The role of interferon-γ in suppressing bleomycin-induced pulmonary fibrosis in rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WANG Haoling ,  XIE Ming , LIU Tao

Department of Respiratory Medicine，West China Hospital，Sichuan University.Chengdu，Sichuan，610041，ChinaCorresponding Author：XIE Min，E-mail：xiemin@scsfec.com;

Corresponding author：

XIE Ming, Email: xiemin@scsfec.com

Keywords：

Pulmonary fibrosis; Connective tissue growth factor; Transforming growth factor -β1; Interferon-γ; Dexamethasone

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Objective To investigate the role of IFN-γ in suppressing bleomycin-induced pulmonary fibrosis in rats.Methods Seventy-five SD rats were randomly divided into five groups (15 rats in each group)，ie.a normal group，a bleomycin-induced pulmonary fibrosis model group，a dexamethasone-treated group，a high-dose IFN-γ-treated group (150 000 U/kg) and a low-dose IFN-γ-treated group (50 000 U/kg).Five rats in each group were randomly killed in 7th day，14th day and 28th day after relative treatment respectively，and lung tissue samples were harvested for histopathology study.HE and Masson staining were used to determine the extent of alveolus inflammation and pulmonary fibrosis respectively.Histoimmunochemical method were adapted to determine protein levels of TGF-β1，CTGF，type Ⅰcollagen and type Ⅲ collagen in pulmonary tissues.Results Histopathological study showed that treatment with either dexamethasone or IFN-γ (both high dose and low dose) remarkably meliorated the extent of alveolus inflammation and suppressed pulmonary fibrosis (compared with model group，all P lt;0.05).Histoimmunochemical study suggested that both dexamethasone and IFN-γ could inhibit the expression of TGF-β1，CTGF，type Ⅰand type Ⅲ collagen (compared with model group，all P lt;0.05)，and the suppression of TGF-β1，type Ⅰand type Ⅲ collagen expression was more obvious in high-dose IFN-γ-treated group than those in low-dose group (P lt;0.05).Conclusions INF-γ possesses apparent anti-fibrosis effect that is similar to dexamethasone but with less side effect.Such effect may resulted from reduced production of type Ⅰand type Ⅲ collagen through expression inhibition of cytokines such as TGF-β1 and CTGF.

Citation： WANG Haoling,XIE Ming,LIU Tao. The role of interferon-γ in suppressing bleomycin-induced pulmonary fibrosis in rats. Chinese Journal of Respiratory and Critical Care Medicine, 2007, 6(2): 105-109. doi: Copy

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14.	Thannickal VJ，Toews GB，White ES，et al.Mechanisms of pulmonary fibrosis.Annu Rev Med，2004，55：395-417.
15.	高晓方，崔社怀.干扰素γ对实验大鼠肺纤维化的治疗作用及机制的初步研究.第三军医大学学报，2005，27：143-145.
16.	黄山英，宋良文，刘涛，等.重组中国人γ干扰素对小鼠肺损伤的防治作用.中华结核和呼吸杂志，2005，28：760-762.
17.	孙丽，宋良文，刘涛，等.中国人γ-IFN对放射性肺纤维化的防治作用.中华放射医学与防护杂志，2006，26：144-147.
18.	徐钰，高占成，陈彬，等.γ-干扰素转基因表达对不同时期博莱霉素致小鼠肺间质纤维化的作用.中国呼吸与危重监护杂志，2005，4：130-134.
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20.	Majumdar S，Li D，Ansari T，et al.Different cytokine profiles in cryptogenic fibrosing alveolitis and fibrosing alveolitis associated with systemic sclerosis：a quantitative study of open lung biopsies.Eur Respir J，1999，14：251-257.
21.	左一俊.干扰素γ联合糖皮质激素治疗特发性肺纤维化13例的疗效观察.南京医科大学学报，2006，26：1272-1274.
22.	King TE Jr.Interferon gamma-1b for the treatment of idiopathic pulmonary fibrosis.N Engl J Med，2000，342：974-975.
23.	Raghu G，Brown KK，Bradford WZ，et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med，2004，350：125-133.

