Differential roles of p55 and p75 tumor necrosis factor receptors on stretch-induced pulmonary edema in mice

2007 ◽  
Vol 293 (1) ◽  
pp. L60-L68 ◽  
Author(s):  
Michael R. Wilson ◽  
Michael E. Goddard ◽  
Kieran P. O'Dea ◽  
Sharmila Choudhury ◽  
Masao Takata
Keyword(s):  
Tumor Necrosis Factor ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Knockout Mice ◽  
Tumor Necrosis ◽  
Tnf Receptor ◽  
Wild Type ◽  
Double Knockout ◽  
Edema Formation ◽  
Necrosis Factor

Ventilator-induced lung injury plays a crucial role in the outcome of patients with acute lung injury. Previous studies have shown a role for the cytokine tumor necrosis factor-α (TNF) in stretch-induced alveolar neutrophil recruitment, but the involvement of TNF in stretch-induced pulmonary edema is unclear. We investigated the effects of TNF through its individual p55 and p75 receptors on early pulmonary edema formation during high stretch ventilation, before neutrophil infiltration. Anesthetized wild-type or TNF receptor single/double knockout mice were ventilated with high tidal volume (∼38 ml/kg) for 2 h or until they developed arterial hypotension. Pulmonary edema was assessed by physiological parameters including respiratory mechanics and blood gases, and by lavage fluid protein, lung wet:dry weight ratio, and lung permeability measurements using fluorescence-labeled albumin. High stretch ventilation in wild-type and TNF receptor double knockout animals induced similar pulmonary edema, and only 25–30% of mice completed the protocol. In contrast, the p55 receptor knockout mice were strongly protected from edema formation, with all animals completing the protocol. Myeloperoxidase assay indicated that this protective effect was not associated with decreased pulmonary neutrophil sequestration. The p75 receptor knockout mice, however, displayed increased susceptibility to edema formation, and no animals survived the full 2 h. These results demonstrate a novel role for TNF signaling (independent from its effects on neutrophil recruitment) specifically through the p55 receptor, in promoting high stretch-induced pulmonary edema, whereas p75 signaling may play an opposing role.

scholarly journals Complementation of Lymphotoxin α Knockout Mice with Tumor Necrosis Factor–expressing Transgenes Rectifies Defective Splenic Structure and Function

1998 ◽  
Vol 188 (4) ◽  
pp. 745-754 ◽  
Author(s):  
Lena Alexopoulou ◽  
Manolis Pasparakis ◽  
George Kollias
Keyword(s):  
Tumor Necrosis Factor ◽  
B Cell ◽  
Knockout Mice ◽  
Tumor Necrosis ◽  
Follicular Dendritic Cell ◽  
Germinal Centers ◽  
Tnf Receptor ◽  
And Function ◽  
Deficient Mice ◽  
Necrosis Factor

Lymphotoxin (LT)α knockout mice, as well as double LTα/tumor necrosis factor (TNF) knockout mice, show a severe splenic disorganization with nonsegregating T/B cell zones and complete absence of primary B cell follicles, follicular dendritic cell (FDC) networks, and germinal centers. In contrast, as shown previously and confirmed in this study, LTβ-deficient mice show much more conserved T/B cell areas and a reduced but preserved capacity to form germinal centers and FDC networks. We show here that similar to the splenic phenotype of LTβ-deficient mice, complementation of LTα knockout mice with TNF-expressing transgenes leads to a p55 TNF receptor–dependent restoration of B/T cell zone segregation and a partial preservation of primary B cell follicles, FDC networks, and germinal centers. Notably, upon lipopolysaccharide challenge, LTα knockout mice fail to produce physiological levels of TNF both in peritoneal macrophage supernatants and in their serum, indicating a coinciding deficiency in TNF expression. These findings suggest that defective TNF expression contributes to the complex phenotype of the LTα knockout mice, and uncover a predominant role for TNF and its p55 TNF receptor in supporting, even in the absence of LTα, the development and maintenance of splenic B cell follicles, FDC networks, and germinal centers.

