Effects of Leukotriene D on the Airways in Asthma

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102

The cysteinyl leukotrienes (cys-LTs), leukotriene (LT) C4, LTD4, and LTE 4 , are smooth muscle constrictors that signal via the CysLT 1 receptor. Here we report that the cys-LTs play an important role in chronic pulmonary inflammation with fibrosis induced by bleomycin in mice. Targeted disruption of LTC 4 synthase, the pivotal enzyme for cys-LT biosynthesis, protected significantly against alveolar septal thickening by macrophages and fibroblasts and collagen deposition. In contrast, targeted disruption of the CysLT 1 receptor significantly increased both the concentration of cys-LTs in the bronchoalveolar lavage fluid and the magnitude of septal thickening as defined by morphology, digital image analysis, and deposition of reticular fibers. These findings change our understanding of the pathobiology mediated by the cys-LTs by revealing their role in chronic inflammation with fibrosis, likely via the CysLT 2 receptor, and by uncovering a dual role for the CysLT1 receptor, namely proinflammatory acute constriction of smooth muscle and antiinflammatory counteraction of chronic injury.T he cysteinyl leukotrienes (cys-LTs), originally termed slow reacting substance (SRS) because of the gradual progression of their contractile response in smooth muscle relative to the brisk action elicited by histamine (1-3), were viewed only as smooth muscle agonists after their structural definition (4) and chemical synthesis (5). When inhaled, cys-LTs constrict human normal or asthmatic airways with a thousand times the potency of histamine (6-8). They also are more active in eliciting an intradermal wheal and flare response (9). Their role in the pathobiology of bronchial asthma was established by the therapeutic efficacy of agents that block their biosynthesis or their action at a receptor defined by transmission of a smooth muscle response (10, 11).The cys-LTs are generated after arachidonic acid is released from the outer nuclear membrane of cells by cytosolic phospholipase A 2 and converted to the epoxide leukotriene (LT) A 4 by 5-lipoxygenase (5-LO) in the presence of the 5-LO activating protein (12). An integral perinuclear membrane protein, LTC 4 synthase (LTC 4 S), conjugates reduced glutathione to LTA 4 to form LTC 4 (13, 14). After carrier-mediated export (15), LTC 4 is converted to additional receptor-active metabolites, LTD 4 and LTE 4 , by the sequential cleavage from the tripeptide adduct of glutamate (16, 17) and glycine. Alternatively, LTA 4 can be converted by LTA 4 hydrolase to a dihydroxy LT, LTB 4 . Two receptors for the cys-LTs, CysLT 1 receptor and CysLT 2 receptor, have been cloned for the human (18-22) and the mouse (23-25).The therapeutic agents developed for the management of bronchial asthma at the receptor level block the agonist activity of the cys-LTs at the CysLT 1 receptor and not at the CysLT 2 receptor. Targeted disruption of either LTC 4 S or the CysLT 1 receptor elicits marked and comparable attenuation of IgEdependent, mast cell-mediated passive cutaneous anaphylaxis and of zymosan-elicited i...

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confidence: 99%

Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis

Beller

Friend

Maekawa

et al. 2004

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131

102

“…LTC 4 is released by a distinct cellular export mechanism (7), and is converted sequentially to LTD 4 and LTE 4 by extracellular ␥-glutamyltransferase and dipeptidase, respectively (8,9). LTC 4 , LTD 4 , and LTE 4 then act at specific, seven transmembrane domain, G protein-coupled receptors to mediate bronchoconstriction, vasodilation, vascular leakage, and leukocyte emigration (10)(11)(12)(13)(14). To date, two cys-LT receptors, the CysLT1 receptor and the CysLT2 receptor, have been cloned and characterized (15)(16)(17)(18).…”

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confidence: 99%

Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells

Mellor

Maekawa

Austen

et al. 2001

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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).…”

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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).…”

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confidence: 99%

Molecular cloning and expression of human leukotriene-C4 synthase.

Welsch

Creely

Hauser

et al. 1994

121

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...