The lectin-like domain of tumor necrosis factor-α improves alveolar fluid balance in injured isolated rabbit lungs

Objective: Identification of mechanisms that preserve optimal alveolar fluid balance during pulmonary edema is of great clinical importance. This study was performed to determine whether the lectin-like domain of tumor necrosis factor-alpha (designated TIP) can improve fluid balance in experimental lung injury by affecting alveolocapillary permeability and/or fluid clearance. Design: Prospective, randomized laboratory investigation. Setting: University-affiliated laboratory. Subjects: Adult male rabbits. Interventions: TIP, a scrambled peptide (scrTIP), dibutyryl cyclic adenosine monophosphate (db-cAMP), or saline was applied to isolated, ventilated, and buffer-perfused rabbit lungs by ultrasonic nebulization, after which hydrostatic edema or endo/exotoxin-induced lung injury was induced and edema formation was assessed. In studies evaluating the resolution of alveolar edema, 2.5 mL of excess fluid was deposited into the alveolar space of isolated lungs by nebulization in the absence or presence of TIP, scrTIP, amiloride, or ouabain or combinations thereof. Measurements and Main Results: Microvascular permeability was largely increased during hydrostatic edema and endo/exotoxin-induced lung injury in saline-treated lungs, or lungs that received scrTIP, as assessed by capillary filtration coefficient (K-1,K-c) and fluorescein isothiocyanate-labeled albumin flux across the alveolocapillary barrier. In contrast, TIP- or db-cAMP-treated lungs exhibited significantly lower vascular permeability upon hydrostatic challenge. Similarly, extravascular fluid accumulation, as assessed by fluid retention, wet weight to dry weight ratio, and epithelial lining fluid volume measurements, was largely inhibited by TIP or db-cAMP pretreatment. Furthermore, TIP increased sodium-potassium adenosine triphosphatase (Na,K-ATPase) activity 1.6-fold by promoting Na,K-ATPase exocytosis to the alveolar epithelial cell surface and increased amiloride-sensitive sodium uptake, resulting in a 2.2-fold increase in active Na+ transport, and hence improved clearance of excess fluid from the alveolar space. Conclusions: Aerosolized TIP improved alveolar fluid balance by both reducing vascular permeability and enhancing the absorption of excess alveolar fluid in experimental lung injury. These data may suggest a role for TIP as a potential therapeutic agent in pulmonary edema.