Published ahead of print on July 3, 2003, doi:10.1164/rccm.200206-618OC
Am. J. Respir. Crit. Care Med., Volume 168, Number 9, November 2003, 1043-1050
A more recent version of this article appeared on November 1, 2003
Submitted on June 30, 2002
Accepted on June 25, 2003
Identification of the Alveolar edema reabsorption activity of murine Tumor Necrosis Factor
Nadia Elia1, Maxime Tapponnier1, Michael A Matthay2, Juerg Hamacher3, Jean-Claude Pache4, Marie-Anne Brundler4, Martin Totsch4, Patrick De Baetselier5, Lucie Fransen6, Norimasa Fukuda2, Denis R Morel1, and Rudolf Lucas7*
1 Division of Anesthesiological Investigations, University Medical Center, Geneva, Switzerland,
2 Division Cardiovascular Research, Cardiovascular Research Institute, San Francisco, CA, USA,
3 Biochemical Pharmacology, University of Konstanz, Konstanz, Baden-Wuerttemberg, Germany,
4 Division of Clinical Pathology, University Medical Center, Geneva, Switzerland,
5 Laboratory of Cellular Immunology, Flemish Institute for Biotechnology (VIB), University of Brussels, Sint-Genesius-Rode, Vlaams-Brabant, Belgium,
6 Therapeutics, Innogenetics, Ghent, Oost-Vlaanderen, Belgium,
7 Division of Anesthesiological Investigations, University Medical Center, Geneva, Switzerland; Biochemical Pharmacology, University of Konstanz, Konstanz, Baden-Wuerttemberg, Germany
* To whom correspondence should be addressed. E-mail: Rudolf.Lucas{at}uni-konstanz.de.
Tumor Necrosis Factor (TNF) activates sodium channels in type II alveolar epithelial cells, an important mechanism for the reported fluid resorption capacity of the cytokine. Both TNF receptor-dependent and -independent effects were proposed for this activity in vitro, the latter mechanism mediated by the lectin-like domain of the molecule. In this study, the relative contribution of the receptor-dependent versus -independent activities was investigated in an in vivo mouse lung model and an ex vivo rat lung model. Fluid resorption due to murine TNF (mTNF) was functional in mice that were genetically deficient in both types of mTNF receptors, establishing the importance of mTNF receptor-independent effects in this species. In addition, we assessed the capacity of a mTNF-derived peptide (mLtip), that activates sodium transport by a receptor-independent mechanism, to reduce lung water content in an isolated, ventilated, autologous blood perfused rat lung model. The results show that in this model mLtip, in contrast to mTNF, produced a progressive recovery of dynamic lung compliance and airway resistance following alveolar flooding. There was also a significant reduction in lung water. These results indicate that the receptor-independent lectin-like domain of mTNF has a potential physiological role in the resolution of alveolar edema in rats and mice.
Key words: lung, cytokine, edema, sodium channel, lectin
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