Functional identification of the alveolar edema reabsorption activity of murine tumor necrosis factor-alpha

N Elia, M Tapponnier, MA Matthay, J Hamacher, JC Pache, Marie-Anne Brundler, M Totsch

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    Abstract

    Tumor necrosis factor-alpha (TNF-alpha) activates sodium channels in Type II alveolar epithelial cells, an important mechanism for the reported fluid resorption capacity of the cytokine. Both TNF-alpha 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-alpha (mTNF-alpha) was functional in mice that were genetically deficient in both types of mTNF-alpha receptor, establishing the importance of mTNF-alpha receptor-independent effects in this species. In addition, we assessed the capacity of an mTNF-alpha-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-alpha, 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-alpha has a potential physiological role in the resolution of alveolar edema in rats and mice.
    Original languageEnglish
    Pages (from-to)1043-1050
    Number of pages8
    JournalAmerican Journal of Respiratory and Critical Care Medicine
    Volume168
    Issue number9
    Early online date11 Sep 2003
    DOIs
    Publication statusPublished - 11 Sep 2003

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