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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    • "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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    • "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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