. View Article : Google Scholar : PubMed/NCBI
10	Pociask DA, Sime PJ and Brody AR: Asbestos-derived reactive oxygen species activate TGF-beta1. Lab Invest. 84:1013–1023. 2004. View Article : Google Scholar : PubMed/NCBI
11	Xu L, Cui WH, Zhou WC, Li DL, Li LC, Zhao P, Mo XT, Zhang Z and Gao J: Activation of Wnt/beta-catenin signalling is required for TGF-β/Smad2/3 signalling during myofibroblast proliferation. J Cell Mol Med. 21:1545–1554. 2017. View Article : Google Scholar : PubMed/NCBI
12	Bian D, Zhang J, Wu X, Dou Y, Yang Y, Tan Q, Xia Y, Gong Z and Dai Y: Asiatic acid isolated from Centella asiatica inhibits TGF-β1-induced collagen expression in human keloid fibroblasts via PPAR-gamma activation. Int J Biol Sci. 9:1032–1042. 2013. View Article : Google Scholar : PubMed/NCBI
13	Meng XM, Zhang Y, Huang XR, Ren GL, Li J and Lan HY: Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 6:36984–36997. 2015. View Article : Google Scholar : PubMed/NCBI
14	Si L, Xu J, Yi C, Xu X, Ma C, Yang J, Wang F, Zhang Y and Wang X: Asiatic acid attenuates the progression of left ventricular hypertrophy and heart failure induced by pressure overload by inhibiting myocardial remodeling in mice. J Cardiovasc Pharmacol. 66:558–568. 2015. View Article : Google Scholar : PubMed/NCBI
15	Xu X, Si L, Xu J, Yi C, Wang F, Gu W, Zhang Y and Wang X: Asiatic acid inhibits cardiac hypertrophy by blocking interleukin-1β-activated nuclear factor-κB signaling in vitro and in vivo. J Thorac Dis. 7:1787–1797. 2015.PubMed/NCBI
16	Xu C, Wang W, Xu M and Zhang J: Asiatic acid ameliorates tubulointerstitial fibrosis in mice with ureteral obstruction. Exp Ther Med. 6:731–736. 2013. View Article : Google Scholar : PubMed/NCBI
17	Ramachandran V and Saravanan R: Efficacy of asiatic acid, a pentacyclic triterpene on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-induced diabetic rats. Phytomedicine. 20:230–236. 2013. View Article : Google Scholar : PubMed/NCBI
18	Barnes J and Mayes MD: Epidemiology of systemic sclerosis: Incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 24:165–170. 2012. View Article : Google Scholar : PubMed/NCBI
19	Highland KB and Silver RM: New developments in scleroderma interstitial lung disease. Curr Opin Rheumatol. 17:737–745. 2005. View Article : Google Scholar : PubMed/NCBI
20	Tang LX, He RH, Yang G, Tan JJ, Zhou L, Meng XM, Huang XR and Lan HY: Asiatic acid inhibits liver fibrosis by blocking TGF-beta/Smad signaling in vivo and in vitro. PLoS One. 7:e313502012. View Article : Google Scholar : PubMed/NCBI
21	Dong SH, Liu YW, Wei F, Tan HZ and Han ZD: Asiatic acid ameliorates pulmonary fibrosis induced by bleomycin (BLM) via suppressing pro-fibrotic and inflammatory signaling pathways. Biomed Pharmacother. 89:1297–1309. 2017. View Article : Google Scholar : PubMed/NCBI
22	Asano Y, Ihn H, Yamane K, Kubo M and Tamaki K: Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts. J Clin Invest. 113:253–264. 2004. View Article : Google Scholar : PubMed/NCBI
23	Zhang H, Ran X, Hu CL, Qin LP, Lu Y and Peng C: Therapeutic effects of liposome-enveloped ligusticum chuanxiong essential oil on hypertrophic scars in the rabbit ear model. PLoS One. 7:e311572012. View Article : Google Scholar : PubMed/NCBI