1. Demedts M，Costabel U.ATS/ERS international multidisciplinary consensus classification of the idiopathic interstitial pneumonias.Eur Respir J，2002，19：794-796.
2. Waghray M，Cui Z，Horowitz JC，et al.Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts.FASEB J，2005，19：854-856.
3. Geiser T.Idiopathic pulmonary fibrosis--a disorder of alveolar wound repair? Swiss Med Wkly 2003，133：405-411.
4. Tabibzadeh S.Homeostasis of extracellular matrix by TGF-beta and lefty.Front Biosci，2002，7：d1231-d1246.
5. Kothapalli D，Grotendorst GR.CTGF modulates cell cycle progression in cAMP-arrested NRK fibroblasts.J Cell Physiol，2000，182：119-126.
6. Eickelberg O，Pansky A，Koehler E，et al.Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblastis.FASEB J，2001，15：797-806.
7. Lortat-Jacob H，Esterre P，Grimaud JA.Interferon-gamma，an anti-fibrogenic cytokine which binds to heparan sulfate.Pathol Res Pract，1994，190：920-922.
8. Ziesche R，Hofbauer E，Wittmann K，et al.A preliminary study of long-term treatment with interferon gamma-1b and low dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med，1999，341：1264-1269.
9. Szapiel SV，Elson NA.Fulmer JD，et al.Bleomycin-induced interstitial pulmonary disease in the nude，athymic mouse.Am Rev Respir Dis，1979，120：893-899.
10. Isaacs，A.，Lindermann，J.Virus interference.I.The interferon.Proc R Soc Lond B Biol Sci，1957，147：258-267.
11. Lasky JA，Ortiz LA.Antifibrotic therapy for the treatment of pulmonary fibrosis.Am J Med Sci，2001，322：213-221.
12. Oemar BS，Luscher TF.Connective tissue growth factor.Friend or foe? Arterioscler Thromb Vasc Biol，1997，17：1483-1489.
13. Van Hoozen BE，Grimmer KL，Marelich GP，et al.Early phase collagen synthesis in lungs of rats exposed to bleomycin.Toxicology，2000，147：1-13.
14. Thannickal VJ，Toews GB，White ES，et al.Mechanisms of pulmonary fibrosis.Annu Rev Med，2004，55：395-417.
15. 高晓方，崔社怀.干扰素γ对实验大鼠肺纤维化的治疗作用及机制的初步研究.第三军医大学学报，2005，27：143-145.
16. 黄山英，宋良文，刘涛，等.重组中国人γ干扰素对小鼠肺损伤的防治作用.中华结核和呼吸杂志，2005，28：760-762.
17. 孙丽，宋良文，刘涛，等.中国人γ-IFN对放射性肺纤维化的防治作用.中华放射医学与防护杂志，2006，26：144-147.
18. 徐钰，高占成，陈彬，等.γ-干扰素转基因表达对不同时期博莱霉素致小鼠肺间质纤维化的作用.中国呼吸与危重监护杂志，2005，4：130-134.
19. Strieter RM.Pathogenesis and natural history of usual interstitial pneumonia：the whole story or the last chapter of a long novel.Chest，2005，128：526S-532S.
20. Majumdar S，Li D，Ansari T，et al.Different cytokine profiles in cryptogenic fibrosing alveolitis and fibrosing alveolitis associated with systemic sclerosis：a quantitative study of open lung biopsies.Eur Respir J，1999，14：251-257.
21. 左一俊.干扰素γ联合糖皮质激素治疗特发性肺纤维化13例的疗效观察.南京医科大学学报，2006，26：1272-1274.
22. King TE Jr.Interferon gamma-1b for the treatment of idiopathic pulmonary fibrosis.N Engl J Med，2000，342：974-975.
23. Raghu G，Brown KK，Bradford WZ，et al.A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.N Engl J Med，2004，350：125-133.

Chinese Journal of Respiratory and Critical Care Medicine

The role of interferon-γ in suppressing bleomycin-induced pulmonary fibrosis in rats

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