ABSTRACT
BACKGROUND: The pathological characteristics of pulmonary interstitial fibrosis are the proliferation of a large number of fibroblasts and the increasing deposition of matrix collagen that takes the place of normal lung structure. Fluvastatin can inhibit the proliferation of fibroblasts and many other cells.OBJECTIVE: To investigate the effects of fluvastatin in inhibiting the proliferation of rat lung fibroblasts cultured in vitro and its influence on bleomycin-induced pulmonary fibrosis and ventilation function.DESIGN: A randomized controlled trial.SETTING: Department of Respiratory Diseases, Xijing Hospital, Fourth Military Medical University of Chinese PLA; Teaching and Research Section of Pathology, Department of Basic Medicine, Fourth Military Medical University of Chinese PLA; Research Institute ofOrthopedics, Xijing Hospital,Fourth Military Medical University of Chinese PLA.PARTICIPANTS: The study was conducted in the laboratory of Department of Respiratory Diseases, Xijing Hospital of Fourth Military Medical University of Chinese PLA from January to December 2001. Thirty-one healthy adult male Sprague-Dawley(SD) rats of grade Ⅰ were selected in this study.INTERVENTIONS: The fibroblasts derived from the lung normal of one rat were cultured in vitro in media containing fluvastatin. The effect of fluvastatin on the growth curve and the effect of its different concentrations(0, 1 × 10-7,1 ×10-6, 1 ×10-5, 1 ×10-4, 1 ×10 3and 1 ×10-2 mol/L, fluvastatin of 0 mol/L was taken as the blank control group) in inhibiting the cultured cells were observed with MTT colorimetry. The effect of fluvastatin on the division index of the fibroblasts was analyzed by direct cell counting Hydroxyproline colorimetry was used to detect the influence of fluvastatin on the collagen secretion in the media. The other 30 SD rats were divided into six groups: normal control group, bleomycin-induced group and fluvastatin-treated groups(TH 1,TE1, TH15 and TL15 groups) named according to the date of giving fluvastatin,i. e. the 1st day and the 15th day, after the rats were given bleomycin A5. All the rats were killed 28 days later. The number of fibroblasts, the thickness of alveolar wall and the area of mesenchyma in lung tissue were measured by HE staining. The extracellular matrix and collagen in lung tissue were observed by Masson and sirius red staining, and hydroxyproline in lung tissue homogenates was measured.MAIN OUTCOME MEASURES: Fibroblast growth curve and division index of rat lung, hydroxyproline in the media and lung tissue homogenates,number of fibroblasts and the thickness of alveolar wall, the area of mesenchyma, extracellular matrix and collagen contents in lung tissue.RESULTS: Fluvastatin could inhibit the proliferation of the rat lung fibroblasts cultured in vitro(t=4.20 to 17.52, P < 0.01), and its inhibitory effect was increased with the increased dose of fluvastatin, which showed a dose-dependent effect. The 1 × 10-4 mol/L fluvastatin could completely inhibit the proliferation of the cultured cells, and the A490 value from the 2nd day on the fibroblasts by MTT colorimetry was not insignificantly different from those on the 1st day( P > 0.05) . The division index of the fibroblasts and secretion of collagen were obviously decreased by fluvastatin( t = 8. 037,P <0.01; t =3.99 to 10. 84, P <0.05 or P <0.01). In vivo, the number of fibroblasts, the thickness of lung alveolar wall, the area of mesenchyma and the content of hydroxyproline in lung tissue were significantly higher in bleomycin group than in control group( t =4. 62 to 11.93, P < 0. 01), while those in the fluvastatin-treated groups were lower than those in bleomycin group in different degrees( t = 2.69 to 7.65, P < 0.05 to 0.01 ) . The distribution of extracellular matrix and types Ⅰ and Ⅲ collagen in lung tissue were obviously increased in bleomycin group as compared with that in control group, but decreased in different degrees in fluvastatin-treated groups.CONCLUSION: Fluvastatin can significantly inhibit the proliferation of rat lung fibroblasts in vitro, suggesting that it may be an effective drug for pulmonary fibrosis. Treatment at earlier stage is more effective than at advanced stage.
ABSTRACT
Objective To investigate the therapeutic effect of fluvastatin in bleomycin-induced pulmonary fibrosis in rats. Methods Pulmonary fibrosis was induced in SD rats by intratracheal instillation of bleomycin A_ 5 . The rats were than divided randomly into three groups: the rats in the first group received daily fluvastatin 20mg/kg (group Flu),those of the second group received normal saline (group BLM) orally only,and those of controls (group N) received normal saline both intratracheally and orally. Five rats in each group were sacrificed 1,3,7,14 and 28 days after intratracheal instillation of bleomycin. Pathological changes in the lungs were evaluated by HE stain and Masson′s trichrome stain. Collagen content of the lung tissue was assessed by hydroxyproline concentration. Alveolar macrophages,polymorphonuclear leukocytes and lymphocytes in bronchoalveolar lavage fluid (BALF) were counted. Hyaluronic acid (HA) and laminin (LN) in BALF were determined by radioimmunoassay. Results The degree of alveolitis and pulmonary fibrosis in group Flu was improved as compared with that of group BLM. Hydroxyproline concentrations of group Flu were significantly lower than that of group BLM 7 days after bleomycin A_ 5 instillation. Total cell counts and percentage of polymorphonuclear leukocytes and lymphocytes in BALF were significantly reduced in group Flu. HA and LN levels in BALF were also lower in group Flu compared with group BLM. Conclusion Fluvastatin could alleviate bleomycin-induced pulmonary fibrosis in rats.
ABSTRACT
Objective To investigate the effect of radiation-induced heart injury on cardiac troponin I (cTnI)and endothelin-1(ET-1) and observe the preventive and therapeutic effect of fluvastatin. Methods Healthy female SD rats were randomly divided into three groups: control group(c), irradiation alone group(R) and fluvastatin therapeutic group (F). Rats of F group had been gastrogavaged with fluvastatin at dose of 20mg?kg -1?d -1 from 1week before irradiation to the end of the experiment. In C group and R group, rats were gastrogavaged with the same volume isotonic sodium chloride. The rats of R and F group were irradiated with accelerator linear at a dose of 20Gy thoracically. Rats were executed at 5,15,30d and 60d after irradiation, then cTnI in serum and ET-1 in blood plasma were detected. Results On 5d, the content of cTnI in R group increased significantly than that in C group(P
ABSTRACT
Objective:To observe the inhibitory effect of fluvastatin (Flu) on the proliferation of the rat lung fibroblasts cultured in vitro . Methods: Normal rat lung derived fibroblasts were cultured in media containing Flu. The influences of Flu on the growth curve of the fibroblasts were observed by cell count and MTT colorimetry. The inhibition effect of Flu serial dilutions on the fibroblasts proliferation was investigated. Influence of Flu on division index of the fibroblasts was analyzed by direct cell count. Chemical colorimetry was used to detect the hydroxyproline in the media. Results: Flu inhibited the proliferation of the normal rat lung fibroblasts in the manner of dose dependence( P