Naja naja atra venom ameliorates pulmonary fibrosis by inhibiting inflammatory response and oxidative stress

BMC Complementary and Alternative Medicine

Zheng-Hong Qin²  Xuechu Zhen³  Guanghui Wang¹  Rong Han²  Jin-Hua Gu²  Jian-Qun Kou²  Kui Cui² 

[1] Department of Pharmacology and Laboratory of Molecular Neuropathology, Soochow University School of Pharmaceutical Science, Suzhou 215006, China;Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China;Department of Pharmacology and Laboratory of Neuropsychopharmacology, Soochow University School of Pharmaceutical Science, Suzhou 215006, China

关键词: Oxidative stress;    TGF-βm;    NF-κB;    Hydroxyproline;    Pulmonary fibrosis;    Naja naja atra venom;   

Others  :  1085245
DOI  :  10.1186/1472-6882-14-461

 received in 2013-09-05, accepted in 2014-11-14,  发布年份 2014

【 摘 要 】

Background

Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.

In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action.

Methods

To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 μg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-β/Smad signaling pathway and oxidative stress were examined.

Results

The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1β and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-β/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model.

Conclusions

The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

【 授权许可】

   
2014 Cui et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Noble PW, Barkauskas CE, Jiang D: Pulmonary fibrosis: patterns and perpetrators. J Clin Invest 2012, 122(8):2756-2762.
• [2]Wynn TA: Cellular and molecular mechanisms of fibrosis. J Pathol 2008, 214(2):199-210.
• [3]Todd NW, Luzina IG, Atamas SP: Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair 2012, 5(1):11. BioMed Central Full Text
• [4]Zhao L, Wang X, Chang Q, Xu J, Huang Y, Guo Q, Zhang S, Wang W, Chen X, Wang J: Neferine, a bisbenzylisoquinline alkaloid attenuates bleomycin-induced pulmonary fibrosis. Eur J Pharmacol 2010, 627(1–3):304-312.
• [5]Sener G, Topaloglu N, Sehirli AO, Ercan F, Gedik N: Resveratrol alleviates bleomycin-induced lung injury in rats. Pulm Pharmacol Ther 2007, 20(6):642-649.
• [6]Chen CY, Peng WH, Wu LC, Wu CC, Hsu SL: Luteolin ameliorates experimental lung fibrosis both in vivo and in vitro: implications for therapy of lung fibrosis. J Agric Food Chem 2010, 58(22):11653-11661.
• [7]Tsai KD, Yang SM, Lee JC, Wong HY, Shih CM, Lin TH, Tseng MJ, Chen W: Panax notoginseng Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice. Evid Based Complement Alternat Med 2011, 2011:404761.
• [8]Wang HD, Yamaya M, Okinaga S, Jia YX, Kamanaka M, Takahashi H, Guo LY, Ohrui T, Sasaki H: Bilirubin ameliorates bleomycin-induced pulmonary fibrosis in rats. Am J Respir Crit Care Med 2002, 165(3):406-411.
• [9]Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ: Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012, 366(21):1968-1977.
• [10]Zhu KZ, Liu YL, Gu JH, Qin ZH: Antinociceptive and anti-inflammatory effects of orally administrated denatured naja naja atra venom on murine rheumatoid arthritis models. Evid Based Complement Alternat Med 2013, 2013:616241.
• [11]Y-l L, H-m L, Zou R, Wu J-c, Han R, Raymond LN, Reid PF, Qin Z-h: Suppression of complete Freund’s adjuvant-induced adjuvant arthritis by cobratoxin. Acta Pharmacol Sin 2009, 30(2):219-227.
• [12]Hou L, He Q, Zhao L, Kong T, Guan J, Jing Z: Efect of fractions isolated from naja naja atra venom on antioxidation in animal. Zhong Yao Cai 2004, 27:845-848.
• [13]Wang SZ, He H, Han R, Zhu JL, Kou JQ, Ding XL, Qin ZH: The protective effects of cobra venom from naja naja atra on acute and chronic nephropathy. Evid Based Complement Alternat Med 2013, 2013:478049.
• [14]Pera T, Zuidhof A, Valadas J, Smit M, Schoemaker RG, Gosens R, Maarsingh H, Zaagsma J, Meurs H: Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD. Eur Respir J 2011, 38(4):789-796.
• [15]Sheppard D: Transforming growth factor beta: a central modulator of pulmonary and airway inflammation and fibrosis. Proc Am Thorac Soc 2006, 3(5):413-417.
• [16]Bonniaud P, Margetts PJ, Ask K, Flanders K, Gauldie J, Kolb M: TGF-beta and Smad3 signaling link inflammation to chronic fibrogenesis. J Immunol 2005, 175(8):5390-5395.
• [17]Warburton D, Shi W, Xu B: TGF-beta-Smad3 signaling in emphysema and pulmonary fibrosis: an epigenetic aberration of normal development? Am J Physiol Lung Cell Mol Physiol 2013, 304(2):L83-L85.
• [18]Kinnula VL, Fattman CL, Tan RJ, Oury TD: Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. Am J Respir Crit Care Med 2005, 172(4):417-422.
• [19]Kinnula VL, Myllarniemi M: Oxidant-antioxidant imbalance as a potential contributor to the progression of human pulmonary fibrosis. Antioxid Redox Signal 2008, 10(4):727-738.
• [20]Matute-Bello G, Downey G, Moore BB, Groshong SD, Matthay MA, Slutsky AS, Kuebler WM: An official american thoracic society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 2011, 44(5):725-738.
• [21]Chua F, Gauldie J, Laurent GJ: Pulmonary fibrosis: searching for model answers. Am J Respir Cell Mol Biol 2005, 33(1):9-13.
• [22]Moore BB, Hogaboam CM: Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008, 294(2):L152-L160.
• [23]Masotti L, Ceccarelli E, Cappelli R, Barabesi L, Forconi S: Arterial blood gas analysis and alveolar-arterial oxygen gradient in diagnosis and prognosis of elderly patients with suspected pulmonary embolism. J Gerontol A Biol Sci Med Sci 2000, 55(12):M761-M764.
• [24]Kraemer R, Latzin P, Pramana I, Ballinari P, Gallati S, Frey U: Long-term gas exchange characteristics as markers of deterioration in patients with cystic fibrosis. Respir Res 2009, 10:106. BioMed Central Full Text
• [25]Mizuno H, Fujimoto Z, Atoda H, Morita T: Crystal structure of an anticoagulant protein in complex with the Gla domain of factor X. Proc Natl Acad Sci U S A 2001, 98(13):7230-7234.
• [26]Kini RM: Structure-function relationships and mechanism of anticoagulant phospholipase A2 enzymes from snake venoms. Toxicon 2005, 45(8):1147-1161.
• [27]Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, Sasaki H: Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005, 128(3):1475-1482.