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

Elia, Nadia; Tapponnier, Maxime; Matthay, Michael A.; Hamacher, Jürg; Pache, Jean Claude; Bründler, Marie Anne; Tötsch, Martin; Baetseĺier, Patrick De; Fransen, Lucie; Fukuda, Norimasa; Morel, Denis R.; Lucas, Rudolf

doi:10.1164/rccm.200206-618oc

Cited by 67 publications

(90 citation statements)

References 30 publications

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“…The apparently contradictory results concerning the outcome of TNF treatment on edema reabsorption between the in situ and in vivo flooded rat lung models (null effect vs inhibitory effect, respectively) could reflect differences between experiments with living animals or "dead" organs. Likewise, we previously found null effects in ex vivo blood-perfused (21) or Krebs-Henseleit bufferperfused (data not shown) flooded rat lung models. Furthermore, in the ex vivo blood-perfused flooded rat lung, there was no significant increase in alveolar leukocytes in TNF-treated lungs compared with the saline control (21).…”

Section: Discussionsupporting

confidence: 61%

“…In contrast to its role in the formation of edema or the inhibition of edema reabsorption, TNF was shown to increase fluid reabsorption during bacterial infection (13) and ischemia reperfusion (14) models in rats. Although antagonistic Abs against the TNFRs were shown to interfere with the sodium uptake-activating effect of TNF in human A549 cells (16), in a flooded mouse model in situ, the edema reabsorption-stimulating activity of murine TNF was shown to be identical in wild-type and double-TNFR knockout mice, indicating that receptor-independent activities of TNF predominate in this activity (21). In line with this assumption, a TNF lectin-deficient mutant, which still efficiently binds to both TNFRs, completely lacked the ability to activate sodium uptake in A549 cells (16).…”

Section: Discussionmentioning

confidence: 97%

“…The functions of the lectin-like domain of TNF can be mimicked by a synthetic circular peptide that contains 17 aa (Tip peptide (Tip)). In a blood-perfused flooded rat lung model, the murine Tip peptide was recently shown to activate edema reabsorption, in contrast to native murine TNF, which did not increase the fluid clearance (21). In view of the apparently conflicting data regarding the effects of TNF on pulmonary edema, we therefore investigated the relative contributions of receptor-dependent vs lectin-like activities of hTNF on edema reabsorption by means of blocking each functional domain with, on the one hand, a human soluble TNFR type 1 construct (sTNFR1) construct and, in contrast, the oligosaccharide N,NЈ-diacetylchitobiose.…”

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confidence: 96%

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Dichotomal Role of TNF in Experimental Pulmonary Edema Reabsorption

Braun

Hamacher

Morel³

et al. 2005

The Journal of Immunology

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109

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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.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 96%

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Dichotomal Role of TNF in Experimental Pulmonary Edema Reabsorption

Braun

Hamacher

Morel³

et al. 2005

The Journal of Immunology

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109

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“…In our study, this model comprised alveolar epithelium infected with the highly pathogenic H5N1 viruses that induce higher levels of proinflammatory cytokines and chemokines than does seasonal H1N1 virus. Activation of proinflammatory pathways was previously shown to result in down-regulation of sodium and chloride transporters responsible for vectorial fluid transport across the alveolar epithelium (17), increasing paracellular protein permeability. To our knowledge, ours is the first demonstration of this phenomenon in an experimental model of virus-infected alveolar epithelium.…”

Section: Discussionmentioning

confidence: 99%

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Chan

Kuok

Leung

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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184

181

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Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium’s protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone inhibits the action of TNF on ENaC expression and activity

Dagenais

Fréchette²,

Clermont³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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We have reported that TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na+channel (ENaC) by ∼70% in alveolar epithelial cells. Because dexamethasone has been shown to upregulate ENaC mRNA expression and is well known to downregulate proinflammatory genes, we tested if it could alleviate the effect of TNF on ENaC expression and activity. In cotreatment with TNF, we found that dexamethasone reversed the inhibitory effect of TNF and upregulated α, β, and γENaC mRNA expression. When the cells were pretreated for 24 h with TNF before cotreatment, dexamethasone was still able to increase αENaC mRNA expression to 1.8-fold above control values. However, in these conditions, β and γENaC mRNA expression was reduced to 47% and 14%, respectively. The potential role of TNF and dexamethasone on αENaC promoter activity was tested in A549 alveolar epithelial cells. TNF decreased luciferase (Luc) expression by ∼25% in these cells, indicating that the strong diminution of αENaC mRNA must be related to posttranscriptional events. Dexamethasone raised Luc expression by fivefold in the cells and augmented promoter activity by 2.77-fold in cotreatment with TNF. In addition to its effect on αENaC gene expression, dexamethasone was able to maintain amiloride-sensitive current as well as the liquid clearance abilities of TNF-treated cells within the normal range. All these results suggest that dexamethasone alleviates the downregulation of ENaC expression and activity in TNF-treated alveolar epithelial cells.

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

Cited by 67 publications

References 30 publications

Dichotomal Role of TNF in Experimental Pulmonary Edema Reabsorption

Dichotomal Role of TNF in Experimental Pulmonary Edema Reabsorption

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Dexamethasone inhibits the action of TNF on ENaC expression and activity

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