Dichotomal Role of TNF in Experimental Pulmonary Edema Reabsorption

Abstract

Distinct from its receptor binding sites, TNF carries a lectin-like domain, situated at the tip of the molecule, which specifically binds oligosaccharides, such as N,N′-diacetylchitobiose. In view of the apparently conflicting data concerning TNF actions in pulmonary edema, we investigated the contribution of, on the one hand, the receptor binding sites and, in contrast, the lectin-like domain of the cytokine on pulmonary fluid reabsorption in in situ and in vivo flooded rat lungs. Receptor binding sites were blocked with the human soluble TNFR type 1 construct (sTNFR1), whereas the lectin-like domain was blunted with the oligosaccharide N,N′-diacetylchitobiose. We observed that in situ, TNF failed to stimulate alveolar liquid clearance, but did so together with the sTNFR1, and this activity was neutralized by N,N′-diacetylchitobiose. In vivo TNF inhibited liquid clearance, but activated it when complexed with the sTNFR1. A TNF-derived peptide mimic of the lectin-like domain activated fluid reabsorption in flooded lungs, and this activity was blunted by cotreatment with TNF. Our results thus indicate that in these models the receptor binding sites of TNF inhibit, whereas its lectin-like domain activates, edema reabsorption.

Dexamethasone inhibits the action of TNF on ENaC expression and activity

“…Although the time of TNF stimulation, acute vs. chronic, could explain these differences in part, recent reports suggest that TNF could promote both activities. Whereas the lectin-binding domain of TNF (Ltip) has been demonstrated to promote increased lung liquid clearance in tumor necrosis factor receptor I (TNF-RI) and TNF-RII KO mice (23) and in the rat lung (8), TNF instilled in the rat lung has been found recently to decrease lung liquid clearance (8). In this latter study, inactivation of the TNF receptor-binding domain by soluble TNF-RI or inactivating antibodies enabled TNF, via its Ltip domain, to increase lung liquid clearance (8).…”

“…Whereas the lectin-binding domain of TNF (Ltip) has been demonstrated to promote increased lung liquid clearance in tumor necrosis factor receptor I (TNF-RI) and TNF-RII KO mice (23) and in the rat lung (8), TNF instilled in the rat lung has been found recently to decrease lung liquid clearance (8). In this latter study, inactivation of the TNF receptor-binding domain by soluble TNF-RI or inactivating antibodies enabled TNF, via its Ltip domain, to increase lung liquid clearance (8). It has been shown, by patch-clamp experiments in A549 cells, that infusion of TNF was able to increase amiloride-sensitive current within a few minutes (32).…”

Non-Cardiogenic Pulmonary Edema

“…Cytokines have various effects on activating endothelium inducing endothelial expression of adhesion molecules and leukocyte chemotaxis leading to a local inflammatory response in the lung. The cytokine, TNFinduces macrophages and T H 1 cells and activates ECs and macrophages (Braun et al, 2005). Studies have been conflicting as far as elevation of TNF-in patients with ARDS pulmonary edema, for example, Bauer demonstrated that TNF-concentrations were significantly higher in patients with ARDS than those of pneumonia or of the control subjects (Bauer et al, 2000).…”

“…Large amounts of TNF-are released in response to LPS endotoxin, bacterial products and IL-1. TNF-works with IL-1 and IL-6 to produce actions on various organ systems (Schutte et al, 1996;Braun et al, 2005;Bauer et al, 2000). TNF-also induces EC activation and barrier dysfunction both of which occur in the pathogenesis of pulmonary edema and ALI/ARDS.…”

“…TNF-also induces EC activation and barrier dysfunction both of which occur in the pathogenesis of pulmonary edema and ALI/ARDS. It can promote edema by TNF receptor dependent chemokine production and adhesion molecule expression and leads to neutrophil chemotaxis (Braun et al, 2005;Ward, 1996). It also causes a decrease in transendothelial electrical resistance across human pulmonary artery EC (HPAEC) (Petrache et al 2003).…”