Giri, S.N., Hyde, D.M. & Hollinger, M.A. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax 48, 959-966

Department of Veterinary Pharmacology and Toxicology, University of California, Davis 95616.
Thorax (Impact Factor: 8.29). 11/1993; 48(10):959-66. DOI: 10.1136/thx.48.10.959
Source: PubMed


Increased production of transforming growth factor beta (TGF-beta) seems to have an important role in the pathophysiology of bleomycin induced lung fibrosis. This is attributed to the ability of TGF-beta to stimulate infiltration of inflammatory cells and promote synthesis of connective tissue, leading to collagen deposition.
The study was designed to evaluate the antifibrotic potential of TGF-beta antibody in mice treated with bleomycin, which is a model of lung fibrosis. Under methoxyflurane anaesthesia, each mouse received intratracheally either 50 microliters sterile isotonic saline or 0.125 units bleomycin in 50 microliters. Within five minutes after the instillation, mice received into the tail vein 100 microliters non-immune rabbit IgG, TGF-beta 2 antibody, or a combination of TGF-beta 2 and TGF-beta 1 antibodies at various dose regimens. Mice were killed 14 days after the instillation and their lungs processed for morphological and biochemical studies.
Administration of 250 micrograms of TGF-beta 2 antibody after instillation of bleomycin followed by 100 micrograms on day 5 and 100 micrograms on day 9 significantly reduced the bleomycin induced increases in the accumulation of lung collagen from 445.8 (42.3) micrograms/lung to 336.7 (56.6) micrograms/lung at 14 days. Similarly, the combined treatment with 250 micrograms TGF-beta 2 antibody and 250 micrograms TGF-beta 1 antibody after bleomycin instillation followed by 100 micrograms of each antibody on day 5 also caused a significant reduction in bleomycin induced increases in lung collagen accumulation and myeloperoxidase activity at 14 days.
These results suggest that TGF-beta has an important role in the aetiology of bleomycin induced lung fibrosis; the neutralisation of TGF-beta by systemic treatment with its antibodies offers a new mode of pharmacological intervention which may be useful in treating lung fibrosis.

