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: Historically, platelets were viewed as simple anucleate cells responsible for initiating thrombosis and maintaining hemostasis, but clearly they are also key mediators of inflammation and immune cell activation. An emerging body of evidence links platelet function and thrombosis to vascular inflammation. peroxisome proliferator-activated receptors (PPARs) play a major role in modulating inflammation and, interestingly, PPARs (PPAR/ and PPAR) were recently identified in platelets. Additionally, PPAR agonists attenuate platelet activation; an important discovery for two reasons. First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression. Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade. Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.PPAR Research 02/2008; 2008(1687-4757):328172. DOI:10.1155/2008/328172 · 1.64 Impact Factor
Article: The Role of PPARs in Lung Fibrosis[Show abstract] [Hide abstract]
ABSTRACT: Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticosteroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis, including cellular differentiation, inflammation, and wound healing. PPARα agonists, including the hypolidipemic fibrate drugs, inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the mouse model of lung fibrosis induced by bleomycin, a PPARα agonist significantly inhibited the fibrotic response, while PPARα knockout mice developed more serious fibrosis. PPARβ/δ appears to play a critical role in regulating the transition from inflammation to wound healing. PPARβ/δ agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARγ agonists. PPARγ ligands oppose the profibrotic effect of TGF-β, which induces differentiation of fibroblasts to myofibroblasts, a critical effector cell in fibrosis. PPARγ ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARα and PPARγ agonists should facilitate rapid development of successful treatment strategies based on current and ongoing research.PPAR Research 02/2007; 2007:71323. DOI:10.1155/2007/71323 · 1.64 Impact Factor