A Novel Tumor Necrosis Factor-mediated Mechanism of Direct Epithelial Sodium Channel Activation

作者：Czikora Istvan; Alli Abdel; Bao Hui Fang; Kaftan David; Sridhar Supriya; Apell Hans Juergen; Gorshkov Boris; White Richard; Zimmermann Astrid; Wendel Albrecht; Pauly Evers Meike; Hamacher Juerg; Garcia Gabay Irene; Fischer Bernhard; Verin Alexander; Bagi Zsolt; Pittet Jean Francois; Shabbir Waheed; Lemmens Gruber Rosa; Chakraborty Trinad; Lazrak Ahmed; Matthay Michael A; Eaton Douglas C; Lucas Rudolf^*

来源：American Journal of Respiratory and Critical Care Medicine, 2014, 190(5): 522-532.

DOI：10.1164/rccm.201405-0833OC

• epithelial sodium channel
• pneumonia
• protein kinase C-alpha
• pulmonary edema
• tumor necrosis factor

Rationale: Alveolar liquid clearance is regulated by Na+ uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na+-K+-ATPase in type II alveolar epithelial cells. Dysfunction of these Na+ transporters during pulmonary inflammation can contribute to pulmonary edema. %26lt;br%26gt;Objectives: In this study, we sought to determine the precise mechanism by which the TIP peptide, mimicking the lectin-like domain of tumor necrosis factor (TNF), stimulates Na+ uptake in a homologous cell system in the presence or absence of the bacterial toxin pneumolysin (PLY). %26lt;br%26gt;Methods: We used a combined biochemical, electrophysiological, and molecular biological in vitro approach and assessed the physiological relevance of the lectin-like domain of TNF in alveolar liquid clearance in vivo by generating triple-mutant TNF knock-in mice that express a mutant TNF with deficient Na+ uptake stimulatory activity. %26lt;br%26gt;Measurements and Main Results: TIP peptide directly activates ENaC, but not the Na+-K+-ATPase, upon binding to the carboxyterminal domain of the a subunit of the channel. In the presence of PLY, a mediator of pneumococcal-induced pulmonary edema, this binding stabilizes the ENaC-PIP2-MARCKS complex, which is necessary for the open probability conformation of the channel and preserves ENaC-alpha protein expression, by means of blunting the protein kinase C-alpha pathway. Triple-mutant TNF knock-in-mice are more prone than wild-type mice to develop edema with low-dose intratracheal PLY, correlating with reduced pulmonary ENaC-alpha subunit expression. %26lt;br%26gt;Conclusions: These results demonstrate a novel TNF-mediated mechanism of direct ENaC activation and indicate a physiological role for the lectin-like domain of TNF in the resolution of alveolar edema during inflammation.

• 出版日期2014-9-1
• 单位河北医科大学