scholarly journals Interleukin-1 and Tumor Necrosis Factor Activities Partially Account for Calvarial Bone Resorption Induced by Local Injection of Lipopolysaccharide

1999 ◽  
Vol 67 (8) ◽  
pp. 4231-4236 ◽  
Author(s):  
Cheng-Yang Chiang ◽  
George Kyritsis ◽  
Dana T. Graves ◽  
Salomon Amar
Keyword(s):  
Tumor Necrosis Factor ◽  
Bone Resorption ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Receptor Type ◽  
Tnf Receptor ◽  
Receptor Signaling ◽  
Wild Type ◽  
Necrosis Factor

ABSTRACT The present study was undertaken to test the hypothesis that tumor necrosis factor (TNF) and/or interleukin-1 (IL-1) activity mediates lipopolysaccharide (LPS)-induced bone resorption in vivo. To test this hypothesis, Escherichia coli LPS or Porphyromonas gingivalis LPS was injected into the subcutaneous tissues overlying mouse calvariae. Histological sections, prepared from the center of the lesion, were stained for tartrate-resistant acid phosphatase, and histomorphometric analysis was performed to quantify the osteoclast number and the area of bone resorption. In time course experiments using normal mice, a peak of bone resorption occurred 5 days after endotoxin stimulation. In dose-response experiments, IL-1 receptor type 1 deletion (IL-1R−/−), TNF double-receptor p55/p75 deletion (TNF p55−/−/p75−/−), combined TNF p55 and IL-1 receptor type 1 deletion (TNF p55−/−/IL-1R−/−), and IL-1β-converting enzyme-deficient (ICE−/−) mice and the respective wild-type mice were injected with 500, 100, or 20 μg of P. gingivalis LPS and sacrificed 5 days after LPS injection. At the highest dose (500 μg), significant decreases in osteoclast number occurred in mutant mice compared to wild-type mice: (i) a 64% reduction for the TNF p55−/−/IL-1R−/− mice, (ii) a 57% reduction for the IL-1R−/− mice, (iii) a 41% reduction for the TNF p55−/−/p75−/− mice, and (iv) a 38% reduction for the ICE−/− mice. At the two lower doses, bone resorption was apparent but no significant differences between mutant and wild-type animals were observed. The present data indicate that at higher doses, LPS-induced bone resorption is substantially mediated by IL-1 and TNF receptor signaling. Furthermore, IL-1 receptor signaling appears to be slightly more important than TNF receptor signaling. At lower LPS doses, other pathways leading to osteoclast activity that are independent of TNF and IL-1 are involved.

Dextran sulfate inhibits PMN-dependent hydrostatic pulmonary edema induced by tumor necrosis factor

1991 ◽  
Vol 70 (3) ◽  
pp. 1121-1128 ◽  
Author(s):  
D. C. Hocking ◽  
T. J. Ferro ◽  
A. Johnson
Keyword(s):  
Tumor Necrosis Factor ◽  
Protective Effect ◽  
Pulmonary Edema ◽  
Tumor Necrosis ◽  
Dextran Sulfate ◽  
Ringer Solution ◽  
Lung Weight ◽  
Edema Formation ◽  
Neutrophil Sequestration ◽  
Necrosis Factor

