Sensitivity to bleomycin-induced lung injury is not moderated by an antigen-limited T-cell repertoire.

Department of Microbiology and Immunology, Division of Pulmonary and Critical Care Medicine, University of Rochester, Rochester, New York 14642, USA.
Experimental Lung Research (Impact Factor: 1.41). 10/2005; 31(7):685-700. DOI: 10.1080/01902140591007218
Source: PubMed


Pulmonary fibrosis is a progressive scarring disease of the lung. It has been suggested that fibrosis is an inflammatory process, and cytokines such as tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta have been shown to play key roles in the pathogenesis of fibrotic lung disease. However, the source of these cytokines remains in question and there is controversy over the role that infiltrating inflammatory cells play in fibrosis. T cells could play a key role by releasing cytokines upon engaging autoantigens revealed as a result of necrosis or apoptosis following epithelial injury. Some studies have shown that disrupting T-cell function leads to more severe disease, whereas others have shown that T-cell deficiency protects against fibrotic injury. To investigate whether specific antigen engagement by T cells is required for the development of fibrosis, bleomycin was instilled into the lungs of mice expressing a transgenic T-cell receptor beta (TCRbeta) gene. Expression of the TCRbeta transgene prevents effective recognition of antigens other than a single epitope of hen egg lysozyme. These mice therefore have defective antigen-specific responses but a normal representation of mature T-cell subsets. If antigen-specific T-cell engagement is required for the development of lung fibrosis, bleomycin-induced fibrosis should be reduced in the TCRbeta transgenic mice. In fact, there is no difference in the inflammatory or fibrotic response to bleomycin between TCRbeta transgenic and control mice. Thus, if T cells are required for fibrogenesis, it must involve an antigen-independent mechanism.

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    • "In contrast, it is known that PPARα plays an antiinflammatory role in lung fibrosis although the mechanism is not well understood [72] [73]. It is clear that the intricacies of PPARα function must be discerned to design effective and safe drug strategies. "
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    • "The role of PPARα in lung fibrosis was investigated in mice using the bleomycin model of lung injury and fibrosis . Intratracheal instillation of the antineoplastic agent bleomycin causes acute lung inflammation that develops into severe fibrosis, with proliferation of α-SMA-positive myofibroblasts , increased collagen deposition, and loss of normal alveolar architecture [48] [49]. PPARα-knockout mice treated with bleomycin developed more severe inflammation and fibrosis than wild-type mice, with increased immunohistochemical detection of TNF-α and IL-1β, increased apoptosis of interstitial cells, and decreased survival [50]. "
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