The Therapeutic Effects Of IL-12 On Rats With Pulmonary Fibrosis Induced By Bleomycin

Background: Pulmonary fibrosis (PF) is the common end of many pulmonary interstitial dieases including idiopathic pulmonary fibrosis(IPF), pneumoconiosis, allergic pneumonia and fibrosis induced by medicine and radioactive ray, fibrosing alveolitis caused by collagen vascular disease(CVD). Idiopathic pulmonary fibrosis (IPF) is a disease of unknown cause that usually leads to death within 5 years after diagnosis. It is characterized by sequential acute lung injury resulting in progressive fixed tissue fibrosis, architectural distortion and loss of function. The diagnostic histological changes are called usual interstitial pneumonia and is showed temporal heterogeneity, whereby normal lung tissue is interspersed with interstitial fibrosis, honeycomb cysts and fibroblast foci. Despite our better understanding of IPF pathogenesis, the etiology and the precise cellular and molecular mechanisms involved are still not well known,current therapies are of unproven benefit. It is very urgent and necessary to find a new way to improve the prognosis of IPF patients.Recently studies showed the balance between CD4 (+) T helper 1(Th1) lymphocytes and Th2 in the lungs play an important role in idiopathic pulmonary fibrosis. Th1 cells produce pro-inflammatory cytokines like IFN-γ, while Th2 cells produce the cytokines IL-4. The cytokines produced by Th1 cells stimulate the phagocytosis and destruction of microbial pathogens while Th2 cytokines like IL-4 generally stimulate the production of antibodies which promote fibrotic process. These points suggest excessive express of Th2 cytokine such as IL-4 and decreased expression of Th1 cytokine like INF-γis responsible for the onset and progress of IPF. The differentiation of Th1 cells and Th2 cells depends on the cytokines they are exposed to. IL-12 can cause Th1 differentiation and block Th2 cell production. The aim of our test was to investigate the relationships among the Th1/Th2 cytokine balance, IL-12 and IPF, to identify possible candidate pathways that might offer possible therapeutic targets changing the natural course of this disease.Objective:To study the therapeutic effects and mechanisms of IL-12 on rats with pulmonary fibrosis induced by bleomycin.Methods:Sixty female Wistar rats in good conditions were divided into four groups at random, which included model group (BLM group),treatment group(IL-12 group) , treatment control group(BSA group) and control group (NS group).The pulmonary fibrosis was induced by trachea administration of bleomycin (15 mg/kg body weight, 4 mg/ml).The same quantity of NS was given to the NS group by the same way. The intervention drugs were given 24 hours from the first day to 12th day after the model rates established. On the 7^th, l4th, 28th day afterwards,five rats of each group were sacrificed respectively and their lung tissue and bronchoalveolar lavage fluid(BALF) were collected. The lung weights, body weights and histopathological changes were observed, the alveolitis and pulmonary fibrosis were scored, and the gray scale was analyzed. The lung coefficient, the hydroxyproline(Hyp) of lung tissues homogenate, the level of IL-4 and IFN-γin the BALF were detected and the ratio of IL-4/IFN-γwas calculated.Results:(1) In the BLM group,the alveolitis and fibrosis were more obviously than the NS group,the lung weights, lung coefficient,the concentration of Hyp in the lung tissues,the score of alveolitis and fibrosis were higher,The expression of IL-4 in BALF and the ratio of IL-4/IFN-γwere elevated than the NS group (P<0.05,0.01,0.01,0.01,0.01,0.01,0.01,respectively), the gray scale analysis showed that there was an increase in the percentage of anachromasis area(7,14 d ,P<0.01), catachromasis area (28 d , P<0.01), But the level of IFN-γin BALF was decreased (P<0.05). (2) There was no significant difference between the BLM group and BSA group in the all test data above. (3) Alveolitis and fibrosis induced by bleomycin could be obviously alleviated by IL-12. Compared with the BLM and BSA group ,t he percentage of anachromasis area and the score of alveolitis in 7^th, 1 4th day, the percentage of catachromasis area and the score of fibrosis in 28th day , the lung weights in 7^th day, lung coefficients, the concentration of Hyp in the lung tissues, the expression of IL-4 in BALF and the ratio of IL-4/IFN-γwere all decreased (P<0.05 ,0 .01 ,0 .05 , 0.01 ,0 .01 ,0 .05, 0.01 ,0 .01 , 0.01,respectively) in the IL-2 group. But the level of IFN-γwere increased(P<0.01).Conclusion: IL-12 can play an anti-fibrotic effect on the rats with pulmonary fibrosis induced by bleomycin by regulating Th1/Th2 cytokine balance.