We tested the hypothesis that neutrophil sequestration is required for the development of tumor necrosis factor- (TNF) induced neutrophil- (PMN) dependent pulmonary edema. TNF (3.2 X 10(5) U/kg ip) was injected into guinea pigs 18 h before lung isolation. After isolation, the lung was perfused with a phosphate-buffered Ringer solution. Dextran sulfate (mol wt 500,000) prevented the changes in pulmonary capillary pressure (Ppc; 8.5 +/- 0.8 vs. 12.8 +/- 0.8 cmH2O), lung weight gain (dW; +0.240 +/- 0.135 vs. +1.951 +/- 0.311 g), and pulmonary edema formation or wet-to-dry wt ratio [(W - D)/D; 6.6 +/- 0.2 vs. 8.3 +/- 0.5] at 60 min induced by PMN infusion into a TNF-pretreated lung. The unsulfated form of dextran had no protective effect [Ppc, dW, and (W - D)/D at 60 min: 11.9 +/- 0.9 cmH2O, +1.650 +/- 0.255 g, and 7.3 +/- 0.2, respectively], whereas the use of another anionic compound, heparin, inhibited the TNF + PMN response [Ppc, dW, and (W - D)/D at 60 min: 5.6 +/- 0.4 cmH2O, +0.168 +/- 0.0.052 g, and 6.4 +/- 0.2, respectively]. Isolated lungs showed increased PMN myeloperoxidase (MPO) activity compared with control in TNF-treated lungs at baseline and 60 min after PMN infusion. Dextran sulfate, dextran, and heparin inhibited the increase in MPO activity. The data indicate that inhibition of PMN sequestration alone is not sufficient for the inhibition of PMN-mediated TNF-induced hydrostatic pulmonary edema and that a charge-dependent mechanism mediates the protective effect of dextran sulfate.

Evidence that genetic deletion of the TNF receptor p60 or p80 in macrophages modulates RANKL-induced signaling

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4113-4121 ◽  
Author(s):  
Yasunari Takada ◽  
Bharat B. Aggarwal
Keyword(s):  
Tumor Necrosis Factor ◽  
Cross Talk ◽  
Tumor Necrosis ◽  
No Production ◽  
Dependent Manner ◽  
Tnf Receptor ◽  
Wild Type ◽  
Tnf Receptors ◽  
Genetic Deletion ◽  
Necrosis Factor

Abstract In the current report, we investigated the possibility of a cross-talk between receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor α (TNF-α) using macrophage cell lines derived from wild-type mice and from mice with genetic deletion of the type 1 TNF receptor (p60-/-), the type 2 TNF receptor (p80-/-), or both receptors (p60-/-p80-/-). Deletion of TNF receptors sensitized the cells to RANKL-induced NF-κB activation, in order from least to most sensitive of p60-/- less than p80-/- less than p60-/-p80-/-. The effect on nuclear factor-κB (NF-κB) activation correlated with RANKL-induced IκBα kinase activation. Deletion of both TNF receptors also potentiated RANKL-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) activations in a dose- and time-dependent manner. Nitric oxide (NO) production and expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) induced by RANKL was also maximally induced in double knock-out cells. RANKL had no effect on the proliferation of wild-type cells, but deletion of TNF receptors induced growth modulatory effects. We also found that tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which mediates RANKL signaling, was constitutively bound to RANK in TNF receptor-deleted cells but not in wild-type cells, and this binding was enhanced by RANKL. Overall our results show that RANKL signaling is modulated by the TNF receptors and thus provide evidence of cross-talk between the receptors of 2 cytokines. (Blood. 2004;104: 4113-4121)

Statistical Prediction of the Type of Gastric Aspiration Lung Injury Based on Early Cytokine/Chemokine Profiles

2006 ◽  
Vol 104 (1) ◽  
pp. 73-79 ◽  
Author(s):  
Alan D. Hutson ◽  
Bruce A. Davidson ◽  
Krishnan Raghavendran ◽  
Patricia R. Chess ◽  
Alan R. Tait ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Lung Injury ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Inflammatory Protein ◽  
Gastric Aspiration ◽  
Factor Alpha ◽  
Necrosis Factor

