Thalidomide Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice

Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
The Journal of Immunology (Impact Factor: 4.92). 08/2007; 179(1):708-14. DOI: 10.4049/jimmunol.179.1.708
Source: PubMed


Pulmonary fibrosis in humans can occur as a result of a large number of conditions. In idiopathic pulmonary fibrosis (IPF), pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for IPF. We have recently reported that IL-6 and TGF-beta(1) plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid (ATRA) prevented bleomycin-induced lung fibrosis through the inhibition of these cytokines. Thalidomide (Thal) has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced pulmonary fibrosis in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-beta(1), collagen type Ialpha1 (COL1A1), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thal decreased the expressions of IL-6, TGF-beta(1), VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1) production of IL-6, TGF-beta(1), VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2) both IL-6-dependent proliferation and TGF-beta(1)-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on pulmonary fibrosis. These data may provide a rationale to explore clinical use of Thal for the prevention of pulmonary fibrosis.

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Available from: Shigeo Hisamori, May 26, 2015
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    • "The inflammation process leads to the release of cytokines including interleukin-6 (IL-6), which operates through specific hepatic receptors to prevent the synthesis of albumin.[34] On the other hand, IL-6, through a positive autocrine feedback loop, stimulates the proliferation of lung fibroblasts.[3637] "
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    ABSTRACT: Sulfur mustard (SM) is an incapacitating chemical warfare agent, which has been widely employed in particular regions including Iran. We investigated and reported delayed biochemical and hematological complications of SM in severely toxic Iranian veterans 23 years after exposure. Forty-two Iranian veterans, residents of Khorasan Razavi, poisoned by SM, and suffering from clinical complications were investigated. A total of 30 healthy male volunteers were also selected as a control group. Biochemical and hematological variables were measured for the case and control groups. Data were analyzed using a Student's t-test by InStat software (GraphPad Inc., San Diego, CA) to determine significant differences between the data from the two groups. The percentages of reticulocytes were significantly higher in patients (0.82 ± 0.04, P < 0.05). Total protein and albumin levels were significantly lower in veterans (total protein: 7.58 ± 0.07 g/dL, albumin: 4.97 ± 0.04 g/dL, P < 0.01). In addition, we observed a significant increase in serum cholesterol (226.74 ± 5.23 mg/dL, P < 0.01), triglyceride (173.53 ± 17.05 mg/dL, P < 0.05), and gamma-glutamyl transferase (GTT) activity of the patients (44.04 ± 3.35 IU/L, P < 0.05). Results showed that SM can cause long-term effects on some biochemical factors of veterans. As many of the functional tests of liver and kidney between two groups were statistically unchanged, it seems that the observed biochemical changes may be secondary to delayed respiratory complications of the patients.
    Journal of research in medical sciences 10/2013; 18(10):855-9. · 0.65 Impact Factor
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    • "Angiogenesis is regulated by a balance between the angiogenic and angiostatic regulators of blood vessel growth. VEGF is the principal angiogenic factor and is proven to be a proinflammatory and permeability-inducing factor in BLM-induced pulmonary fibrosis [12]. Based on this information, inhibition of the VEGF/VEGFR pathway in PF may have protective effects against angiogenesis and fibrogenesis. "
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    ABSTRACT: Background Recent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis. Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis. The aim of our study was to assess whether endostatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in rats. Methods The rats were randomly divided into five experimental groups: (A) saline only, (B) BLM only, (C) BLM plus early endostatin treatment, (D) BLM plus late endostatin treatment, and (F) BLM plus whole-course endostatin treatment. We investigated the microvascular density (MVD), inflammatory response and alveolar epithelial cell apoptosis in rat lungs in each group at different phases of disease development. Results Early endostatin administration attenuated fibrotic changes in BLM-induced pulmonary fibrosis in rats. Endostatin treatment decreased MVD by inhibiting the expression of VEGF/VEGFR-2 (Flk-1) and the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). Endostatin treatment also decreased the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid during the early inflammatory phase of BLM-induced pulmonary fibrosis. In addition, the levels of tumour necrosis factor-α (TNF-α) and transforming growth factor β1 (TGF-β1) were reduced by endostatin treatment. Furthermore, endostatin decreased alveolar type II cell apoptosis and had an epithelium-protective effect. These might be the mechanism underlying the preventive effect of endostatin on pulmonary fibrosis. Conclusions Our findings suggest that endostatin treatment inhibits the increased MVD, inflammation and alveolar epithelial cell apoptosis, consequently ameliorating BLM-induced pulmonary fibrosis in rats.
    Respiratory research 05/2013; 14(1):56. DOI:10.1186/1465-9921-14-56 · 3.09 Impact Factor
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    • "Indeed, the ability of thalidomide to inhibit angiogenesis was confirmed in a rabbit cornea micropocket assay [8]. Furthermore, the antifibrotic effects of thalidomide have been reported in animal models of bleomycin-induced pulmonary fibrosis [32], liver cirrhosis [19–21, 29], myocardial infarction [34], and peritoneal fibrosis [25]. "
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    ABSTRACT: Thalidomide is clinically recognized as a therapeutic agent for multiple myeloma and has been known to exert anti-angiogenic actions. Recent studies have suggested the involvement of angiogenesis in the progression of peritoneal fibrosis. The present study investigated the effects of thalidomide on the development of peritoneal fibrosis induced by injection of chlorhexidine gluconate (CG) into the mouse peritoneal cavity every other day for 3 weeks. Thalidomide was given orally every day. Peritoneal tissues were dissected out 21 days after CG injection. Expression of CD31 (as a marker of endothelial cells), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), α-smooth muscle actin (as a marker of myofibroblasts), type III collagen and transforming growth factor (TGF)-β was examined using immunohistochemistry. CG group showed thickening of the submesothelial zone and increased numbers of vessels and myofibroblasts. Large numbers of VEGF-, PCNA-, and TGF-β-positive cells were observed in the submesothelial area. Thalidomide treatment significantly ameliorated submesothelial thickening and angiogenesis, and decreased numbers of PCNA- and VEGF-expressing cells, myofibroblasts, and TGF-β-positive cells. Moreover, thalidomide attenuated peritoneal permeability for creatinine, compared to the CG group. Our results indicate the potential utility of thalidomide for preventing peritoneal fibrosis.
    ACTA HISTOCHEMICA ET CYTOCHEMICA 04/2011; 44(2):51-60. DOI:10.1267/ahc.10030 · 1.39 Impact Factor
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