Leukotrienes, Leukotriene Receptor Antagonists and Leukotriene Synthesis Inhibitors in Asthma: An Update. Part I: Synthesis, Receptors and Role of Leukotrienes in Asthma

Devillier, Philippe; Baccard, Nathalie; Advenier, C.

doi:10.1006/phrs.1998.0458

Cited by 55 publications

(48 citation statements)

References 97 publications

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“…Since the only known in vivo activity of GGL is LTC 4 -to-LTD 4 conversion, and LT are well-documented mediators of inflammation, it is likely that failure to generate LTD 4 following intraperitoneal injection of zymosan A results in failure to accumulate neutrophils during acute inflammation in this model. It is conceivable that LTE 4 formation is responsible for stimulation of neutrophil influx, but we view this possibility as unlikely given that LTE 4 is known to be 2 orders of magnitude less potent than LTC 4 and LTD 4 (8,17,20).…”

Section: Vol 21 2001 Disruption Of Ggl Results In Disruption Of Ltdmentioning

confidence: 88%

“…Further, during the development of peritonitis, GGL-deficient mice show an attenuation in neutrophil recruitment but not of plasma protein influx. These findings demonstrate an important role for GGL in the inflammatory response and suggest that LTC 4 and LTD 4 have distinctly different functions in the inflammatory process.Leukotrienes (LT) are a group of biologically active metabolites of arachidonic acid and have been implicated in the pathophysiology of many inflammatory diseases, including asthma, arthritis, psoriasis, and inflammatory bowel disease (8,17,20). Unlike many other inflammatory mediators, LT are not stored but synthesized de novo in response to inflammatory stimuli (17).…”

mentioning

confidence: 99%

“…Leukotrienes (LT) are a group of biologically active metabolites of arachidonic acid and have been implicated in the pathophysiology of many inflammatory diseases, including asthma, arthritis, psoriasis, and inflammatory bowel disease (8,17,20). Unlike many other inflammatory mediators, LT are not stored but synthesized de novo in response to inflammatory stimuli (17).…”

mentioning

confidence: 99%

“…They are known to stimulate a wide spectrum of inflammatory processes, including vasoconstriction, increases in postcapillary venule permeability, local recruitment of eosinophils, bronchoconstriction, and mucous secretion (8,9,17,19,20). LT have been the focus of extensive investigation in recent years because of the potency of their inflammatory effects, particularly in asthma, and promising therapeutic results with novel inhibitors of their synthesis and/or antagonists of their receptors (9,19).…”

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confidence: 99%

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Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Shi¹,

Han²,

Habib³

et al. 2001

Molecular and Cellular Biology

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To study the function of ␥-glutamyl leukotrienase (GGL), a newly identified member of the ␥-glutamyl transpeptidase (GGT) family, we generated null mutations in GGL (GGL tm1 ) and in both GGL and GGT (GGL tm1 -GGT tm1 ) by a serial targeting strategy using embryonic stem cells. Mice homozygous for GGL tm1 show no obvious phenotypic changes. Mice deficient in both GGT and GGL have a phenotype similar to the GGT-deficient mice, but ϳ70% of these mice die before 4 weeks of age, at least 2 months earlier than mice deficient only in GGT. These double-mutant mice are unable to cleave leukotriene C 4 (LTC 4 ) to LTD 4 , indicating that this conversion is completely dependent on the two enzymes, and in some organs (spleen and uterus) deletion of GGL alone abolished more than 90% of this activity. In an experimental model of peritonitis, GGL alone is responsible for the generation of peritoneal LTD 4 . Further, during the development of peritonitis, GGL-deficient mice show an attenuation in neutrophil recruitment but not of plasma protein influx. These findings demonstrate an important role for GGL in the inflammatory response and suggest that LTC 4 and LTD 4 have distinctly different functions in the inflammatory process.Leukotrienes (LT) are a group of biologically active metabolites of arachidonic acid and have been implicated in the pathophysiology of many inflammatory diseases, including asthma, arthritis, psoriasis, and inflammatory bowel disease (8,17,20). Unlike many other inflammatory mediators, LT are not stored but synthesized de novo in response to inflammatory stimuli (17). Synthesis of LT is an intracellular process initiated by the conversion of free arachidonic acid to LTA 4 , an epoxide intermediate, by the key enzyme 5-lipoxygenase and the accessory protein 5-lipoxygenase-activating protein. LTA 4 can be converted to LTB 4 by LTA 4 hydrolase or conjugated with glutathione (GSH) by LTC 4 synthase to form LTC 4 . LTC 4 is then transported to the extracellular microenvironment where it is converted to LTD 4 (the cysteinyl glycine conjugate of LTA 4 ) and then to LTE 4 (the cysteinyl conjugate of LTA 4 ).LTC 4 and its metabolites, LTD 4 and LTE 4 , are referred to as cysteinyl LT and were originally identified as the active components of the slow reacting substance of anaphylaxis. They are known to stimulate a wide spectrum of inflammatory processes, including vasoconstriction, increases in postcapillary venule permeability, local recruitment of eosinophils, bronchoconstriction, and mucous secretion (8,9,17,19,20). LT have been the focus of extensive investigation in recent years because of the potency of their inflammatory effects, particularly in asthma, and promising therapeutic results with novel inhibitors of their synthesis and/or antagonists of their receptors (9,19).Cysteinyl LT exert their effects through specific receptors;however, there has been significant uncertainty about the interaction of cysteinyl LT with their receptors and the relative potencies of individual cysteinyl LT. In vivo studies...

