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 journalArticle

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-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
JournalTransplantation
Volume78
Issue number4
DOIs
StatePublished - Aug 27 2004
Externally publishedYes

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Bone Marrow Transplantation
Pneumonia
Endothelial Cells
Tumor Necrosis Factor-alpha
Apoptosis
Homologous Transplantation
Lung Injury
Lung
Vascular Endothelium
Lipopolysaccharides
Histocompatibility
Tumor Necrosis Factor Receptors
In Situ Nick-End Labeling
Bronchoalveolar Lavage Fluid
Wounds and Injuries
Graft vs Host Disease
Transferases
Caspase 3
Carrier Proteins
Pathology

Keywords

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

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

A role for tumor necrosis factor-α-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome. / Gerbitz, Armin; Nickoloff, Brian J.; Olkiewicz, Krystyna; Willmarth, Nicole E.; Hildebrandt, Gerhard; Liu, Chen; Kobzik, Lester; Eissner, Günther; Holler, Ernst; Ferrara, James L M; Cooke, Kenneth R.

In: Transplantation, Vol. 78, No. 4, 27.08.2004, p. 494-502.

Research output: Contribution to journalArticle

Gerbitz, A, Nickoloff, BJ, Olkiewicz, K, Willmarth, NE, Hildebrandt, G, Liu, C, Kobzik, L, Eissner, G, Holler, E, Ferrara, JLM & Cooke, KR 2004, 'A role for tumor necrosis factor-α-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome', Transplantation, vol. 78, no. 4, pp. 494-502. https://doi.org/10.1097/01.TP.0000128839.13674.02
Gerbitz, Armin ; Nickoloff, Brian J. ; Olkiewicz, Krystyna ; Willmarth, Nicole E. ; Hildebrandt, Gerhard ; Liu, Chen ; Kobzik, Lester ; Eissner, Günther ; Holler, Ernst ; Ferrara, James L M ; Cooke, Kenneth R. / A role for tumor necrosis factor-α-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome. In: Transplantation. 2004 ; Vol. 78, No. 4. pp. 494-502.
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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-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.",
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T1 - A role for tumor necrosis factor-α-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome

AU - Gerbitz, Armin

AU - Nickoloff, Brian J.

AU - Olkiewicz, Krystyna

AU - Willmarth, Nicole E.

AU - Hildebrandt, Gerhard

AU - Liu, Chen

AU - Kobzik, Lester

AU - Eissner, Günther

AU - Holler, Ernst

AU - Ferrara, James L M

AU - Cooke, Kenneth R

PY - 2004/8/27

Y1 - 2004/8/27

N2 - 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.

AB - 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.

KW - Bone marrow transplantation

KW - Cytokines

KW - Endothelium

KW - Graft-versus-host disease

KW - Lung

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