A role for tumor necrosis factor-α-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome

Armin Gerbitz, Brian J. Nickoloff, Krystyna Olkiewicz, Nicole E. Willmarth, Gerhard Hildebrandt, Chen Liu, Lester Kobzik, Günther Eissner, Ernst Holler, James L.M. Ferrara, Kenneth R. Cooke

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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-α and lipopolysaccharide. Both TNF-α 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)-α levels, and is accompanied by evidence for EC activation. Administration of a soluble TNF-α binding protein (recombinant human TNF-α 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-α 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.

Original languageEnglish (US)
Pages (from-to)494-502
Number of pages9
Issue number4
StatePublished - Aug 27 2004
Externally publishedYes


  • Bone marrow transplantation
  • Cytokines
  • Endothelium
  • Graft-versus-host disease
  • Lung

ASJC Scopus subject areas

  • Transplantation


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