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. 2013 Dec 16;14(12):24476-91.
doi: 10.3390/ijms141224476.

Atorvastatin attenuates bleomycin-induced pulmonary fibrosis via suppressing iNOS expression and the CTGF (CCN2)/ERK signaling pathway

Bo Zhu, Ai-Qun Ma  1 , Lan Yang, Xiao-Min Dang
Affiliations

Atorvastatin attenuates bleomycin-induced pulmonary fibrosis via suppressing iNOS expression and the CTGF (CCN2)/ERK signaling pathway

Bo Zhu et al. Int J Mol Sci. .

Abstract

Pulmonary fibrosis is a progressive and fatal lung disorder with high mortality rate. To date, despite the fact that extensive research trials are ongoing, pulmonary fibrosis continues to have a poor response to available medical therapy. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known for its broad pharmacological activities, remains a remedy against multiple diseases. The present study investigated the antifibrotic potential of atorvastatin against bleomycin-induced lung fibrosis and to further explore the possible underlying mechanisms. Our results showed that atorvastatin administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level. Atorvastatin reduced malondialdehyde (MDA) level and lung indices. Atorvastatin also markedly decreased the expression of inducible nitric oxide synthase (iNOS) in lung tissues and, thus, prevented nitric oxide (NO) release in response to bleomycin challenge. Furthermore, atorvastatin exhibited target down-regulation of connective tissue growth factor (CTGF (CCN2)) and phosphorylation extracellular regulated protein kinases (p-ERK) expression. Taken together, atorvastatin significantly ameliorated bleomycin-induced pulmonary fibrosis in rats, via the inhibition of iNOS expression and the CTGF (CCN2)/ERK signaling pathway. The present study provides evidence that atorvastatin may be a potential therapeutic reagent for the treatment of lung fibrosis.

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Figures

Figure 1.
Figure 1.
Histological evaluation of atorvastatin on bleomycin-induced lung in rats. (A) Lung tissue sections of control animals showing normal lung morphologies: thin lined interalveolar septa with well organized alveolar space; (B) Lung tissue sections of bleomycin-induced animals showing distorted lung morphologies: collapsed alveolar spaces with inflammatory exudates, wider and thickened interalveolar septa; (C) Lung tissue section of atorvastatin treated animals: lower inflammatory infiltrates with lessened alveolar thickening; and (D) Lung tissue section of atorvastatin alone administered animals showing similar morphology with that of control animals. Representative histological section of the lungs was stained by hematoxylin and eosin (×400).
Figure 2.
Figure 2.
Effects of atorvastatin on histopathogical changes of bleomycin-induced lung with Masson’s trichrome stain (×400). (A,D) Lung tissue sections of control and atorvastatin alone administrated animals with normal lung morphologies: scarcely deposited collagen in the lung parenchyma; (B) Lung tissue sections of bleomycin-induced animals showing dense collagen accumulations: collagen accumulations in lung parenchyma; and (C) Lung sections of atorvastatin treated animals showing reduced collagen depositions: reduced alveolar thickening with meager collagen.
Figure 3.
Figure 3.
Effects of atorvastatin on the hydroxyproline content in the lungs of bleomycin-induced pulmonary fibrosis rats. Values are given as mean ± SD for groups of eight rats each. ##p < 0.01 vs. the control group; ** p < 0.01 vs. the bleomycin group.
Figure 4.
Figure 4.
Effects of atorvastatin on the (A) malondialdehyde (MDA) and (B) nitric oxide (NO) levels in the lungs of bleomycin-induced pulmonary fibrosis rats. Values are given as mean ± SD for groups of 8 rats each. ##p < 0.01 vs. the control group; * p < 0.05 and ** p < 0.01 vs. the bleomycin group, respectively.
Figure 5.
Figure 5.
Western blot analysis of iNOS levels in the lungs of bleomycin-induced pulmonary fibrosis rats. The increased levels of iNOS protein expression were significantly inhibited by administration of atorvastatin. (A) Representative blots are shown and protein size is expressed in kDa; and (B) Densitometric quantification data are expressed as the intensity ratio of target proteins to GAPDH (mean ± SD, n = 5). #p < 0.05 and ##p < 0.01 vs. the control group, respectively; * p < 0.05 and ** p < 0.01 vs. the bleomycin group, respectively.
Figure 6.
Figure 6.
Western blot analysis of CTGF (CCN2) levels in the lungs of bleomycin-induced pulmonary fibrosis rats. The increased levels of CTGF (CCN2) protein expression were obviously suppressed by administration of atorvastatin. (A) Representative blots are shown and protein size is expressed in kDa; and (B) Densitometric quantification data are expressed as the intensity ratio of target proteins to GAPDH (mean ± SD, n = 5). ##p < 0.01 vs. the control group; ** p < 0.01 vs. the bleomycin group.
Figure 7.
Figure 7.
Effects of atorvastatin on the phosphatidylinositol ERK signaling in the lungs of bleomycin-induced pulmonary fibrosis rats. The increased levels of phosphor-ERK were significantly inhibited by administration of atorvastatin. (A) Representative blots of phosphor-ERK and total ERK are shown and protein size is expressed in kDa; and (B) Densitometric quantification data are expressed as the intensity ratio of target proteins to GAPDH (mean ± SD, n = 5). #p < 0.05 and ##p < 0.01 vs. the control group, respectively; ** p < 0.01 vs. the bleomycin group.
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