A Free Radical Scavenger (Lazaroid U75412E) Attenuates Tumor Necrosis Factor-Alpha Generation in a Rabbit Model of Smoke-Induced Lung Injury

Wang, S.; Lantz, R. Clark; Rider, Evelyn D.; Chen, Guan Jie; Breceda, Veronica; Hays, Allison M.; Robledo, Raymond F.; Tollinger, Brian J.; Dinesh, Supritha; Witten, Mark L.

doi:10.1159/000196704

Cited by 17 publications

(14 citation statements)

References 22 publications

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“…This finding is consistent with results of previous work that utilized the pretreatment of smoke-exposed animals with U75412E (34,35). Lazaroid treatment prevented smoke-induced changes in blood Pa02, PaC02, pH, and COHb°lo.…”

Section: Discussionsupporting

confidence: 92%

“…In vivo efficacy of lazaroids has been documented in animal models of lung injuries induced by endotoxins (17), silica (16), oxidants (11), phorbol esters (22), and bleomycin (21). In an established rabbit model, lazaroid U75412E attenuated chemical mediators after smoke insult (34,35). These studies suggest that lazaroids may exert their protective action not only by a direct antioxidant activity (1,19,29,30) and inhibition of lipid peroxidation (17) but also by suppressing the expression and/or release of cytokines (28), such as interleukin-8 (22) and tumor necrosis factor-a (TNF-a) (35).…”

Section: Introductionmentioning

confidence: 99%

“…In an established rabbit model, lazaroid U75412E attenuated chemical mediators after smoke insult (34,35). These studies suggest that lazaroids may exert their protective action not only by a direct antioxidant activity (1,19,29,30) and inhibition of lipid peroxidation (17) but also by suppressing the expression and/or release of cytokines (28), such as interleukin-8 (22) and tumor necrosis factor-a (TNF-a) (35). This study provides further evidence that U75412E can protect against respiratory epithelial damage and gas exchange impairment caused by smoke.…”

Section: Introductionmentioning

confidence: 99%

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Early Alterations of Lung Injury Following Acute Smoke Exposure and 21-Aminosteroid Treatment

et al. 1999

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In a simulated fire-related smoke exposure protocol, New Zealand white rabbits were utilized to investigate the potential effects of the 21-aminosteroid (lazaroid) analog U75412E on the early events of acute lung injury. Inhalation of a total of 1.6 mg/kg U75412E aerosolized at a rate of 1.53 mg/min at 0.5 hr after smoke exposure significantly attenuated the extent of lung injury at 1 hr, as evidenced by decreased bronchoalveolar lavage (BAL) concentration of total protein, 6-keto-prostaglandin F 1 -α, and blood gas defect. Histopathologic examination demonstrated that the lazaroid significantly attenuated smoke-induced lung injury as evidenced by a decrease in wet lung/body weight ratio, necrosis, and sloughing of airway epithelial cells. Electron microscopy showed that the lazaroid decreased smoke-induced interstitial edema and the vacuolization of alveolar type II epithelium (21.6 ± 9.7 vs 8.5 ± 3.6 vacuoled blebs/cell, smoke only vs smoke + lazaroid). However, U75412E did not attenuate smoke-induced changes in BAL concentration of tumor necrosis factor-α, total cell count, and granulocyte percentage. These observations suggest that U75412E may exert its action through cooperative mechanisms, such as the modulation of arachidonic acid metabolism, in addition to its characterized antioxidative effects.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early Alterations of Lung Injury Following Acute Smoke Exposure and 21-Aminosteroid Treatment

et al. 1999

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“…Earlier studies showed that exposure to cotton smoke enhanced basal production of superoxide by rabbit alveolar macrophages within 70 min postinjury [3]. Wang et al [25] reported that inhalation of smoke generated by combustion of diesel fuel and polycarbonate plastic shavings increased basal production of superoxide by rabbit alveolar macrophages by 2 h postexposure but did not alter zymosan-induced superoxide generation. In contrast, Witten et al [27] found that inhalation of diesel fuel-polycarbonate plastic smoke inhibited PMA-induced superoxide production in rabbit alveolar macrophages at 40 min postexposure.…”

