Effects of recombinant human superoxide dismutase on tumor necrosis factor-induced lung injury in awake sheep

1993 ◽  
Vol 74 (6) ◽  
pp. 2641-2648 ◽  
Author(s):  
T. Amari ◽  
K. Kubo ◽  
T. Kobayashi ◽  
M. Sekiguchi
Keyword(s):  
Pulmonary Hypertension ◽  
Superoxide Dismutase ◽  
Tumor Necrosis Factor ◽  
Lung Injury ◽  
Superoxide Anion ◽  
Tumor Necrosis ◽  
Late Phase ◽  
Sod Activity ◽  
Lung Lymph ◽  
Necrosis Factor

Tumor necrosis factor alpha (TNF) is a mediator of acute lung injury after endotoxemia, but the precise mechanism of TNF-induced lung injury remains unclear. To clarify the role of oxygen radicals, especially superoxide anion, in TNF-induced lung injury, we examined the effects of recombinant human superoxide dismutase (rhSOD; 4,200 U/mg) on lung physiological and biochemical changes after TNF infusion in awake sheep (n = 17). We prepared chronically instrumented sheep for lung lymph collection and hemodynamic monitoring. Recombinant human TNF (3.5 micrograms/kg iv) induced a biphasic response in awake sheep. Pulmonary hypertension peaked within 15 min of initiation of TNF and remained elevated for 3 h, followed by increased lung vascular permeability. rhSOD attenuated the pulmonary hypertension in both early and late phases but caused no change in the timing or magnitude of lung fluid balance changes during the late phase. Thromboxane A2 (thromboxane B2) and prostacyclin (6-ketoprostaglandin F1 alpha) metabolite levels in plasma and lymph increased after the TNF infusion, and rhSOD attenuated these changes. The intravenous infusion of rhSOD resulted in the appearance of significant levels of SOD activity in both plasma and lung lymph before and after TNF infusion. These findings suggest that superoxide anion may be implicated in the pathogenesis of the pulmonary hypertension induced by TNF in sheep.

Effects of thromboxane synthase inhibition on tumor necrosis factor-induced lung injury in sheep

1992 ◽  
Vol 73 (2) ◽  
pp. 618-624 ◽  
Author(s):  
T. Koizumi ◽  
K. Kubo ◽  
T. Kobayashi ◽  
M. Sekiguchi
Keyword(s):  
Pulmonary Hypertension ◽  
Tumor Necrosis Factor ◽  
Lung Injury ◽  
Tumor Necrosis ◽  
Pulmonary Hemodynamics ◽  
Thromboxane Synthase ◽  
Arterial Blood ◽  
Lung Lymph ◽  
Necrosis Factor

To examine the role of thromboxane (Tx) A2 in the pathogenesis of acute lung injury caused by tumor necrosis factor alpha (TNF), we tested the effects of OKY-046, a selective thromboxane synthase inhibitor, on pulmonary hemodynamics, lung lymph balance, circulating leukocytes, arterial blood gas analysis, and TxA2 (as TxB2) and prostacyclin (as 6-keto-prostaglandin F1 alpha) levels in plasma and lung lymph after TNF infusion in awake sheep. Infusion of human recombinant TNF (3.5 micrograms/kg) into a chronically instrumented awake sheep caused a transient increase in pulmonary arterial pressure (Ppa). The Ppa peaked within 15 min of the start of TNF infusion from 23.3 +/- 1.1 (SE) cmH2O of baseline to 42.3 +/- 2.3 cmH2O and then decreased toward baseline. The pulmonary hypertension was accompanied by transient hypoxemia, peripheral leukopenia, and the increases in TxB2 in plasma and lung lymph. These changes were followed by an increase in flow of protein-rich lung lymph, consistent with an increase in pulmonary microvascular permeability. OKY-046 significantly prevented the rises of Ppa and TxB2 concentrations in plasma and lung lymph during early phase after TNF infusion. OKY-046, however, did not attenuate the increase of lung lymph flow, transient hypoxemia, and leukopenia. From these data, and by comparison with our previous studies of OKY-046-pretreated sheep during endotoxemia, we conclude that TxA2 has an important role of the increase in the early pulmonary hypertension, but it is not related to the early hypoxemia, leukopenia, and lung lymph balances in TNF-induced lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor-alpha increases Mn-SOD expression: protection against oxidant injury

