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This Article Full Text Full Text (PDF) All Versions of this Article: 285/5/L996    most recent 00144.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Kiefmann, R. Articles by Goetz, A. E. Search for Related Content PubMed PubMed Citation Articles by Kiefmann, R. Articles by Goetz, A. E.

Role of poly(ADP-ribose) synthetase in pulmonary leukocyte recruitment

Rainer Kiefmann,¹ Kai Heckel,¹ Martina Dörger,² Sonja Schenkat,² Mechthild Stoeckelhuber,³ Józefa Wsierska-Gdek,⁴ and Alwin E. Goetz¹

¹Department of Anesthesiology, and Institutes for ²Surgical Research and ³Anatomy, University of Munich, 81377 Munich, Germany; and ⁴Institute for Cancer Research, University of Vienna, 1090 Vienna, Austria

Submitted 9 May 2003 ; accepted in final form 11 July 2003

During systemic inflammation, recruitment and activation of leukocytes in the pulmonary microcirculation may result in a potentially life-threatening acute lung injury. We elucidated the role of the poly(ADP-ribose) synthetase (PARS), a nucleotide-polymerizing enzyme, in the regulation of leukocyte recruitment within the lung with regard to the localization in the pulmonary microcirculation and in correlation to hemodynamics in the respective vascular segments and expression of intercellular adhesion molecule 1 during endotoxemia. Inhibition of PARS by 3-aminobenzamide reduced the endotoxin-induced leukocyte recruitment within pulmonary arterioles, capillaries, and venules in rabbits as quantified by in vivo fluorescence microscopy. Microhemodynamics and thus shear rates in all pulmonary microvascular segments remained constant. Simultaneously, inhibition of PARS with 3-aminobenzamide suppressed the endotoxin-induced adhesion molecules expression as demonstrated for intercellular adhesion molecule 1 by immunohistochemistry and Western blot analysis. We confirmed this result with the use of PARS knockout mice. The inhibitory effect of 3-aminobenzamide on leukocyte recruitment was associated with a reduction of pulmonary capillary leakage and edema formation. We first provide evidence that PARS activation mediates the leukocyte sequestration in pulmonary microvessels through upregulation of adhesion molecules. As reactive oxygen species released from leukocyte are supposed to cause an upregulation of adhesion molecules we conclude that PARS inhibition contributes to termination of this vicious cycle and inhibits the inflammatory process.

acute lung injury; endotoxin; in vivo fluorescence intravital microscopy; leukocyte/endothelial interaction; intercellular adhesion molecule 1

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