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

Li X, Shen Y, Lu Y, Yang J - Korean J. Physiol. Pharmacol. (2015)

Bottom Line: Aldose reductase (AR) is known to play a crucial role in the mediation of diabetic and cardiovascular complications.Epalrestat is an aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy.Knockdown of AR gene expression reversed TGF-β1-induced proliferation of fibroblasts, up-regulation of α-SMA and collagen I expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Wannan Medical College, Wuhu 241002, China.

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 immunohistochemisty, 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.

No MeSH data available.


Related in: MedlinePlus

Effect of Epalrestat on the expression of TGF-β1 and AR in bleomycin-induced pulmonary fibrosis rats. (A and B) The expression of TGF-β1 mRNA and protein in lung tissue were determined by real-time PCR and Western blot. (C and D) The expression of AR mRNA and protein in lung tissue were determined by real-time PCR and Western blot. (E) The expression of AR in lung tissue was determined with immunohistochemisty staining (arrows indicate AR positive staining). Data are means±S.E.M. n=8. **p<0.01 vs. Control; #p<0.05, ##p<0.01 vs. Bleomycin. EPS, Epalrestat; AR, aldose reductase.
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Figure 3: Effect of Epalrestat on the expression of TGF-β1 and AR in bleomycin-induced pulmonary fibrosis rats. (A and B) The expression of TGF-β1 mRNA and protein in lung tissue were determined by real-time PCR and Western blot. (C and D) The expression of AR mRNA and protein in lung tissue were determined by real-time PCR and Western blot. (E) The expression of AR in lung tissue was determined with immunohistochemisty staining (arrows indicate AR positive staining). Data are means±S.E.M. n=8. **p<0.01 vs. Control; #p<0.05, ##p<0.01 vs. Bleomycin. EPS, Epalrestat; AR, aldose reductase.

Mentions: TGF-β1 seems to play a major profibrotic role, inducing fibroblast into myofibroblast differentiation and increasing collagen expression. In line with previous studies [32], bleomycin dramatically increased the expression of TGF-β1 (both mRNA and protein) in lungs of rats (Fig. 3A and B). On this basis, we further found that the expression of AR was obviously increased in lungs from bleomycin-induced pulmonary fibrosis rats (Fig. 3C~E). And importantly epalrestat obviously inhibited bleomycin-induced upregulation of TGF-β1 and AR expression (both mRNA and protein) (p<0.05) (Fig. 3).


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

Li X, Shen Y, Lu Y, Yang J - Korean J. Physiol. Pharmacol. (2015)

Effect of Epalrestat on the expression of TGF-β1 and AR in bleomycin-induced pulmonary fibrosis rats. (A and B) The expression of TGF-β1 mRNA and protein in lung tissue were determined by real-time PCR and Western blot. (C and D) The expression of AR mRNA and protein in lung tissue were determined by real-time PCR and Western blot. (E) The expression of AR in lung tissue was determined with immunohistochemisty staining (arrows indicate AR positive staining). Data are means±S.E.M. n=8. **p<0.01 vs. Control; #p<0.05, ##p<0.01 vs. Bleomycin. EPS, Epalrestat; AR, aldose reductase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553399&req=5

Figure 3: Effect of Epalrestat on the expression of TGF-β1 and AR in bleomycin-induced pulmonary fibrosis rats. (A and B) The expression of TGF-β1 mRNA and protein in lung tissue were determined by real-time PCR and Western blot. (C and D) The expression of AR mRNA and protein in lung tissue were determined by real-time PCR and Western blot. (E) The expression of AR in lung tissue was determined with immunohistochemisty staining (arrows indicate AR positive staining). Data are means±S.E.M. n=8. **p<0.01 vs. Control; #p<0.05, ##p<0.01 vs. Bleomycin. EPS, Epalrestat; AR, aldose reductase.
Mentions: TGF-β1 seems to play a major profibrotic role, inducing fibroblast into myofibroblast differentiation and increasing collagen expression. In line with previous studies [32], bleomycin dramatically increased the expression of TGF-β1 (both mRNA and protein) in lungs of rats (Fig. 3A and B). On this basis, we further found that the expression of AR was obviously increased in lungs from bleomycin-induced pulmonary fibrosis rats (Fig. 3C~E). And importantly epalrestat obviously inhibited bleomycin-induced upregulation of TGF-β1 and AR expression (both mRNA and protein) (p<0.05) (Fig. 3).

Bottom Line: Aldose reductase (AR) is known to play a crucial role in the mediation of diabetic and cardiovascular complications.Epalrestat is an aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy.Knockdown of AR gene expression reversed TGF-β1-induced proliferation of fibroblasts, up-regulation of α-SMA and collagen I expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Wannan Medical College, Wuhu 241002, China.

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 immunohistochemisty, 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.

No MeSH data available.


Related in: MedlinePlus