Functional desensitization of beta agonist responses in human lung mast cells.

Chong, Lee K.; Morice, Alyn H.; Yeo, W. W.; Schleimer, Robert P.; Peachell, Peter T.

doi:10.1165/ajrcmb.13.5.7576689

Cited by 56 publications

(41 citation statements)

References 37 publications

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“…[17][18][19] In the present study, we found that IgE-dependent histamine release from cultured human mast cells was inhibited significantly by isoproterenol, salbutamol, fenoterol, and clenbuterol and that the inhibition was apparently attenuated by prolonged treatment with the agonists. On the other hand, although forskolin, an activator of adenylate cyclase, 28,29) apparently inhibited histamine release from cultured mast cells, it did not cause an attenuation of the inhibition even after prolonged treatment for up to 240 min.…”

Section: Effects Of Pretreatment For 3 Dsupporting

confidence: 54%

“…11,13,14) On the other hand, desensitization has also been observed in the inhibition of human mast cell histamine release by b 2 -adrenoceptor agonists. [17][18][19] Chong and Peachell 18) reported that isoproterenol inhibition of histamine release from human lung mast cells is considerably more susceptible to desensitizing treatments than the isoproterenol relaxation of bronchial smooth muscle. In contrast to histamine release, however, desensitization of PGD 2 and LT release inhibition by b 2 -adrenoceptor agonists has rarely been investigated.…”

mentioning

confidence: 99%

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Differential Effects of .BETA.2-Adrenoceptor Desensitization on the IgE-Dependent Release of Chemical Mediators from Cultured Human Mast Cells

Tsuji

Kato

Kimata

et al. 2004

Biological & Pharmaceutical Bulletin

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Agonist binding to b 2 -adrenoceptors causes activation of adenylate cyclase through coupling to a stimulatory component of GTP-binding protein (Gs protein) and results in an elevation of intracellular cAMP levels. cAMP plays an important role in inducing cellular responses as a second messenger. It is well known, however, that the responsiveness of b 2 -adrenoceptors wanes after continuous or repeated exposure to the agonists, a phenomenon referred to as desensitization.1-3) The initial step of the desensitization is caused by phosphorylation of intracellular domains of b 2 -adrenoceptors. The receptor phosphorylation results in an uncoupling between receptor proteins and Gs proteins. Two types of protein kinase are considered to be responsible for the phosphorylation. One is a cAMP-dependent protein kinase A (PKA) and the other is a cAMP-independent G proteincoupled receptor kinase such as b 2 -adrenergic receptor kinase (b-ARK). Phosphorylation by b-ARK facilitates the binding of b-arrestin to the receptors, which interferes with the receptor coupling to Gs protein. Prolonged exposure of the receptors to agonists may facilitate the receptor internalization, followed by their degradation. Furthermore, b 2 -adrenoceptor gene expression may be downregulated when cells are exposed continuously to the agonists for a long period. Although receptor desensitization is an important mechanism to maintain homeostasis, the same mechanism may interfere with the therapeutic effects of b 2 -adrenoceptor agonists. 4,5) It has been reported that b 2 -adrenoceptor agonists inhibit IgE-mediated release of mediators such as histamine, prostaglandin D 2 (PGD 2 ), and cysteinyl leukotrienes (LT) from human lung fragments, [6][7][8][9] and dispersed human lung and skin mast cells. [10][11][12][13] We also reported that b 2 -adrenoceptor agonists inhibit the chemical mediator release in cultured human mast cells.14-16) b 2 -Adrenoceptor agonists inhibit mediator release from human mast cells far more potently than disodium cromoglycate. 6,8,13,14) Furthermore, b 2 -adrenoceptor agonists inhibit PGD 2 and LT release more potently than histamine release from human mast cells. 11,13,14) On the other hand, desensitization has also been observed in the inhibition of human mast cell histamine release by b 2 -adrenoceptor agonists. [17][18][19] Chong and Peachell 18) reported that isoproterenol inhibition of histamine release from human lung mast cells is considerably more susceptible to desensitizing treatments than the isoproterenol relaxation of bronchial smooth muscle. In contrast to histamine release, however, desensitization of PGD 2 and LT release inhibition by b 2 -adrenoceptor agonists has rarely been investigated.In the present study therefore, we examined and compared the inhibitory effects of b 2 -adrenoceptor agonists on the release of histamine, PGD 2 , and LT from cultured human mast cells after prolonged treatment with the agonists. Laboratory and Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd.; Gunma 370-1295 ...

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Section: Effects Of Pretreatment For 3 Dsupporting

confidence: 54%

mentioning

confidence: 99%

Differential Effects of .BETA.2-Adrenoceptor Desensitization on the IgE-Dependent Release of Chemical Mediators from Cultured Human Mast Cells

Tsuji

Kato

Kimata

et al. 2004

Biological & Pharmaceutical Bulletin

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“…The mast cell response to b 2 -agonists becomes rapidly tolerant in vitro, reflecting the low receptor density of b 2 -receptors on these cells [41,42]. In asthmatic patients, there is tolerance to the mast cell protective effect of b 2 -agonists (against adenosine and allergen), but not to the protective effect against direct bronchoconstrictors [43,44].…”

Section: Mast Cell Stabilisationmentioning

confidence: 99%

Scientific rationale for using a single inhaler for asthma control

Barnes¹

2007

European Respiratory Journal

138

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Clinical trials have recently demonstrated that using a budesonide/formoterol combination inhaler as regular maintenance treatment twice daily but also as a rescue therapy for breakthrough symptoms can provide more effective control of asthma, particularly in reducing exacerbations, than using a short-acting b 2 -agonist or formoterol as rescue therapy. This suggests that the corticosteroid component of the combination therapy plays an important role in rescue therapy.Formoterol as a rescue therapy is effective in relieving symptoms by relaxing airway smooth muscle but is also likely to have important inhibitory effects on mast cells, plasma exudation and neutrophilic inflammation.Inhaled corticosteroids have much more rapid suppressing effects on airway inflammation than previously recognised and the increased dose used as rescue therapy may prevent the increase in airway inflammation that occurs during the evolution of an exacerbation, thus preventing its development.It is likely that the molecular interactions between b 2 -agonists and corticosteroids also enhance the effect of the combination therapy as rescue therapy. There is now a strong scientific rationale for single inhaler therapy in asthma, but more research is now needed to better understand the mechanisms involved.

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“…Adrenalin ist das wichtigste Medikament, um die pathophysiologischen Abläufe der Anaphylaxie umzukehren. Es ist am wirksamsten, wenn es innerhalb der ersten Minuten einer schweren allergischen Reaktion verabreicht wird [287, 841,842]. In der Präklinik wird Adrenalin mithilfe eines vorgefüllten Autoinjektors in einer Dosierung von 300 µg als intramuskulä-re Eigeninjektion verwendet.…”

Section: Zweitgabe Von Adrenalin Bei Anaphylaxieunclassified