Endotoxin-induced lung injury in rats: role of eicosanoids

Chang, Shun‐Ping; Westcott, Jay Y.; Pickett, Walter C.; Murphy, R.C.; Voelkel, N. F.

doi:10.1152/jappl.1989.66.5.2407

Cited by 34 publications

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“…These results are consistent with previous reports describing increased LT levels in the BAL fluid of patients with ARDS and experimental animals with endotoxemia. 19,20,32 In contrast, absence of LTs in the BAL fluid obtained from endotoxin-challenged 5-LO-deficient mice that had preserved HPV suggests that an increase in pulmonary LT concentrations contributes to the attenuation of HPV.…”

Section: Discussionmentioning

confidence: 98%

“…Lung tissue levels of LTC 4 are elevated for the first 3 hours after endotoxin challenge in rats. 20 Therefore, it is probable that increased cysLT levels were present in the lung at earlier times after endotoxin challenge and that MK571 blocked the deleterious effects of cysLTs during this period.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

“…The presence of LTs in the bronchoalveolar lavage (BAL) fluid of patients with ARDS, as well as increased cysLT levels in lung tissue of endotoxin-challenged rodents, has been reported. 19,20 Infusion of LTs into animals produces acute lung injury resembling the clinical presentation of endotoxemia and ARDS, includ-ing pulmonary hypertension and increased vascular permeability resulting in pulmonary edema and hypoxemia. 21 However, studies examining the effects of pharmacological inhibitors of 5-LO and LT receptors on endotoxin-induced lung injury have yielded conflicting results, some showing protection and others showing no protection.…”

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confidence: 99%

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Attenuation of Hypoxic Pulmonary Vasoconstriction by Endotoxemia Requires 5-Lipoxygenase in Mice

Ichinose

Zapol

Sapirstein

et al. 2001

Circulation Research

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Abstract-Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing systemic oxygenation. To assess the role of leukotrienes (LTs) in the attenuation of HPV during endotoxemia, the increase in left lung pulmonary vascular resistance (LPVR) before and during left mainstem bronchus occlusion (LMBO) was measured in mice with and without a deletion of the gene encoding 5-lipoxygenase (5-LO). LMBO increased the LPVR equally in saline-challenged wild-type and 5-LO-deficient mice (96Ϯ20% and 94Ϯ19%, respectively). Twenty-two hours after challenge with Escherichia coli endotoxin, the ability of LMBO to increase LPVR was markedly impaired in wild-type mice (27Ϯ7%; PϽ0.05) but not in 5-LO-deficient mice (72Ϯ9%) or in wild-type mice pretreated with MK886, an inhibitor of 5-LO activity (76Ϯ10%). Compared with wild-type mice, endotoxin-induced disruption of lung structures and inflammatory cell influx in the lung were markedly attenuated in 5-LO-deficient mice. Administration of MK571, a selective cysteinyl LT 1 receptor antagonist, 1 hour before endotoxin challenge preserved HPV and attenuated pulmonary injury in wild-type mice but did not prevent the endotoxin-induced increase in pulmonary myeloperoxidase activity. Taken together, these findings demonstrate that a 5-LO product, most likely a cysteinyl LT, contributes to the attenuation of HPV and to pulmonary injury after challenge with endotoxin. (Circ Res. 2001;88:832-838.)Key Words: cysteinyl leukotrienes Ⅲ pulmonary injury Ⅲ left mainstem bronchus occlusion H ypoxic pulmonary vasoconstriction (HPV) is characterized by vasoconstriction of pulmonary vessels in poorly ventilated hypoxic lung regions, thus optimizing pulmonary gas exchange. The sensor and effector mechanisms responsible for HPV reside in vascular smooth muscle cells of pulmonary arterioles 1,2 ; however, the precise mechanisms that mediate HPV remain incompletely understood. 3 HPV is markedly impaired in patients with clinical sepsis or the acute respiratory distress syndrome (ARDS). 4,5 Experimental endotoxemia has also been shown to impair HPV in several animal species. 6,7 Although the mechanisms responsible for the sepsis-induced attenuation of HPV remain incompletely elucidated, various inflammatory mediators including prostaglandins, 8 thromboxanes, 9 platelet-activating factor, 6 and cytokines 10 have all been implicated. Recently, we reported that increased pulmonary NO levels are necessary, but not sufficient, to impair HPV in a murine sepsis model. 11 These studies suggested that, in addition to increased pulmonary NO levels, the attenuation of HPV after endotoxin challenge requires unknown endotoxin-induced inflammatory products.Leukotrienes (LTs) are potent lipid mediators of inflammation derived from arachidonic acid (AA) metabolism. 12 Synthesis of LTs is initiated by the conversion of AA to HPETE by arachidonate 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). This intermediate can be dehydrated to the epoxide intermediate LTA 4 , which c...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Attenuation of Hypoxic Pulmonary Vasoconstriction by Endotoxemia Requires 5-Lipoxygenase in Mice

Ichinose

Zapol

Sapirstein

et al. 2001

Circulation Research

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“…Endotoxin increases the release of a variety of chemical mediators in the lungs, including reactive oxygen metabolite (30,33) and cyclooxygenase metabolites (5,34). Hydroxyl radicals (⅐OH) are an extremely reactive oxygen metabolite formed in the lung tissues under pathological conditions (35).…”

