The dual role of TNF in pulmonary edema

Yang, Guang; Hamacher, Jürg; Gorshkov, Boris A; White, Richard E.; Sridhar, Supriya; Verin, Alexander D.; Chakraborty, Trinad; Lucas, Rudolf

doi:10.4103/0975-3583.59983

Cited by 53 publications

(61 citation statements)

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“…Taken together, these results indicate that in murine models of hydrostatic edema, the receptor binding sites of TNF inhibit, whereas its lectin-like domain activates edema reabsorption [86,88]. As such, as depicted in Figure 2, there are at least two spatially distinct functional domains in TNF exhibiting opposing effects in terms of edema formation and clearance.…”

Section: The Lectin-like Domain Of Tumor Necrosis Factor: a Promismentioning

confidence: 89%

“…These data suggest that, physiologically, the activity of the lectin-like domain of TNF represent a function of the cytokine that is hidden by the adverse effects mediated by the TNF receptor binding sites [88]. However, in the presence of the soluble TNF receptors, this lectin-like activity can prevail, thus, providing an explanation of why positive effects of TNF in alveolar liquid clearance were mainly reported in infection models, which are characterized not only by increased levels of TNF, but also of its soluble receptors [89].…”

Section: The Lectin-like Domain Of Tumor Necrosis Factor: a Promismentioning

confidence: 99%

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Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

Lucas

Czikora

Sridhar

et al. 2013

Toxins

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Severe pneumonia is the main single cause of death worldwide in children under five years of age. The main etiological agent of pneumonia is the G+ bacterium Streptococcus pneumoniae, which accounts for up to 45% of all cases. Intriguingly, patients can still die days after commencing antibiotic treatment due to the development of permeability edema, although the pathogen was successfully cleared from their lungs. This condition is characterized by a dramatically impaired alveolar epithelial-capillary barrier function and a dysfunction of the sodium transporters required for edema reabsorption, including the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed sodium potassium pump (Na+-K+-ATPase). The main agent inducing this edema formation is the virulence factor pneumolysin, a cholesterol-binding pore-forming toxin, released in the alveolar compartment of the lungs when pneumococci are being lysed by antibiotic treatment or upon autolysis. Sub-lytic concentrations of pneumolysin can cause endothelial barrier dysfunction and can impair ENaC-mediated sodium uptake in type II alveolar epithelial cells. These events significantly contribute to the formation of permeability edema, for which currently no standard therapy is available. This review focuses on discussing some recent developments in the search for the novel therapeutic agents able to improve lung function despite the presence of pore-forming toxins. Such treatments could reduce the potentially lethal complications occurring after antibiotic treatment of patients with severe pneumonia.

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Section: The Lectin-like Domain Of Tumor Necrosis Factor: a Promismentioning

confidence: 89%

Section: The Lectin-like Domain Of Tumor Necrosis Factor: a Promismentioning

confidence: 99%

Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

Lucas

Czikora

Sridhar

et al. 2013

Toxins

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“…A critical involvement of TNF-α in edema formation has been documented in a series of experimental and clinical studies, which have previously been reviewed in detail (27). In brief, TNF-α reduces the expression of ENaC mRNA in alveolar epithelial cells and thereby decreases amiloride-sensitive sodium uptake (28).…”

Section: Regulation Of Active Salt and Water Transport And Edema Formmentioning

confidence: 99%

Cytokine-Regulation of Na+-K+-Cl− Cotransporter 1 and Cystic Fibrosis Transmembrane Conductance Regulator—Potential Role in Pulmonary Inflammation and Edema Formation

Weidenfeld

Kuebler

2017

Front. Immunol.

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Pulmonary edema, a major complication of lung injury and inflammation, is defined as accumulation of extravascular fluid in the lungs leading to impaired diffusion of respiratory gases. Lung fluid balance across the alveolar epithelial barrier protects the distal airspace from excess fluid accumulation and is mainly regulated by active sodium transport and Cl− absorption. Increased hydrostatic pressure as seen in cardiogenic edema or increased vascular permeability as present in inflammatory lung diseases such as the acute respiratory distress syndrome (ARDS) causes a reversal of transepithelial fluid transport resulting in the formation of pulmonary edema. The basolateral expressed Na+-K+-2Cl− cotransporter 1 (NKCC1) and the apical Cl− channel cystic fibrosis transmembrane conductance regulator (CFTR) are considered to be critically involved in the pathogenesis of pulmonary edema and have also been implicated in the inflammatory response in ARDS. Expression and function of both NKCC1 and CFTR can be modulated by released cytokines; however, the relevance of this modulation in the context of ARDS and pulmonary edema is so far unclear. Here, we review the existing literature on the regulation of NKCC1 and CFTR by cytokines, and—based on the known involvement of NKCC1 and CFTR in lung edema and inflammation—speculate on the role of cytokine-dependent NKCC1/CFTR regulation for the pathogenesis and potential treatment of pulmonary inflammation and edema formation.

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“…The peptide moreover activates ENaC in resting or toxin-treated alveolar epithelial cells [19, 20] and improves rat lung function upon lung transplantation in rats [19]. These results indicate that the lectin-like domain of TNF has a potential therapeutic value in preventing the formation and activating the reabsorption of pulmonary edema [21]. …”

Section: Introductionmentioning

confidence: 99%

A Computational Study of the Oligosaccharide Binding Sites in the Lectin-Like Domain of Tumor Necrosis Factor and the TNF-derived TIP Peptide

Dulebo¹,

Ettrich²,

Lucas³

et al. 2012

Current Pharmaceutical Design

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The lectin-like domain of Tumor Necrosis Factor (TNF), mimicked by the TIP peptide, activates amiloride-sensitive sodium uptake in type II alveolar epithelial cells and as such increases alveolar liquid clearance in dysfunctional lungs. This protective effect is blunted upon mutation of residues T105, E107 and E110 in human TNF into alanine or upon pre-incubation of the cytokine with the disaccharide N,N’-diacetylchitobiose. In this study, we used molecular docking and molecular dynamics simulation to predict the binding sites for N,N’-diacetylchitobiose and trimannose-O-ethyl in the lectin-like domain of TNF and in the TIP peptide. Specific sites (K98, S99, P100, Q102 and E116) in the three loops of the lectin-like domain provide specific binding for both oligosaccharides, but none of the residues crucial for anti-edema activity are involved in hydrogen bonding with oligosaccharides or are subjected to steric hindrance by them. These results thus suggest that neither chitobiose nor trimannose affect crucial amino acids, while they occupy the cavity in the lectin-like domain. Consequently, both crucial amino acids and the emptiness of the cavity in the lectin-like domain may be critical for TNF’s lectin-like activity. Analogously, the R4, E5, P7, Y16 amino acids of the TIP peptide are involved in forming hydrogen bonds with both oligosaccharides, whereas residues T6, E8 and E11 (corresponding to T105, E107 and E110 in hTNF) play an important role in stabilizing the peptide-oligosaccharide complex, supporting the hypothesis that amino acids in the polar region (TPEGAE) of the TIP peptide represent only a partial binding motif for sugars.

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The dual role of TNF in pulmonary edema

Cited by 53 publications

References 100 publications

Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

Cytokine-Regulation of Na+-K+-Cl− Cotransporter 1 and Cystic Fibrosis Transmembrane Conductance Regulator—Potential Role in Pulmonary Inflammation and Edema Formation

A Computational Study of the Oligosaccharide Binding Sites in the Lectin-Like Domain of Tumor Necrosis Factor and the TNF-derived TIP Peptide

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