Amelioration of Bleomycin-induced Pulmonary Fibrosis of Rats by an Aldose Reductase Inhibitor, Epalrestat

다국어 초록 (Multilingual Abstract)

Aldose reductase (AR) is known to play a crucial role in the mediation of diabetic and cardiovascular complications. Recently, several studies have demonstrated that allergen-induced airway remodeling and ovalbumin-induced asthma is mediated by AR. Epalrestat is an aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Whether AR is involved in pathogenesis of pulmonary fibrosis and whether epalrestat attenuates pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. The expression of AR, TGF-β₁, α-SMA and collagen I was analyzed by immunohis-tochemisty, real-time PCR or western blot. In vivo, epalrestat treatment significantly ameliorated the bleomycin-mediated histological fibrosis alterations and blocked collagen deposition concomitantly with reversing bleomycin-induced expression up-regulation of TGF-β₁, AR, α-SMA and collagen I (both mRNA and protein). In vitro, epalrestat remarkably attenuated proliferation of pulmonary fibroblasts and expression of α-SMA and collagen I induced by TGF-β₁, and this inhibitory effect of epalrestat was accompanied by inhibiting AR expression. Knockdown of AR gene expression reversed TGF-β₁-induced proliferation of fibroblasts, up-regulation of α-SMA and collagen I expression. These findings suggest that AR plays an important role in bleomycin-induced pulmonary fibrosis, and epalrestat inhibited the progression of bleomycin-induced pulmonary fibrosis is mediated via inhibiting of AR expression.

참고문헌 (Reference)

1 Hinz B, "The myofibroblast: one function, multiple origins" 170 : 1807-1816, 2007

2 Phan SH, "The myofibroblast in pulmonary fibrosis" 122 (122): 286S-289S, 2002

3 Zhang H, "Tectorigenin inhibits the in vitro proliferation and enhances miR-338* expression of pulmonary fibroblasts in rats with idiopathic pulmonary fibrosis" 131 : 165-173, 2010

4 Ashcroft T, "Simple method of estimating severity of pulmonary fibrosis on a numerical scale" 41 : 467-470, 1988

5 El-Kabbani O, "Selectivity determinants of the aldose and aldehyde reductase inhibitor-binding sites" 64 : 1970-1978, 2007

6 Li XW, "Role of eukaryotic translation initiation factor 3a in bleomycin-induced pulmonary fibrosis" 749 : 89-97, 2015

7 Zhang Y, "Role of aldose reductase in TGF-beta1-induced fibronectin synthesis in human mesangial cells" 37 : 2735-2742, 2010

8 Srivastava SK, "Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options" 26 : 380-392, 2005

9 Khalil N, "Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors(T beta R-I and T beta R-II)in idiopathic pulmonary fibrosis" 56 : 907-915, 2001

10 Thavarajah K, "Pulmonary complications of tumor necrosis factor-targeted therapy" 103 : 661-669, 2009

11 Li L, "Protective effects of Eucommia lignans against hypertensive renal injury by inhibiting expression of aldose reductase" 139 : 454-461, 2012

12 Ravindranath TM, "Novel role for aldose reductase in mediating acute inflammatory responses in the lung" 183 : 8128-8137, 2009

13 Scotton CJ, "Molecular targets in pulmonary fibrosis: the myofibroblast in focus" 132 : 1311-1321, 2007

14 Kisseleva T, "Mechanisms of fibrogenesis" 233 : 109-122, 2008

15 Jiang HD, "MS80, a novel sulfated oligosaccharide, inhibits pulmonary fibrosis by targeting TGF-beta1 both in vitro and in vivo" 30 : 973-979, 2009

16 Hotta N, "Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial" 29 : 1538-1544, 2006

17 Coker RK, "Localisation of transforming growth factor beta1and beta3 mRNA transcripts in normal and fibrotic human lung" 56 : 549-556, 2001

18 Li ZY, "Lignans from the bark of Eucommia ulmoides inhibited Ang II-stimulated extracellular matrix biosynthesis in mesangial cells" 9 : 8-, 2014

19 Wynn TA, "Integrating mechanisms of pulmonary fibrosis" 208 : 1339-1350, 2011

20 Yadav UC, "Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice" 4 : e30134-, 2009

21 Tammali R, "Inhibition of aldose reductase prevents colon cancer metastasis" 32 : 1259-1267, 2011

22 O'Connell OJ, "Idiopathic pulmonary fibrosis: treatment update" 28 : 986-999, 2011

23 Gross TJ, "Idiopathic pulmonary fibrosis" 345 : 517-525, 2001

24 Anil Kumar P, "Focus on molecules : aldose reductase" 85 : 739-740, 2007

25 Sato K, "Epalrestat increases intracellular glutathione levels in Schwann cells through transcription regulation" 2 : 15-21, 2013

26 Ramirez MA, "Epalrestat : an aldose reductase inhibitor for the treatment of diabetic neuropathy" 28 : 646-655, 2008

27 Steele JW, "Epalrestat : a review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus" 3 : 532-555, 1993

28 Gu J, "Effects of lignans extracted from Eucommia ulmoides and aldose reductase inhibitor epalrestat on hypertensive vascular remodeling" 133 : 6-13, 2011

29 Gu L, "Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation" 28 : 382-391, 2007

30 Takahashi K, "Amelioration of acute kidney injury in lipopolysaccharide-induced systemic inflammatory response syndrome by an aldose reductase inhibitor, fidarestat" 7 : e30134-, 2012

31 Vedantham S, "Aldose reductase, oxidative stress and diabetic cardiovascular complications" 10 : 234-240, 2012

32 Zou L, "Aldose reductase regulates platelet-derived growth factor-induced proliferation through mediating cell cycle progression in rat mesangial cells" 30 : 409-416, 2012

33 Jiang T, "Aldose reductase regulates TGF-beta1-induced production of fibronectin and type IV collagen in cultured rat mesangial cells" 11 : 105-112, 2006

34 Huang P, "Aldose reductase is a potent regulator of TGF-β1 induced expression of fibronectin in human mesangial cells" 37 : 3097-3103, 2010

35 Yasunari K, "Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose" 35 : 1092-1098, 2000

36 Yadav UC, "Aldose reductase inhibition suppresses the expression of Th2 cytokines and airway inflammation in ovalbumin-induced asthma in mice" 183 : 4723-4732, 2009

37 Srivastava SK, "Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders" 191 : 330-338, 2011

38 Yadav UC, "Aldose reductase inhibition prevents metaplasia of airway epithelial cells" 5 : e14440-, 2010

39 Yadav UC, "Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3β pathway in mice" 8 : e57442-, 2013

40 Hotta N, "Aldose Reductase Inhibitor-Diabetes Complications Trial Study Group. Longterm clinical effects of epalrestat, an aldose reductase inhibitor, on progression of diabetic neuropathy and other microvascular complications: multivariate epidemiological analysis based on patient background factors and severity of diabetic neuropathy" 29 : 1529-1533, 2012

41 Steiling K, "Airway gene expression in chronic obstructive pulmonary disease" 6 : 697-700, 2009

42 Sime PJ, "Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung" 100 : 768-776, 1997