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The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats

Lai

Ruan

Kou

2005

Journal of Applied Physiology

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The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats. J Appl Physiol 98: 620 -628, 2005. First published October 1, 2004; doi:10.1152/japplphysiol.00539.2004.-Circulatory endotoxin can stimulate vagal pulmonary C fibers and rapidly adapting receptors (RARs) in rats, but the underlying mechanisms are not clear. We investigated the involvement of hydroxyl radicals and cyclooxygenase metabolites in the stimulation of C fibers and RARs by circulatory endotoxin (50 mg/kg) in 112 anesthetized, paralyzed, and artificially ventilated rats. In rats pretreated with the vehicle, endotoxin stimulated C fibers and RARs and caused a slight increase in total lung resistance (RL) and a decrease in dynamic lung compliance. In rats pretreated with dimethylthiourea (a hydroxyl radical scavenger) alone, indomethacin (a cyclooxygenase inhibitor) alone, or a combination of the two, C-fiber and RAR responses [C fiber: change (⌬) ϭ Ϫ62, Ϫ79, and Ϫ85%; RAR: ⌬ ϭ Ϫ80, Ϫ84, and Ϫ84%, respectively] were reduced, and the RL response was prevented. The suppressive effects of a combination of dimethylthiourea and indomethacin on the C-fiber and RAR responses were not superior to indomethacin alone. In rats pretreated with isoproterenol (a bronchodilator), the C-fiber response was not significantly affected (⌬ ϭ Ϫ26%), the RAR response was reduced (⌬ ϭ Ϫ88%), and the RL response was prevented. None of these pretreatments affected the dynamic lung compliance response. These results suggest that 1) both hydroxyl radicals and cyclooxygenase metabolites are involved in the endotoxin-induced stimulation of C fibers and RARs, and 2) the involvement of these two metabolites in the C-fiber stimulation may be due to their chemical effects, whereas that in the RAR stimulation may be due to their bronchoconstrictive effects. pulmonary C fibers; rapidly adapting receptors; reactive oxygen metabolites ENDOTOXEMIA CAUSES TACHYPNEA, leading to hyperventilation in septic shock patients (3, 4), but the causes are not completely understood. The tachypnea induced by circulatory endotoxin in rats is prevented by bilateral cervical vagotomy, suggesting that it is a vagally mediated respiratory reflex (42). Electrophysiological studies in rats have revealed that lung C-fiber nerve endings (C fibers) and pulmonary rapidly adapting receptors (RARs), two major types of lung vagal sensory receptors, are activated by circulatory endotoxin (21). Both lung C fibers and RARs play an important role in the detection of pulmonary pathophysiological conditions and eliciting resultant respiratory reflexes (9,25,40). The physiological characteristics of these two types of lung receptors are different (9,25,40). For example, lung C fibers are very sensitive to chemical stimuli (e.g., chemical mediators) but relatively insensitive to mechanical stimuli (e.g., bronchoconstriction). In contrast, RARs can be stimulated by chemical mediators and/or changes in lung mechanics. The mechanisms...

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Tissue eicosanoids and vascular permeability in rats with chronic biliary obstruction

1993

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Advanced cirrhosis is known to be associated with extrahepatic organ dysfunction, but the mechanism for this cirrhosis complication is largely unknown. We measured tissue albumin leakage in rats with biliary cirrhosis or acute cholestasis and tested the hypothesis that arachidonic acid metabolites contribute to the vascular permeability change. Six weeks after bile duct ligation, rats with biliary cirrhosis exhibited increased extravascular leakage of 125I-albumin in lung (p < 0.001) and kidney (p < 0.01) but not in heart or brain. In contrast, in cholestatic rats 10 days after bile duct ligation, only the kidney albumin leak was significantly increased (p < 0.01). Tissue thromboxane B2 levels, measured with an enzyme immunoassay, were increased in lung, kidney and liver of cirrhotic and cholestatic rats. To determine whether thromboxane A2 contributes to the vascular permeability defects in cirrhosis, we pretreated cirrhotic rats with the thromboxane synthase inhibitor dazoxiben (10 mg/kg intraperitoneally every 8 hr) for 20 hr before assessment of vascular permeability. Dazoxiben blocked the increase in thromboxane B2 level in lung but not in kidney and lowered the lung but not the kidney albumin leak index. In cholestatic rats given a higher dose of dazoxiben (40 mg/kg intraperitoneally every 8 hr) for 20 hr, the kidney thromboxane B2 level but not albumin leak was significantly lowered. We conclude that chronic biliary obstruction in rats leads to increased vascular permeability in selected extrahepatic organs and that thromboxane A2 contributes to the vascular permeability increase in the lung. Whether thromboxane A2 plays a role in renal albumin leakage will require further study.

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Endotoxin-induced lung injury in rats: role of eicosanoids

Cited by 34 publications

References 0 publications

Attenuation of Hypoxic Pulmonary Vasoconstriction by Endotoxemia Requires 5-Lipoxygenase in Mice

Attenuation of Hypoxic Pulmonary Vasoconstriction by Endotoxemia Requires 5-Lipoxygenase in Mice

The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats

Tissue eicosanoids and vascular permeability in rats with chronic biliary obstruction

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