AIM: To investigate the effect of sodium valproate (VPA) on bleomycin-induced pulmonary fibrosis (PF) and its mechanism. METHODS: SD rats (n=42) were randomly divided into model group and treatment group. Bleomycin at dose of 5 mg/kg was intratracheally injected to establish a rat PF model. The rats in treatment group were given normal saline (NS, 0.5 mL/d), VPA (300 mg·kg-1·d-1) or dexamethasone (DEX, 0.6 mg·kg-1·d-1) via intraperitoneal injection from the 14th day to the 28th day after modeling. The rats in model group were sacrificed on 0 d, 14 day and 28 d after modeling . The rats in treatment group were killed at 14th day after treatment. The effects of VPA on PF were evaluated by HE and Masson staining. The hydroxyproline (HYP) content in the rat lung tissues was detected, and the expression of α-smooth muscle actin (α-SMA) and E-cadherin was determined by Western blotting. RESULTS: HE staining showed that the alveolar structure and interstitial morphology in VPA group were better than those in NS group and DEX group. The level of collagen in VPA group was significantly lower than that in DEX group and NS group by determining the HYP content and Masson staining. VPA reduced the expression of α-SMA, a mesenchymal marker protein of PF, while increased the expression of epithelial marker protein E-cadherin. CONCLUSION: VPA reduces collagen content and distribution, and up-regulates the expression of the epithelial marker protein E-cadherin, while down-regulates mesenchymal marker protein α-SMA, thereby preventing the rat lung tissues from bleomycin-induced PF.
Ryu JH, Daniels CE. Advances in the management of idiopathic pulmonary fibrosis[J]. F1000 Med Rep, 2010, 2:28.
[3]
Vyas-Read S, Shaul PW, Yuhanna IS, et al. Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells[J]. Am J Physiol Lung Cell Mol Physiol, 2007, 293(1):L212-L221.
[4]
Nasreen N, Mohammed KA, Mubarak KK, et al. Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-β1 in vitro[J]. Am J Physiol Lung Cell Mol Physiol,2009, 297(1): L115-L124.
Watanabe T, Tajima H, Hironori H, et al. Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate cell line[J]. Int J Mol Med, 2011, 28(6):919-925.
Selman M, Pardo A, Richeldi L, et al. Emerging drugs for idiopathic pulmonary fibrosis[J]. Expert Opin Emerg Drugs, 2011, 16(2):341-362.
[9]
Agostini C, Gurrieri C. Chemokine/cytokine cocktail in idiopathic pulmonary fibrosis[J]. Proc Am Thorac Soc, 2006, 3(4):357-363.
[10]
Noh H, Oh EY, Seo JY, et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factorβ1-induced renal injury[J]. Am J Physiol Renal Phy-siol, 2009, 297(3):F729-F739.
[11]
Kee HJ, Bae EH, Park S, et al. HDAC inhibition suppresses cardiac hypertrophy and fibrosis in DOCA-salt hypertensive rats via regulation of HDAC6/HDAC8 enzyme activity[J]. Kidney Blood Press Res, 2013, 37(4-5):229-239.
[12]
Mannaerts I, Nuytten NR, Rogiers V, et.al. Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cells in vitro and in vitro[J]. Hepatology, 2010, 51(2):603-614.
[13]
Piera-Velazquez S, Li ZD, Jimenez SA. Role of endothe-lial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders[J]. Am J Pathol,2011, 179(3):1074-1080.