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Functional Identification of the Alveolar Edema Reabsorption Activity of Murine Tumor Necrosis Factor-

Division of Anesthesiological Investigations and Division of Clinical Pathology, University Medical Center, Geneva, Switzerland; Cardiovascular Research Institute, San Francisco, California; Laboratory of Cellular Immunology, Flemish Institute for Biotechnology, University of Brussels, Campus Rode, Sint-Genesius-Rode, Belgium; Innogenetics, Industriepark Zwijnaarde, Ghent, Belgium; and Biochemical Pharmacology, University of Konstanz, Konstanz, Germany

Correspondence and requests for reprints should be addressed to Rudolf Lucas, Ph.D., Biochemical Pharmacology, University of Konstanz, Universitätsstrasse 10, 78457 Konstanz, Germany. 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 receptor-independent activities was investigated in an in situ 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- receptor, establishing the importance of mTNF- receptor–independent effects in this species. In addition, we assessed the capacity of an mTNF-–derived peptide (mLtip), which 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 after 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: edema • cytokine • sodium transport

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