1991 ◽  
Vol 260 (4) ◽  
pp. L296-L301 ◽  
Author(s):  
B. B. Warner ◽  
M. S. Burhans ◽  
J. C. Clark ◽  
J. R. Wispe
Keyword(s):  
Superoxide Dismutase ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Actinomycin D ◽  
Pulmonary Adenocarcinoma ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Sod Activity ◽  
Adenocarcinoma Cells ◽  
Necrosis Factor

Antioxidant enzymes, including superoxide dismutase, are important for protecting the lung against O2 injury. Manganese superoxide dismutase (Mn-SOD) is a superoxide anion (O2-.) scavenger located in the mitochondria, a primary site of O2-. production during hyperoxia. We studied the effects of tumor necrosis factor (TNF-alpha), a macrophage-derived cytokine, on Mn-SOD expression in human pulmonary adenocarcinoma cells. TNF-alpha significantly increased Mn-SOD activity and mRNA in a dose-and time-dependent manner. Mn-SOD activity was increased 3-fold and mRNA 20-fold after a 48-h incubation with TNF-alpha (25 ng/ml). To examine the mechanism of this increase, cells were incubated for 48 h with TNF-alpha (25 ng/ml) with or without cycloheximide (10 microns) or actinomycin D (10 micrograms/ml). Actinomycin D blocked the induction of Mn-SOD mRNA by TNF-alpha, but cycloheximide did not. These findings suggest that the effect of TNF-alpha requires gene transcription but not synthesis of new protein intermediates. To test the hypothesis that increased Mn-SOD protects against oxidative injury, pulmonary adenocarcinoma cells were incubated in TNF-alpha (25 ng/ml) for 48 h and then exposed to paraquat (PQ+), an intracellular O2-. generator. Cells pretreated with TNF-alpha had significantly improved survival in PQ+ compared with controls. At the LD50 (6 microns) for control cells, 95% of TNF-alpha-treated cells survived, 85% at the LD75 (10 microns), and 77% at the LD90 (14 microns). Our results suggest that the induction of Mn-SOD by TNF-alpha in pulmonary adenocarcinoma cells is pretranslationally mediated and that increasing Mn-SOD activity with TNF-alpha confers protection against O2 radicals.

Endotoxin protection of rats from pulmonary oxygen toxicity: possible cytokine involvement

1990 ◽  
Vol 68 (2) ◽  
pp. 549-553 ◽  
Author(s):  
J. T. Berg ◽  
R. C. Allison ◽  
V. R. Prasad ◽  
A. E. Taylor
Keyword(s):  
Superoxide Dismutase ◽  
Enzyme Activity ◽  
Tumor Necrosis Factor ◽  
Lung Injury ◽  
Antioxidant Enzyme ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Oxygen Toxicity ◽  
Antioxidant Enzyme Activity ◽  
Necrosis Factor

Treatment with endotoxin protects rats against lung injury during hyperoxia (greater than 98% oxygen at 1 atmosphere absolute for 60 h). This study demonstrates that serum from endotoxin-treated donor rats also protects recipients from oxygen toxicity. Rats treated with serum from saline-treated donors were not protected, and protection was not explained by residual endotoxin in protective sera. Unlike endotoxin-protected rats (where lung antioxidant enzyme activity is elevated after hyperoxia), postexposure superoxide dismutase (SOD) and catalase (CAT) activities in the lungs of serum-protected rats were not affected. Levels of tumor necrosis factor (TNF) and interleukin 1 (IL-1) in protective sera were increased. This study demonstrates that increases in lung SOD and CAT activity are not required for endotoxin protection from hyperoxia and suggests that TNF and IL-1 may participate in the mechanism of endotoxin protection.

