Bronchoconstriction Produced in Man by Leukotrienes C and D

Holroyde, Martin C.; Cole, Milton B.; Altounyan, R. E. C.; Dixon, M; Elliott, E. V.

doi:10.1016/s0140-6736(81)90254-3

Cited by 231 publications

(41 citation statements)

References 10 publications

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“…The sulphidopeptide leukotrienes, LTC4 and LTD4, the major components of slow reacting substance of anaphylaxis (SRS-A) (Samuelsson et al, 1980), are potent bronchoconstrictors important in the pathology of airways disease (Hanna et al, 1981;Holroyde et al, 1981;Jonesetal., 1981).…”

Section: Introductionmentioning

confidence: 99%

Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C₄ and D₄

Burka

Saad

1984

British J Pharmacology

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Section: Introductionmentioning

confidence: 99%

Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C₄ and D₄

Burka

Saad

1984

British J Pharmacology

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“…It is now well established that LTs affect leukocyte chemotaxis, pulmonary smooth muscle contraction, vascular tone and permeability, and mucous secretion (4)(5)(6)(7)(8). As such, the LTs have been implicated as potential mediators of immediate hypersensitivity and inflammatory conditions (9,10).…”

mentioning

confidence: 99%

“…Antibodies directed against human LTC4S were prepared by immunizing rabbits with bovine thyroglobulin-conjugated synthetic peptide corresponding to amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13] of the enzyme (MKDEVAL-LAAVTL). The IgG fractions of preimmune (control) and peptide antisera were prepared by adsorption to protein A-Sepharose (Pierce).…”

mentioning

confidence: 99%

Molecular cloning and expression of human leukotriene-C4 synthase.

Welsch

Creely

Hauser

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

121

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Leukotriene-C4 synthase (LTC4S; EC 2.5.1.37) catalyzes the committed step in the biosynthesis of the peptidoleukotrienes, which are important in the pathogenesis of asthma. Antibodies were generated to a synthetic peptide based on the partial amino acid sequence previously reported for human LTC4S [Nicholson, D. W (M, = 16,568) that has a calculated pI value of 11.1. The deduced protein sequence is composed predominantly of hydrophobic amino acids; hydropathy analysis predicts three transmembrane domains connected by two hydrophilic loops. Analysis of the deduced sequence identified two potential protein kinase C phosphorylation sites and a potential N-linked glycosylation site. The amino acid sequence for human LTC4S is unique and shows no homology to other glutathione S-transferases. LTC4S was found to be most similar to 5-lipoxygenase activating protein (31% identity, 53% similarity), another protein involved in leukotriene biosynthesis. Active enzyme was expressed in bacterial, insect, and mammalian cells as shown by the biosynthesis of LTC4 in incubation mixtures containing LTA4 and reduced glutathione. The cloning and expression of human LTC4S provide the basis for a better understanding of this key enzyme in peptidoleukotriene biosynthesis.Leukotrienes (LTs) are potent biological mediators derived from arachidonic acid and are formed in response to a variety ofimmunologic and inflammatory stimuli (1-3). It is now well established that LTs affect leukocyte chemotaxis, pulmonary smooth muscle contraction, vascular tone and permeability, and mucous secretion (4-8). As such, the LTs have been implicated as potential mediators of immediate hypersensitivity and inflammatory conditions (9, 10).Initially, the production of LTs results from the oxygenation and subsequent dehydration of arachidonic acid to yield the unstable epoxide intermediate LTA4; both of these enzymatic reactions are catalyzed by 5-lipoxygenase (5-LO) (11). Cellular 5-LO activity requires an additional cofactor, 5-LO activating protein (FLAP) (12). It has been suggested that FLAP activates 5-LO by specifically binding arachidonic acid and transferring this substrate to the 5-LO enzyme (13). The LTA4 formed by 5-LO-FLAP can then be stereoselectively hydrolyzed to biologically active LTB4 by the cytosolic enzyme LTA4 hydrolase or conjugated with reduced glutathione by the membrane-bound enzyme LTC4 synthase (LTC4S; EC 2.5.1.37) to form the peptidoleukotriene LTC4.LTC4 is then converted to LTD4 by y-glutamyltranspeptidase and subsequently metabolized to LTE4 by cysteinylglycine dipeptidase (14).Collectively, the peptidoleukotrienes (LTC4, LTD4, and LTE4) have been demonstrated to be involved in inflammatory and anaphylactic reactions. They were first isolated and identified as the active mediators of the slow-reacting substance of anaphylaxis and are released from the lung tissue of asthmatics upon exposure to specific allergens (15). Additionally, exogenous application of peptidoleukotrienes results in many phenomena characteristic o...