24	Bei Y, Hua-Huy T, Nicco C, Duong-Quy S, Le-Dong NN, Tiev KP, Chéreau C, Batteux F and Dinh-Xuan AT: RhoA/Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis. Exp Lung Res. 42:44–45. 2016. View Article : Google Scholar : PubMed/NCBI
25	Servettaz A, Goulvestre C, Kavian N, Nicco C, Guilpain P, Chéreau C, Vuiblet V, Guillevin L, Mouthon L, Weill B and Batteux F: Selective oxidation of DNA topoisomerase 1 induces systemic sclerosis in the mouse. J Immunol. 182:5855–5864. 2009. View Article : Google Scholar : PubMed/NCBI
26	Servettaz A, Guilpain P, Goulvestre C, Chéreau C, Hercend C, Nicco C, Guillevin L, Weill B, Mouthon L and Batteux F: Radical oxygen species production induced by advanced oxidation protein products predicts clinical evolution and response to treatment in systemic sclerosis. Ann Rheum Dis. 66:1202–1209. 2007. View Article : Google Scholar : PubMed/NCBI
27	Blackburn RM: Too much of a good thing: Adenosine overload in adenosine-deaminase-deficient mice. Trends Pharmacol Sci. 24:66–70. 2003. View Article : Google Scholar : PubMed/NCBI
28	Kim HJ, Tashkin DP, Gjertson DW, Brown MS, Kleerup E, Chong S, Belperio JA, Roth MD, Abtin F, Elashoff R, et al: Transitions to different patterns of interstitial lung disease in scleroderma with and without treatment. Ann Rheum Dis. 75:1367–1371. 2016. View Article : Google Scholar : PubMed/NCBI
29	Adtani PN, Narasimhan M, Punnoose AM and Kambalachenu HR: Antifibrotic effect of Centella asiatica Linn and asiatic acid on arecoline-induced fibrosis in human buccal fibroblasts. J Investig Clin Dent. 8:2017. View Article : Google Scholar : PubMed/NCBI
30	Liu J, He T, Lu Q, Shang J, Sun H and Zhang L: Asiatic acid preserves beta cell mass and mitigates hyperglycemia in streptozocin-induced diabetic rats. Diabetes Metab Res Rev. 26:448–454. 2010. View Article : Google Scholar : PubMed/NCBI
31	Sato M, Hirayama S, Lara-Guerra H, Anraku M, Waddell TK, Liu M and Keshavjee S: MMP-dependent migration of extrapulmonary myofibroblast progenitors contributing to posttransplant airway fibrosis in the lung. Am J Transplant. 9:1027–1036. 2009. View Article : Google Scholar : PubMed/NCBI
32	Wolters PJ, Collard HR and Jones KD: Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 9:157–179. 2014. View Article : Google Scholar : PubMed/NCBI
33	Su BH, Tseng YL, Shieh GS, Chen YC, Wu P, Shiau AL and Wu CL: Over-expression of prothymosin-alpha antagonizes TGFβ signalling to promote the development of emphysema. J Pathol. 238:412–422. 2016. View Article : Google Scholar : PubMed/NCBI
34	Sato M, Muragaki Y, Saika S, Roberts AB and Ooshima A: Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest. 112:1486–1494. 2003. View Article : Google Scholar : PubMed/NCBI
35	Wang P, Wang Y, Nie X, Braïni C, Bai R and Chen C: Multiwall carbon nanotubes directly promote fibroblast-myofibroblast and epithelial-mesenchymal transitions through the activation of the TGF-β/Smad signaling pathway. Small. 11:446–455. 2015. View Article : Google Scholar : PubMed/NCBI
36	Yamane K, Ihn H, Kubo M, Yazawa N, Kikuchi K, Soma Y and Tamaki K: Increased serum levels of soluble vascular cell adhesion molecule 1 and E-selectin in patients with localized scleroderma. J Am Acad Dermatol. 42:64–69. 2000. View Article : Google Scholar : PubMed/NCBI