Section: Discussionmentioning

confidence: 99%

Dose Dependence and Time Course of Smoke Inhalation Injury in a Rabbit Model

Bidani

Hawkins

Wang

et al. 1999

Lung

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The dose dependence and time course of smoke inhalation injury were determined in a rabbit model. Animals were insufflated with 18-90 breaths of cotton smoke or room air (control) at a rate of 18 breaths/min and tidal volume of 12 ml/kg. Smoke-exposed animals exhibited dose-related histologic effects with progressive deterioration of respiratory function during the postexposure period of observation (96 h). The smoke-exposed rabbits had reproducible injuries to both airway mucosa and lung parenchyma, manifested by disruption and sloughing of airway and alveolar epithelia, and exudation of protein-rich fluid and leukocytes into the airway and alveolar spaces. Significant effects were evident by 24 h postexposure. Smoke inhalation also affected the respiratory burst of alveolar macrophages. Generation of superoxide anions by alveolar macrophages at 48 h postexposure was increased significantly after smoke inhalation (54 breaths). The present rabbit model should be useful for studying the interactions between pulmonary epithelial cells and leukocytes after smoke inhalation and for determining the role that abnormal functioning of alveolar macrophages plays in the development of smoke inhalation injury.

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“…The precise mechanism(s) underlying the inhibitory effect of NIM on TNF-α is still unknown. In previous studies, it was demonstrated that different antioxidants are able to reduce TNF-α production [41, 42], and it should be mentioned that NIM exhibits antioxidant activity by reducing the generation of superoxide anions and scavenging hypochlorous acid [43]. However, relying on the data regarding the effects of other COX inhibitors on the NF-ĸB pathway [37, 39], there was a basis to hypothesize that NIM might also inhibit TNF-α in a similar fashion.…”

Section: Discussionmentioning

confidence: 99%

Effects of Nimesulide, a Selective Cyclooxygenase-2 Inhibitor, on Cardiovascular Alterations in Endotoxemia

Azab

Kobal²,

Rubin³

et al. 2005

Cardiology

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Prostanoids and cytokines are known to play a pivotal role in the mechanisms leading to endotoxin-induced cardiovascular failure. We investigated the effect of nimesulide (NIM), a selective cyclooxygenase-2 (COX-2) inhibitor, on the cardiovascular alterations occurring during endotoxemia, and on prostaglandin E₂ (PGE₂), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in endotoxemic rats. NIM significantly reduced endotoxin-induced elevation of plasma and myocardial levels of TNF-α, but not those of IL-1β. Searching for the mechanism underlying the anti-TNF-α effect of NIM, it was found that the drug reduced nuclear factor kappa B activation through diminished nuclear levels of p-65 accompanied by a protective effect against the cardiovascular alterations and mortality seen during endotoxemia. In addition, the inhibitory effect of NIM on endotoxin-induced elevation in plasma and hypothalamic levels of PGE₂ was noteworthy, and this may suggest that the large amounts of PGE₂ observed during endotoxemia are mainly produced via COX-2.

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A Free Radical Scavenger (Lazaroid U75412E) Attenuates Tumor Necrosis Factor-Alpha Generation in a Rabbit Model of Smoke-Induced Lung Injury

Cited by 17 publications

References 22 publications

Early Alterations of Lung Injury Following Acute Smoke Exposure and 21-Aminosteroid Treatment

Early Alterations of Lung Injury Following Acute Smoke Exposure and 21-Aminosteroid Treatment

Dose Dependence and Time Course of Smoke Inhalation Injury in a Rabbit Model

Effects of Nimesulide, a Selective Cyclooxygenase-2 Inhibitor, on Cardiovascular Alterations in Endotoxemia

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