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“…For example, peptido LTs are detected in the blood from individuals with acute asthma (1) and in nasal exudates after antigen challenge in patients allergic to ragweed (2). In addition, peptido LTs contract isolated human bronchus (3), cause bron choconstriction in normal and asthmatic subjects (4,5) and stimulate mucus secretion from the trachea of the dog (6) and mucous glycoprotein secretion from human airways in vitro (7). Furthermore, peptido-LTs increase microvascular permeability in guinea pig trachea (8) and human skin (9).…”

mentioning

confidence: 99%

Inhibition of Leukotriene Production by N-(4-(4-(Diphenylmethyl)-1-piperazinyl)butyl)-3-(6-methyl-3-pyridyl) Acrylamide (AL-3264), a New Antiallergic Agent.

et al. 1994

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ABSTRACT-The effects of AL-3264, which exhibits a 5-lipoxygenase (5-LO) inhibiting property by block ing histamine H1-receptors and inhibition of histamine release, were examined on leukotriene (LT) pro duction and LT-mediated responses. AL-3264 (1 30 tiM) inhibited the A23,187-induced LT production from human leukocytes with almost the same potency as that of nordihydroguaiaretic acid. AL-3264 (30 100 mg/kg, p.o.) inhibited the antigen-induced LT production in the abdominal cavity of passively sen sitized rats; its effect was as potent as that of AA-861, a 5-LO inhibitor. AL-3264 (30,uM) suppressed both the initial and sustained phases of the antigen-induced contractions in isolated trachea from actively sensi tized guinea pig. Phenidone (3 1M), a dual inhibitor of 5-LO and cyclooxygenase (CO), suppressed the sus tained phase, while indomethacin was without effect on either phase. AL-3264 (40-160 mg/kg, p.o.) sup pressed the arachidonic acid-induced ear edema in mice, for which 5-LO inhibitors were effective but antihistamines were not. The anti-edematous effect of AL-3264 (160 mg/kg) was reduced by intradermal ad ministration of LTC4 (0.1 pg). These results suggest that AL-3264 suppresses LT production in vivo and in vitro by inhibiting 5-LO activity, and this property may contribute to the antiallergic effect of AL-3264.

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Bronchoconstriction Produced in Man by Leukotrienes C and D

Cited by 231 publications

References 10 publications

Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C₄ and D₄

Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C₄ and D₄

Molecular cloning and expression of human leukotriene-C4 synthase.

Inhibition of Leukotriene Production by N-(4-(4-(Diphenylmethyl)-1-piperazinyl)butyl)-3-(6-methyl-3-pyridyl) Acrylamide (AL-3264), a New Antiallergic Agent.

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Bronchoconstriction Produced in Man by Leukotrienes C and D

Cited by 231 publications

References 10 publications

Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C4 and D4

Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C4 and D4

Molecular cloning and expression of human leukotriene-C4 synthase.

Inhibition of Leukotriene Production by N-(4-(4-(Diphenylmethyl)-1-piperazinyl)butyl)-3-(6-methyl-3-pyridyl) Acrylamide (AL-3264), a New Antiallergic Agent.

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Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C₄ and D₄

Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C₄ and D₄