Generation of leukotrienes by purified human lung mast cells.

MacGlashan, Donald W.; Schleimer, Robert P.; Peters, Stephen P.; Schulman, Edward S.; Adams, G. K.; Newball, Harold H.; Lichtenstein, L M

doi:10.1172/jci110670

Cited by 274 publications

(73 citation statements)

References 12 publications

(3 reference statements)

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“…Owing to the impressive pharmacological data implicating cys-LTs in EIB [11][12][13] and the abundant production of these compounds by the mast cell [32], urinary LTE 4 , which reflects changes in whole-body production of cysLTs [33], was also measured after exercise.…”

Section: Aamentioning

confidence: 99%

Evidence for mast cell activation during exercise-induced bronchoconstriction

O’Sullivan¹,

Roquet²,

Dahlén³

et al. 1998

Eur Respir J

125

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Exercise-induced bronchoconstriction (EIB) is thought to occur in 70-80% of asthmatics, most commonly amongst those with moderate-to-severe airway hyperresponsiveness [1]. It is characterized by transient airflow obstruction resulting in a Š15% decrease in forced expiratory volume in one second (FEV1) following 5-8 min of exercise. The fall in FEV1 reaches a maximum approximately 10 min after exercise and gradually normalizes over the next hour [2]. The precise pathophysiology of EIB remains unclear, although it is widely accepted that during exercise the upper airways are unable to adequately warm and humidify the increased volumes of inspired air. This results in airway cooling and increased airway fluid osmolality in the lower airways [3,4]. One hypothesis suggests that hyperosmolar triggering of mast cells and possibly other inflammatory cells results in the release of bronchoconstricting mediators, e.g. cysteinyl-leukotrienes (cys-LTs), histamine and prostaglandin (PG)D 2 [5].Previous indications for the participation of mast cell mediators in the pathogenesis of EIB are based on pharmacological data. For example, disodium cromoglycate (DSCG), a drug which stabilizes mast cell membranes, is effective in blunting exercise-induced asthma [6,7]. Pretreatment with a number of H 1 receptor antagonists has been shown to attenuate EIB [8][9][10]; however, the degree of protection afforded by this class of drugs has been modest. More recently, studies employing leukotriene receptor antagonists [11,12] and biosynthesis inhibitors [13] have implicated leukotrienes in the airway bronchoconstrictor response to exercise.The direct approach of measuring mast cell mediator release in response to exercise challenge has yielded ambiguous results. Some studies have reported an elevation in plasma and whole blood histamine concentrations following EIB [14,15], while other studies have failed to verify those findings [16,17]. Apart from the methodological problems encountered when sampling plasma histamine [18] and its short half-life in the circulation, approximately 1 min [19], it has been suggested that elevations in plasma histamine mainly reflect the basophilia which normally accompanies exercise [20]. Increases in the levels of tryptase and PGD 2 , both specific mast cell markers, have been detected in nasal lavage following nasal provocation with cold dry air [21], but not after exercise [22,23].The purpose of this study was to provide evidence to establish mast cell activation as a feature of EIB. To this end, a combination of mast cell markers, 9α,11β-PGF 2 Sullivan, A. Roquet, B. Dahlén, F. Larsen, A. Eklund, M. Kumlin, P.M. O'Byrne, S-E. Dahlén. ©ERS Journals 1998. ABSTRACT: Controversy remains about the causative mediators in the bronchoconstrictive response to exercise in asthma. This study examined whether mast cell activation is a feature of exercise-induced bronchoconstriction by measuring urinary metabolites of mast cell mediators. Evidence for mast cell activation during exercise-induced bronchoconstriction....

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Section: Aamentioning

confidence: 99%

Evidence for mast cell activation during exercise-induced bronchoconstriction

O’Sullivan¹,

Roquet²,

Dahlén³

et al. 1998

Eur Respir J

125

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“…Several types of human blood and tissue cell e.g., granulocytes [1,2], lymphocytes [3], macrophages [4,5] and mast cells [6], are capable of synthesizing leukotrienes from arachidonic acid. Leukotriene C4 (LTC4: S(S)-hydroxy-6(R)-S-glutathionyl-7,9trans-11,14-cis-eicosatetraenoic acid) and leukotriene D4 (LTD4: 5(S)-hydroxy-6(R)-Scysteinylglycyl-7,9-trans-11,14-cl,.+eicosatetraenoic acid) have been shown to be strongly bronchoconstrictive in vitro [7] as well as in vivo [S] and therefore may play an important role as mediators in (immediate) hypersensitivity reactions.…”

Section: Introductionmentioning

confidence: 99%

Specific leukotriene formation by purified human eosinophils and neutrophils

Verhagen

Bruynzeel²,

Koedam

et al. 1984

FEBS Letters

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Human granulocytes isolated from peripheral blood have been described to synthesize both LTB4 and LTC4 from arachidonic acid. We have observed that the amount of LTC4 produced by human granulocyte preparations is strongly dependent on the relative amount of eosmophils. To investigate a possibly significant difference in leukotriene synthesis of the eosinophilic and neutrophilic granulocytes, we developed a purification method to isolate both cell types from granulocytes obtained from the blood of healthy donors. Leukotrlenes were generated by incubation of the purified cells with arachidonic acid, calcium lonophore A23187, calcium-chlonde and reduced glutatbione. Surprisingly, eosinophils were found to produce almost exclusively the spasmogenic LTC4. In contrast, neutropbils produce almost exclusively the chemotactic LT&, its w-hydroxylated metabolite 20-hydroxy-LTB4 and two nonenzymically formed LTB4 isomers. Leukotnene Granulocyte Eosmophil

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“…When stimulated ex vivo by cross-linkage of their high-affinity Fc receptors for IgE (Fc RI), dispersed human lung MCs generate cys-LTs (22). When human MCs (hMCs), derived in vitro from cord blood, are primed with recombinant human IL-4 (10 ng͞ml), they express both the terminal biosynthetic enzyme, LTC 4 S, and Fc RI, thereby markedly up-regulating their generation of cys-LTs in response to Fc RI cross-linkage (23).…”

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confidence: 99%