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

2012 ◽  
Vol 303 (1) ◽  
pp. L75-L87 ◽  
Author(s):  
A. Charlotte P. Sewing ◽  
Crystal Kantores ◽  
Julijana Ivanovska ◽  
Alvin H. Lee ◽  
Azhar Masood ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Tumor Necrosis Factor ◽  
Lung Injury ◽  
Right Ventricular ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Tumor Necrosis ◽  
Neonatal Rat ◽  
Tnf Α ◽  
Necrosis Factor

Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation, arrested lung growth, and pulmonary hypertension (PHT), as observed in human infants with severe bronchopulmonary dysplasia. Inhalation of CO2 (therapeutic hypercapnia) has been described to limit cytokine production and to have anti-inflammatory effects on the injured lung; we therefore hypothesized that therapeutic hypercapnia would prevent bleomycin-induced lung injury. Spontaneously breathing rat pups were treated with bleomycin (1 mg/kg/d ip) or saline vehicle from postnatal days 1–14 while being continuously exposed to 5% CO2 (PaCO2 elevated by 15–20 mmHg), 7% CO2 (PaCO2 elevated by 35 mmHg), or normocapnia. Bleomycin-treated animals exposed to 7%, but not 5%, CO2, had significantly attenuated lung tissue macrophage influx and PHT, as evidenced by normalized pulmonary vascular resistance and right ventricular systolic function, decreased right ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. The level of CO2 neither prevented increased tissue neutrophil influx nor led to improvements in decreased lung weight, septal thinning, impaired alveolarization, or decreased numbers of peripheral arteries. Bleomycin led to increased expression and content of lung tumor necrosis factor (TNF)-α, which was found to colocalize with tissue macrophages and to be attenuated by exposure to 7% CO2. Inhibition of TNF-α signaling with the soluble TNF-2 receptor etanercept (0.4 mg/kg ip from days 1–14 on alternate days) prevented bleomycin-induced PHT without decreasing tissue macrophages and, similar to CO2, had no effect on arrested alveolar development. Our findings are consistent with a preventive effect of therapeutic hypercapnia with 7% CO2 on bleomycin-induced PHT via attenuation of macrophage-derived TNF-α. Neither tissue macrophages nor TNF-α appeared to contribute to arrested lung development induced by bleomycin. That 7% CO2 normalized pulmonary vascular resistance and right ventricular function without improving inhibited airway and vascular development suggests that vascular hypoplasia does not contribute significantly to functional changes of PHT in this model.

scholarly journals Tumor necrosis factor-α small interfering RNA alveolar epithelial cell-targeting nanoparticles reduce lung injury in C57BL/6J mice with sepsis

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098465
Author(s):  
Like Qian ◽  
Xi Yin ◽  
Jiahao Ji ◽  
Zhengli Chen ◽  
He Fang ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Tumor Necrosis ◽  
Alveolar Epithelial Cell ◽  
Weight Ratio ◽  
B Cell Lymphoma ◽  
Alveolar Epithelial ◽  
Tnf Α ◽  
Necrosis Factor

Background The role of tumor necrosis factor (TNF)-α small interfering (si)RNA alveolar epithelial cell (AEC)-targeting nanoparticles in lung injury is unclear. Methods Sixty C57BL/6J mice with sepsis were divided into normal, control, sham, 25 mg/kg, 50 mg/kg, and 100 mg/kg siRNA AEC-targeting nanoparticles groups (n = 10 per group). The wet:dry lung weight ratio, and hematoxylin and eosin staining, western blotting, and enzyme-linked immunosorbent assays for inflammatory factors were conducted to compare differences among groups. Results The wet:dry ratio was significantly lower in control and sham groups than other groups. TNF-α siRNA AEC-targeting nanoparticles significantly reduced the number of eosinophils, with significantly lower numbers in the 50 mg/kg group than in 25 mg/kg and 100 mg/kg groups. The nanoparticles also significantly reduced the expression of TNF-α, B-cell lymphoma-2, caspase 3, interleukin (IL)-1β, and IL-6, with TNF-α expression being significantly lower in the 50 mg/kg group than in 25 mg/kg and 100 mg/kg groups. Conclusion TNF-α siRNA AEC-targeting nanoparticles appear to be effective at improving lung injury-related sepsis, and 50 mg/kg may be a preferred dose option for administration.

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