Background Unwitnessed gastric aspiration can be a diagnostic dilemma, and early discrimination of different forms may help to identify individuals with increased risk of development of severe clinical acute lung injury or acute respiratory distress syndrome. The authors hypothesized that inflammatory mediator profiles could be used to help diagnose different types of gastric aspiration. Methods Diagnostic modeling using a newly modified receiver operator characteristic approach was applied to recently published data from our laboratory on lavaged inflammatory mediators from rodents given intratracheal normal saline, hydrochloric acid, small nonacidified gastric particles, or a combination of acid and small gastric particles. Multiple animal groups and postaspiration times of injury were analyzed to gauge the applicability of the predictive approach: rats (6 and 24 h), C57/BL6 wild-type mice (5 and 24 h), and transgenic mice on the same background deficient in the gene for monocyte chemoattractant protein 1 (MCP-1 [-/-] mice; 5 and 24 h). Results Overall, the four types of aspiration were correctly discriminated in 85 of 96 rats (89%), 72 of 78 wild-type mice (92%), and 59 of 73 MCP-1 (-/-) mice (81%) by models that used a maximum of only two mediators. The severe "two-hit" aspirate of the combination of acid and small gastric particles was correctly predicted in 21 of 24 rats, 23 of 23 wild-type mice, and 21 of 21 MCP-1 (-/-) mice. Specific best-fit mediators or mediator pairs varied with aspirate type, animal type, and time of injury. Cytokines and chemokines that best predicted the combination of acid and small gastric particles were cytokine-induced neutrophil chemoattractant 1 (6 h) and MCP-1 (24 h) in rats, tumor necrosis factor alpha/macrophage inflammatory protein 2 (5 h) and tumor necrosis factor alpha/MCP-1 (24 h) in wild-type mice, and tumor necrosis factor alpha/macrophage inflammatory protein 2 (5 h) and tumor necrosis factor alpha/keratinocyte-derived cytokine (24 h) in MCP-1 (-/-) mice. Conclusions These results support the potential feasibility of developing predictive models that use focused measurements of inflammatory mediators to help diagnose severe clinical forms of unwitnessed gastric aspiration, such as the combination of acid and small gastric particles, that may have a high risk of progression to acute lung injury/acute respiratory distress syndrome.

scholarly journals Tumor necrosis factor (TNF)-α induces leptin production through the p55 TNF receptor

2000 ◽  
Vol 278 (2) ◽  
pp. R537-R543 ◽  
Author(s):  
Brian N. Finck ◽  
Rodney W. Johnson
Keyword(s):  
Immune System ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tnf Receptor ◽  
Wild Type ◽  
New Information ◽  
Tnf Α ◽  
Mouse Adipocytes ◽  
Blocking Antibodies ◽  
Necrosis Factor

Tumor necrosis factor (TNF)-α acts directly on adipocytes to increase production of the lipostatic factor, leptin. However, which TNF receptor (TNFR) mediates this response is not known. To answer this question, leptin was measured in plasma of wild-type (WT), p55, and p75 TNFR knockout (KO) mice injected intraperitoneally with murine TNF-α and in supernatants from cultured WT, p55, and p75 TNFR KO adipocytes incubated with TNF-α. Leptin also was measured in supernatants from C3H/HeOuJ mouse adipocytes cultured with blocking antibodies to each TNFR and TNF-α as well as in supernatants from adipocytes incubated with either human or murine TNF-α, which activate either one or both TNFR, respectively. The results using all four strategies show that the induction of leptin production by TNF-α requires activation of the p55 TNFR and that although activation of the p75 TNFR alone cannot cause leptin production, its presence affects the capability of TNF-α to induce leptin production through the p55 TNFR. These results provide new information on the interplay between cells of the immune system and adipocytes.

