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  • Title: A role for tumor necrosis factor-alpha-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome.
    Author: Gerbitz A, Nickoloff BJ, Olkiewicz K, Willmarth NE, Hildebrandt G, Liu C, Kobzik L, Eissner G, Holler E, Ferrara JL, Cooke KR.
    Journal: Transplantation; 2004 Aug 27; 78(4):494-502. PubMed ID: 15446306.
    Abstract:
    BACKGROUND: Idiopathic pneumonia syndrome (IPS) is a frequent and often fatal complication of allogeneic bone marrow transplantation (BMT). We have previously shown that experimental IPS is associated with alloreactive donor T cells and the inflammatory mediators TNF-alpha and lipopolysaccharide. Both TNF-alpha and lipopolysaccharide are known contributors to endothelial injury. Although damage to vascular endothelia has been associated with other complications after BMT, its relationship to lung injury has not been explored. METHODS: We used a well-established murine BMT system, in which lung injury and graft-versus-host disease are induced by minor histocompatibility antigenic differences between donor and host, and the DNA terminal transferase nick-end labeling (TUNEL) procedure to evaluate whether significant pulmonary vascular endothelial cell (EC) apoptosis is present during the development of IPS. RESULTS: Our data demonstrate that pulmonary histopathology after allogeneic BMT is accompanied by significant EC apoptosis and the appearance of activated caspase 3. Further evaluation reveals that EC injury coincides with the onset of pulmonary pathology, is associated with elevations in bronchoalveolar lavage fluid tumor necrosis factor (TNF)-alpha levels, and is accompanied by evidence for EC activation. Administration of a soluble TNF-alpha binding protein (recombinant human TNF-alpha receptor:Fc) from week 4 to week 6 after allogeneic BMT significantly reduces EC apoptosis and lung histopathology observed in this setting. CONCLUSIONS: EC damage mediated by TNF-alpha is directly linked to the development of experimental IPS. Methods that protect or maintain the integrity of the pulmonary vascular endothelium may therefore prove effective in reducing the severity of lung injury after BMT.
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