Functional identification of the alveolar edema reabsorption activity of murine tumor necrosis factor-alpha.
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.
Elia
Nadia
N
Division of Anesthesiological Investigations, University Medical Center, Geneva, Switzerland.
Tapponnier
Maxime
M
Matthay
Michael A
MA
Hamacher
Jurg
J
Pache
Jean-Claude
JC
Brundler
Marie-Anne
MA
Totsch
Martin
M
De Baetselier
Patrick
P
Fransen
Lucie
L
Fukuda
Norimasa
N
Morel
Denis R
DR
Lucas
Rudolf
R
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D004232:Diuretics / Q000494:pharmacology; D005260:Female; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009929:Organ Size; D010446:Peptide Fragments / Q000378:metabolism; D011654:Pulmonary Edema / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000378:metabolism; D015656:Respiratory Mechanics / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D004232:Diuretics; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D015222:Sodium Channels; D014409:Tumor Necrosis Factor-alpha; D000584:Amiloride