Ozone-induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor-α receptors

2001 ◽  
Vol 280 (3) ◽  
pp. L537-L546 ◽  
Author(s):  
Hye-Youn Cho ◽  
Liu-Yi Zhang ◽  
Steven R. Kleeberger
Keyword(s):  
Tumor Necrosis Factor ◽  
Lung Inflammation ◽  
Tumor Necrosis ◽  
Critical Role ◽  
Airway Hyperreactivity ◽  
Tnf Receptor ◽  
Wild Type ◽  
Targeted Disruption ◽  
Factor Α ◽  
Necrosis Factor

This study was designed to investigate the mechanisms through which tumor necrosis factor ( Tnf) modulates ozone (O3)-induced pulmonary injury in susceptible C57BL/6J (B6) mice. B6 [wild-type ( wt)] mice and B6 mice with targeted disruption (knockout) of the genes for the p55 TNF receptor [ TNFR1(−/−)], the p75 TNF receptor [ TNFR2(−/−)], or both receptors [ TNFR1/TNFR2(−/−)] were exposed to 0.3 parts/million O3 for 48 h (subacute), and lung responses were determined by bronchoalveolar lavage. All TNFR(−/−) mice had significantly less O3-induced inflammation and epithelial damage but not lung hyperpermeability than wt mice. Compared with air-exposed control mice, O3 elicited upregulation of lung TNFR1 and TNFR2 mRNAs in wt mice and downregulated TNFR1 and TNFR2 mRNAs in TNFR2(−/−) and TNFR1(−/−) mice, respectively. Airway hyperreactivity induced by acute O3 exposure (2 parts/million for 3 h) was diminished in knockout mice compared with that in wtmice, although lung inflammation and permeability remained elevated. Results suggested a critical role for TNFR signaling in subacute O3-induced pulmonary epithelial injury and inflammation and in acute O3-induced airway hyperreactivity.

scholarly journals Countervailing Influence of Tumor Necrosis Factor-α and Nitric Oxide in Endotoxemia

2001 ◽  
Vol 12 (6) ◽  
pp. 1204-1210
Author(s):  
EDGAR A. JAIMES ◽  
DOMINGO DEL CASTILLO ◽  
MARK S. RUTHERFORD ◽  
LEOPOLDO RAIJ
Keyword(s):  
Nitric Oxide ◽  
Tumor Necrosis Factor ◽  
Knockout Mice ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Wild Type ◽  
Tnf Α ◽  
Biologic Effects ◽  
Factor Α ◽  
Necrosis Factor

Abstract. Tumor necrosis factor-α (TNF-α), a crucial mediator in sepsis, elicits multiple biologic effects, including intravascular thrombosis and circulatory shock. TNF-α exerts its biologic effects through two distinct cell surface receptors, TNF-R1 and TNF-R2. The pathophysiologic interaction between TNF-α and nitric oxide (NO) in glomerular thrombosis caused by endotoxemia in rats and wild-type mice (C57BL6) as well as in knockout mice that are deficient in TNF-R1 (R1 —/—), TNF-R2 (R2 —/—), or both receptors (R1R2 —/—) was studied. Administration of lipopolysaccharide (LPS; Escherichia coli endotoxin) resulted in increased NO and TNF-α production but failed to induce glomerular thrombosis. Concomitant administration of LPS + NG-nitro-L-arginine methyl ester (L-NAME; an NO synthesis inhibitor) resulted in glomerular thrombosis in rats and in wild-type mice. Intraperitoneal administration of pentoxifylline before LPS inhibited TNF-α synthesis and prevented glomerular thrombosis in rats given LPS + L-NAME. In contrast to the results observed in rats and wild-type mice, administration of LPS + L-NAME did not result in glomerular thrombosis in knockout mice with either single or double TNF-α receptor deletion. Thus, during endotoxemia, (1) TNF-α fosters glomerular thrombosis if there is deficiency of NO synthesis and (2) both TNF-α receptors are necessary for TNF-α's prothrombogenic action. Clinically, these novel studies suggest that in gram-negative endotoxemia, inhibition of NO synthesis and selective blockade of TNF-α receptors may provide unique therapeutic approaches for mitigation of glomerular thrombosis and restitution of vascular tone.

Sign in / Sign up

Export Citation Format

Share Document