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Section: Vol 21 2001 Disruption Of Ggl Results In Disruption Of Ltdmentioning

confidence: 88%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Shi¹,

Han²,

Habib³

et al. 2001

Molecular and Cellular Biology

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“…LTA 4 can be further metabolised to the cysteinyl leukotrienes (CysLTs) or LTB 4 . The specific glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) conjugates LTA 4 to form LTC 4 which can then be rapidly converted to LTD 4 by a gammaglutamyl transpeptidase and to LTE 4 by a dipeptidase once exported out the cell by membrane transport proteins such as multi-drug related protein 1 (MRP1) (12)(13)(14)(15). A specific zinc metallohydrolase, LTA 4 hydrolase (LTA 4 H) is responsible for the conversion of LTA 4 to LTB 4 (16).…”

Section: The 5-lipoxygenase Pathwaymentioning

confidence: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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Leukotrienes (LT) are a family of potent eicosanoid lipid mediators with central importance in disease processes such as inflammation and proliferation most notably observed in allergic conditions like asthma (1). There are two general classes of LT according to the presence of a cysteine residue in their amino acid chain: the cysteinyl leukotrienes (CysLTs) including LTC 4 , LTD 4 and LTE 4 and the dihydroxyleukotriene LTB 4 (2). The 5-lipoxygenase pathwayLeukotrienes are produced in a multi-step enzyme pathway called the 5-lipoxygenase (5-LO) pathway, which is active in leucocytes such as neutrophils, eosinophils, mast cells and monocytes (Fig. 1). Arachidonic acid is the precursor for LT synthesis and is hydrolysed from the plasma membrane by cytosolic phospholipase A 2 (and other isoforms) (3, 4) in a calcium-dependent process (5). Upon activation, the rate-limiting enzyme 5-LO oxygenates first free arachidonic acid into the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is then either hydrolysed to 5-hydroxyeicosatetraenoic acid (5-HETE) or transformed into the unstable epoxide leukotriene A 4 (LTA 4 ) by forming a conjugated triene system through dehydration (6). 5-LO translocates from either the nucleus (in macrophages) or cyotosol (in neutrophils) to the nuclear envelope in response to cell activation (7,8). This movement occurs as 5-LO is dependent on a 5-LO activating protein (FLAP) for its function. FLAP remains associated with the nuclear membrane (9) and acts as a Ôtransfer proteinÕ presenting arachidonic acid to 5-LO, a system which allows the favourable conversion of 5-HPETE to LTA 4 compared to 5-HETE (10). Both 5-LO and FLAP are expressed in cells of myeloid lineage (11) restricting the pathway to these cell types. LTA 4 can be further metabolised to the cysteinyl leukotrienes (CysLTs) or LTB 4 . The specific glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) conjugates LTA 4 to form LTC 4 which can then be rapidly converted to LTD 4 by a gammaglutamyl transpeptidase and to LTE 4 by a dipeptidase once exported out the cell by membrane transport proteins such as multi-drug related protein 1 (MRP1) (12-15). A specific zinc metallohydrolase, LTA 4 hydrolase (LTA 4 H) is responsible for the conversion of LTA 4 to LTB 4 (16). CysLTs and LTB 4 act on different G-protein coupled receptors (GPCRs). Each bind to at least two different receptors: CysLTs to CYSLTR1 and CYSLTR2 and LTB 4 to LTB 4 R1 and LTB 4 R2 (or BLT1 and BLT2) (17).Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC 4 , LTD 4 and, LTE 4 ) and the dihydroxy leukotriene LTB 4 are generated by a series of enzymes/ proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotr...

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Neurogenic Inflammation of the Bladder

Bjorling

Beckman

Saban

2003

Bladder Disease, Part A

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Leukotrienes, Leukotriene Receptor Antagonists and Leukotriene Synthesis Inhibitors in Asthma: An Update. Part I: Synthesis, Receptors and Role of Leukotrienes in Asthma

Cited by 55 publications

References 97 publications

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Leukotriene pathway genetics and pharmacogenetics in allergy

Neurogenic Inflammation of the Bladder

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Leukotrienes, Leukotriene Receptor Antagonists and Leukotriene Synthesis Inhibitors in Asthma: An Update. Part I: Synthesis, Receptors and Role of Leukotrienes in Asthma

Cited by 55 publications

References 97 publications

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D4 Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D4 Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Leukotriene pathway genetics and pharmacogenetics in allergy

Neurogenic Inflammation of the Bladder

Contact Info

Product

Resources

About

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response

Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D₄ Synthesis In Vivo and Attenuation of the Acute Inflammatory Response