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: 8.56). 11/1993; 48(10):959-66. DOI: 10.1136/thx.48.10.959
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Shri N Giri, Aug 21, 2015
  • Source
    • "Cytokine (2010), doi:10.1016/ j.cyto.2010.11.019 time-point before fibrosis is established [5] [6], but few data [25] is available concerning treatment of established fibrosis. Moreover, this therapeutic model may resemble more the relevant clinical setting of PF, suggesting that patients with established PF might also benefit from the use of this inhibitory peptide. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary fibrosis encompasses several respiratory diseases characterized by epithelial cell injury, inflammation and fibrosis. Transforming growth factor (TGF)-β1 is one of the main profibrogenic cytokines involved in the pathogenesis of lung fibrosis. It induces fibroblast differentiation into myofibroblasts, which produce high levels of collagen and concomitantly loss of lung elasticity and reduction of the respiratory function. In the present study, we have investigated the effects of P17 (a TGF-β inhibitor peptide) on IMR-90 lung fibroblast differentiation in vitro, as well as on the inhibition of the development of bleomycin-induced pulmonary fibrosis in mice. It was found that in IMR-90 cells, P17 inhibited TGF-β1-induced expression of connective tissue growth factor and α-smooth muscle actin. In vivo, treatment of mice with P17 2days after bleomycin administration decreased lung fibrosis, areas of myofibroblast-like cells and lymphocyte infiltrate. P17 also reduced mRNA expression of collagen type I, fibronectin and the fibronectin splice isoform EDA in the lung, and increased the expression of IFN-γ mRNA. Finally, therapeutic treatment with P17 in mice with already established fibrosis was able to significantly attenuate the progression of lung fibrosis. These results suggest that P17 may be useful in the treatment of pulmonary fibrosis.
    Cytokine 03/2011; 53(3):327-33. DOI:10.1016/j.cyto.2010.11.019 · 2.87 Impact Factor
  • Source
    • "Moreover, TGF-β1 promotes proliferation of smooth muscle cells (Doherty and Broide 2007). In murine models, treatment with exogenous TGF-β1 or targeted overexpression of TGF-β1 mimics a fibrotic phenotype (Roberts et al. 1986; Sime et al. 1997) and neutralization of this cytokine abrogates bleomycin-induced fibrosis (Giri et al. 1993). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Eosinophils are innate immune leukocytes found in relatively low numbers within the blood. Terminal effector functions of eosinophils, deriving from their capacity to release their content of tissue-destructive cationic proteins, have historically been considered primary effector mechanisms against specific parasites, and are likewise implicated in tissue damage accompanying allergic responses such as asthma. However, the past decade has seen dramatic advancements in the field of eosinophil immunobiology, revealing eosinophils to also be key participants in many other facets of innate immunity, from bridging innate and adaptive immune responses to orchestrating tissue remodeling events. Here, we review the multifaceted functions of eosinophils in innate immunity that are currently known, and discuss new avenues in this evolving story.
    Cell and Tissue Research 11/2010; 343(1):57-83. DOI:10.1007/s00441-010-1049-6 · 3.33 Impact Factor
  • Source
    • "From animal studies it has become clear that transient overexpression of active TGF-b in the lung induces a chronic fibrotic response (Sime et al., 1997). Conversely, blocking TGF-b inhibits experimentally induced fibrosis in the lung, skin and liver (Giri et al., 1993; McCormick et al., 1999; Nakamura et al., 2000). Given the fact that smooth muscle metaplasia and more or less extensive fibrosis can be observed in and around deeply infiltrating endometriosis lesions, we hypothesize that active TGF-b1 signaling may be a key feature in the development of this type of endometriosis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we characterized the fibromuscular (FM) tissue, typical of deeply infiltrating endometriosis, investigated which cells are responsible for the FM reaction and evaluated whether transforming growth factor-beta (TGF-beta) signaling is involved in this process. FM differentiation and TGF-beta signaling were assessed in deeply infiltrating endometriosis lesions (n = 20) and a nude mouse model of endometriosis 1, 2, 3 and 4 weeks post-transplantation. The FM reaction was evaluated by immunohistochemistry using different markers of FM and smooth muscle cell differentiation (vimentin, desmin, alpha-smooth muscle actin, smooth muscle myosin heavy chain). TGF-beta signaling was assessed by immunostaining for its receptors and phosphorylated Smad. Deeply infiltrating endometriosis lesions contain myofibroblast-like cells that express multiple markers of FM differentiation. Expression of TGF-beta receptors and phospho-Smad was more pronounced in the endometrial component of the lesions than in the FM component. In the nude mouse model, alpha-smooth muscle actin expression was observed in murine fibroblasts surrounding the lesion, but not in human endometrial stroma. FM differentiation in deeply infiltrating endometriosis is the result of a reaction of the local environment to the presence of ectopic endometrium. It shares characteristics with pathological wound healing, but cannot be explained by TGF-beta signaling alone.
    Human Reproduction 09/2008; 23(12):2692-700. DOI:10.1093/humrep/den153 · 4.59 Impact Factor
Show more