Effects of MK-886, a leukotriene biosynthesis inhibitor, in a rabbit model of endotoxic shock

Can, Cenk; Çınar, Mustafa; Ülker, Sibel; Evinç, Akgün; Koşay, Sezen

doi:10.1016/s0014-2999(98)00262-3

Cited by 14 publications

(11 citation statements)

References 28 publications

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“…Exclusively on the basis of studies using intravascular bolus injection of either live bacteria or bacterial endotoxin, cys-LTs have been suggested to participate in the vascular manifestations of septic shock (12,13). However, we know of no studies that have explored this possibility using a more clinically relevant model of septic shock in which local innate immunity is challenged.…”

mentioning

confidence: 99%

Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis

Benjamim¹,

Canetti

Cunha

et al. 2005

The Journal of Immunology

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The 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) influence both local innate immunity and vascular responses, but the relative importance of effects on these two processes in sepsis is unknown. In a cecal ligation and puncture model of peritonitis with severe sepsis, 5-LO−/− mice showed a reduction in peritoneal neutrophil accumulation and an increase in the number of bacteria in the peritoneal cavity. Despite this impairment of local innate immunity, the null mice exhibited a marked improvement in survival, and this protection was also seen in wild-type animals treated with the LT synthesis inhibitor MK 886. A survival advantage in severe sepsis was also observed in mice treated with the cysteinyl-LT receptor antagonist MK 571, but not with the LTB4 receptor antagonist CP 105, 696. Protection in the 5-LO−/− mice was associated with reduced vascular leak and serum lactate levels. Moreover, wild-type mice treated with MK 571 exhibited less sepsis-induced hypotension. These data demonstrate opposing effects of cysteinyl-LTs on innate immune vs hemodynamic responses, demonstrating protective effects on local immunity and deleterious effects on the vasculature. They also suggest the possible therapeutic utility of targeting vascular events in sepsis with cysteinyl-LT blockade.

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mentioning

confidence: 99%

Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis

Benjamim¹,

Canetti

Cunha

et al. 2005

The Journal of Immunology

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“…Systemic LT levels are increased in sepsis (20 -22) and are correlated with sepsis mortality (20). The role of LTs in influencing the systemic vascular tone in sepsis has been supported by studies that demonstrate that inhibition of 5-LO/5-LO-activating protein activity attenuates the development of sepsis-associated hypotension (23) and that antagonism of cysteinyl LT receptors improves mesenteric perfusion (24) and decreases mesenteric vascular permeability (25). However, recent data suggest that an impaired capacity to synthesize cysteinyl LTs is observed in humans with sepsis and is associated with an increased mortality rate (7).…”

mentioning

confidence: 99%

Lipopolysaccharide Down-Regulates the Leukotriene C4 Synthase Gene in the Monocyte-Like Cell Line, THP-1

Serio

Johns

Luo

et al. 2003

The Journal of Immunology

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We studied the effects of LPS on cysteinyl leukotriene (LT) synthesis and LTC4 synthase expression in mononuclear phagocytes. Conditioning of the monocyte-like cell line, THP-1, with LPS for 7 days resulted in significantly decreased ionophore-stimulated LTC4 release. The putative LPS receptor, Toll-like receptor 4, was expressed in THP-1 cells. LPS down-regulated LTC4 synthase mRNA in THP-1 cells in a dose- and time-dependent manner, with down-regulation observed as early as 4 h. Conditioning of actinomycin D-treated cells with LPS resulted in no change in the rate of LTC4 synthase mRNA decay. LPS treatment of THP-1 cells, transiently transfected with a LTC4 synthase promoter (1.35 kb)-reporter construct, decreased promoter activity. Neutralization of TNF-α and inhibition of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase did not inhibit the effect of LPS. Treatment of cells with a Toll-like receptor 4-blocking Ab and an inhibitor of NF-κB activation resulted in inhibition of the LPS effect, while activation of NF-κB and p50/p65 overexpression down-regulated the LTC4 synthase gene. LPS down-regulates cysteinyl LT release and LTC4 synthase gene expression in mononuclear phagocytes by an NF-κB-mediated mechanism.

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“…Leukotrienes (LT) are one of the proinflammatory lipid mediators synthesized from an arachidonic acid in the 5-lipoxygenase pathway [1] and have been reported to associate with several liver injuries such as fulminant hepatitis [2], liver cirrhosis [3], and sepsis [4]. LT are subclassed based upon their chemical structures and biological activities into two groups, as follows: (1) the cysteinyl LT (cLT; LTC 4 , LTD 4 , and LTE 4 ), known as a mediator of smooth muscle contraction in bronchial asthma, also produce vascular permeability increases leading to the development of tissue edema [5]; and (2) LTB 4 , one of the most potent chemotactic factors for neutrophils [6].…”

Section: Introductionmentioning

confidence: 99%

“…LT are subclassed based upon their chemical structures and biological activities into two groups, as follows: (1) the cysteinyl LT (cLT; LTC 4 , LTD 4 , and LTE 4 ), known as a mediator of smooth muscle contraction in bronchial asthma, also produce vascular permeability increases leading to the development of tissue edema [5]; and (2) LTB 4 , one of the most potent chemotactic factors for neutrophils [6]. Synthesis of both classes involves the dehydration of the membranous arachidonic acid by 5-lipoxygenase in the presence of 5-LO activating protein (FLAP) to produce an unstable LTA 4 , which represents the substrate for two different enzymes, such as LTC 4 synthase (LTC 4 -S) and LTA 4 hydrolase (LTA 4 -H), generating LTC 4 and LTB 4 , respectively. LTC 4 undergoes sequential peptidolysis to form other cLT, LTD 4 …”

Section: Introductionmentioning

confidence: 99%

“…Synthesis of both classes involves the dehydration of the membranous arachidonic acid by 5-lipoxygenase in the presence of 5-LO activating protein (FLAP) to produce an unstable LTA 4 , which represents the substrate for two different enzymes, such as LTC 4 synthase (LTC 4 -S) and LTA 4 hydrolase (LTA 4 -H), generating LTC 4 and LTB 4 , respectively. LTC 4 undergoes sequential peptidolysis to form other cLT, LTD 4 …”

Section: Introductionmentioning

confidence: 99%

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Role of leukotrienes on hepatic ischemia/reperfusion injury in rats

Takamatsu

Shimada

Chijiiwa

et al. 2004

Journal of Surgical Research

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Effects of MK-886, a leukotriene biosynthesis inhibitor, in a rabbit model of endotoxic shock

Cited by 14 publications

References 28 publications

Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis

Opposing and Hierarchical Roles of Leukotrienes in Local Innate Immune versus Vascular Responses in a Model of Sepsis

Lipopolysaccharide Down-Regulates the Leukotriene C4 Synthase Gene in the Monocyte-Like Cell Line, THP-1

Role of leukotrienes on hepatic ischemia/reperfusion injury in rats

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