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

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Abstract
Tumor necrosis factor-α (TNF-α) activates sodium channels in Type II alveolar epithelial cells, an important mechanism for the reported fluid resorption capacity of the cytokine. Both TNF-α 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-α (mTNF-α) was functional in mice that were genetically deficient in both types of mTNF-α receptor, establishing the importance of mTNF-α receptor–independent effects in this species. In addition, we assessed the capacity of an mTNF-α–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-α, 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-α has a potential physiological role in the resolution of alveolar edema in rats and mice.

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