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Available from: Shri N Giri, Oct 06, 2015
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    • "These results clearly indicate that the suppression of CCl4-induced hepatic fibrosis in the vaccinated mice is attributable to the blockage of TGF-β1 signaling and further attenuation of the activation of HSCs. These results are within our expectation, given that several experiments have demonstrated the inhibitory effects of anti–TGF-β1 Abs (passive immunization) on fibrosis [8,9,39]. Although the mechanisms for suppressing hepatic fibrosis by vaccination against TGF-β1 and by the direct injection of anti–TGF-β1 Abs are similar, the advantages of active immunization over Ab injection are obvious: the preparation of vaccines are simpler and less expensive than specific Abs, the application of vaccines are convenient, and the production of anti–TGF-β1 Abs after vaccination is constant and long-lasting, avoiding the fluctuation of the Ab concentrations in the circulation when intermittently injected. "
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    ABSTRACT: Transforming growth factor β1 (TGF-β1) is the pivotal pro-fibrogenic cytokine in hepatic fibrosis. Reducing the over-produced expression of TGF-β1 or blocking its signaling pathways is considered to be a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the feasibility of attenuating hepatic fibrosis by vaccination against TGF-β1 with TGF-β1 kinoids. Two TGF-β1 kinoid vaccines were prepared by cross-linking TGF-β1-derived polypeptides (TGF-β1(25)-[41-65] and TGF-β1(30)-[83-112]) to keyhole limpet hemocyanin (KLH). Immunization with the two TGF-β1 kinoids efficiently elicited the production of high-levels of TGF-β1-specific antibodies against in BALB/c mice as tested by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The antisera neutralized TGF-β1-induced growth-inhibition on mink lung epithelial cells (Mv1Lu) and attenuated TGF-β1-induced Smad2/3 phosphorylation, α-SMA, collagen type 1 alpha 2 (COL1A2), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression in the rat hepatic stellate cell (HSC) line, HSC-T6. Vaccination against TGF-β1 with the kinoids significantly suppressed CCl4-induced collagen deposition and the expression of α-SMA and desmin, attenuated hepatocyte apoptosis and accelerated hepatocyte proliferation in BALB/c mice. These results demonstrated that immunization with the TGF-β1 kinoids efficiently attenuated CCl4-induced hepatic fibrosis and liver injury. Our study suggests that vaccination against TGF-β1 might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.
    PLoS ONE 12/2013; 8(12):e82190. DOI:10.1371/journal.pone.0082190 · 3.23 Impact Factor
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    • "However, there are a multitude of pathways ranging from the initial pathologic stimulus to abnormal collagen synthesis, offering a bewildering range of therapeutic targets, and possibly with uncertain therapeutic effects. Antibodies against TGF-β1 have long been shown to reduce bleomycin-induced lung fibrosis in mice,47 but a randomized clinical trial of recombinant human TGF-β1 antibody (CAT-192) in patients has failed to demonstrate any therapeutic effect on human fibrosis so far, and has had adverse effects.48 This reflects the pleiotropic effects of TGF-β1 on a wide range of cell types, and the complex interactions between different cytokines, which have made TGF-β1-targeted therapy difficult. "
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    ABSTRACT: Osteoradionecrosis (ORN) in the head and neck area is the most devastating long-term complication of radiotherapy, with slow progression and inability to heal spontaneously. ORN can lead to intolerable pain, fractures, and sequestration of devitalized bone and fistulae, making oral feeding impossible and causing facial deformation. In spite of its notorious reputation over at least 90 years, the precise pathogenesis of ORN has not been fully clarified, which has led to obstacles in the management of the disease. Several theories about its pathogenesis have been formulated, and radiation-induced fibrosis is the newest one. According to this theory, ORN is essentially a type of fibrosis induced by radiotherapy, and antifibrosis therapy has been shown to be effective in its treatment. We assumed that ORN, like fibrosis in other organs, is the result of a process of fibrogenesis in which myofibroblasts are the key effector cells. The uninterrupted accumulation of myofibroblasts and consequent persistent excess production of collagenous extracellular matrix and tensile force result in loss of normal function and ultimately radiation-induced fibrosis. During this process, myofibroblasts may be protected from apoptosis by acquiring an immune-privileged capacity, which allows continuous matrix synthesis. If this hypothesis proves to be correct, it would enable better understanding of the cellular and molecular mechanisms underlying the pathogenesis and progression of ORN, and would help improve our ability to prevent occurrence of ORN, give an earlier diagnosis, and treat it more effectively.
    Clinical 07/2012; 4:21-27. DOI:10.2147/CCIDEN.S33722
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    • "Previous work showed that the concentration of IL-17A and TGF-β in BAL rose significantly after the instillation of BLM (Figure 5 and [16-18]), and that these factors supported the development of BIP by promoting the production of pro-inflammatory cytokines and chemokines (including IL-1β, IL-6, KC and MIP-2). Studies using neutralizing Abs and KO mice showed that the elimination of IL-17A and/or TGF-β led to a significant reduction in BLM-induced pulmonary fibrosis [16-18,37]. Other reports showed that IL-10 down-regulated the production of both IL-17A and TGF-β [16] and that IL-10 was a key mediator of the counter-regulatory process responsible for suppressing CpG induced immune activation [23,25,26]. "
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    ABSTRACT: Bleomycin (BLM) induces life-threatening pneumonitis and pulmonary fibrosis in 20% of patients, limiting its use as a chemotherapeutic agent. Oligonucleotides expressing immunostimulatory CpG motifs (CpG ODN) stimulate cells that express Toll-like receptor 9 to initiate an inflammatory response. This short-lived inflammation is physiologically suppressed by a counter-regulatory process that peaks five days later. Using a murine model of BLM-induced lung injury, the effect of CpG ODN treatment on pulmonary inflammation, fibrosis and mortality was examined. Administering CpG ODN 5 days before BLM (so that the peak of the counter-regulatory process induced by CpG ODN coincided with BLM delivery) resulted in a dose-dependent reduction in pulmonary toxicity (p < 0.005). Delaying the initiation of therapy until the day of or after BLM administration worsened the inflammatory process, consistent with the counter-regulatory process rather than initial pro-inflammatory response being critical to CpG induced protection. The protection afforded by CpG ODN correlated with reduced leukocyte accumulation and inflammatory cytokine/chemokine production in the lungs. These changes were associated with the increased production of IL-10, a critical element of the counter-regulatory process triggered by CpG ODN, and the concomitant down-regulation of BLM-induced IL-17A and TGF-β1 (which promote pulmonary toxicity). This work represents the first example of the physiologic counter-regulation of TLR induced immune activation being harnessed to block an unrelated inflammatory response.
    Respiratory research 06/2012; 13(1):47. DOI:10.1186/1465-9921-13-47 · 3.09 Impact Factor
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