Sensitivity to bleomycin-induced lung injury is not moderated by an antigen-limited T-cell repertoire.
ABSTRACT 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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ABSTRACT: The discovery of several subsets of CD4(+) Th lymphocytes has contributed to refine and to challenge our understanding of the roles of CD4(+) T cells in the pathogenesis of fibrotic lung diseases. Here, we review recent findings, indicating that CD4(+) T subpopulations possess contrasting pro- and antifibrotic activities in human and experimental lung fibrosis. Special attention is given to delineate the activity of the newly discovered CD4(+) T lymphocyte subsets (Tregs, Th22, and Th9) on fibroblast function and matrix deposition through the release of growth factors, cytokines, and eicosanoids. It appears that the function of a CD4(+) T lymphocyte subset or of a cytokine can differ with the disease stage (acute vs. chronic), pulmonary localization (bronchial vs. alveolar), cellular level (epithelial cell vs. fibroblast), or immune environment (inflammatory or immunosuppressive). Integrating our recent understanding of the contrasting functions of T lymphocyte subsets in fibrosis provides new insights and opportunities for improved treatment strategies.Journal of leukocyte biology 11/2012; · 4.99 Impact Factor
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ABSTRACT: Dipeptidyl peptidase IV (DP IV)-related proteases and aminopeptidase N (APN) are drug targets in various diseases. Here we investigated for the first time the effects of DP-IV-related protease inhibitors and APN inhibitors on chronic inflammatory lung diseases. A murine model of silica (SiO2)-induced lung fibrosis and in vitro cultures of human lung epithelial cells and monocytes have been used and the influence of silica-treatment and inhibitors on inflammation and fibrosis has been measured. We found increased inflammation and secretion of the chemokines IL-6, MCP-1 and MIP-alpha 2 weeks after SiO2 application, and increased lung fibrosis after 3 months. Treatment with the APN inhibitor actinonin reduced chemokine secretion in the lung and bronchoalveolar lavage fluid, and in cell culture, and decreased the level of fibrosis after 3 months. Treatment with inhibitors of DP-IV-related proteases, or a combination of DP IV inhibitors and APN inhibitors, had no significant effect. We found no obvious side effects of long-term treatment with inhibitors of APN and DP IV. Overall, our findings show that actinonin, an inhibitor of aminopeptidase N, might modulate chemokine secretion in the lung and thus attenuate the development of lung fibrosis. Additional targeting of DP-IV-related proteases had no significant effect on these processes.Life Sciences 11/2008; 84(1-2):1-11. · 2.30 Impact Factor