Prostaglandin D2-induced bronchoconstriction is mediated only in part by the thromboxane prostanoid receptor

Johnston, SL; Freezer, Nicholas; Ritter, W.; O’Toole, Susan M.; Howarth, PH

doi:10.1183/09031936.95.08030411

Cited by 74 publications

(48 citation statements)

References 18 publications

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“…Moreover, the increased excretion of the PGD 2 metabolite may indicate an important role for PGD 2 in the bronchoconstrictive response to mannitol. PGD 2 , as well as 9a,11b-PGF 2 , are potent bronchoconstrictors in man [17], mainly acting on the TP-receptor [18,19]. Pretreatment with selective TP-receptor antagonists attenuated both PGD 2 -and allergen-induced, but not histamine-induced, bronchoconstriction [20][21][22].…”

Section: Discussionmentioning

confidence: 99%

Evidence of mast cell activation and leukotriene release after mannitol inhalation

Brannan

Gulliksson²,

Anderson³

et al. 2003

Eur Respir J

151

108

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The aim of this study was to investigate if mannitol inhalation, as a model of exercise-induced bronchoconstriction (EIB), causes mast cell activation and release of mediators of bronchoconstriction.Urinary excretion of previously identified mediators of EIB was investigated in association with mannitol-induced bronchoconstriction. Twelve asthmatic and nine nonasthmatic subjects inhaled mannitol and urine was collected 60 min before and for 90 min after challenge. The urinary concentrations of leukotriene (LT)E 4 , the prostaglandin (PG)D 2 metabolite and the mast cell marker 9a,11b-PGF 2 were measured by enzyme immunoassay. N t -methylhistamine was measured by radioimmunoassay.In asthmatic subjects, inhalation of a mean¡SEM dose of 272¡56 mg mannitol induced a reduction in forced expiratory volume in one second (FEV1) of 34.5¡2.1%. This was associated with increases in urinary 9a,11b-PGF 2 (91.9¡8.2 versus 66.9¡ 6.6 ng?mmol creatinine -1 , peak versus baseline) and LTE 4 (51.3¡7.5 versus 32.9¡4.7). In nonasthmatic subjects, the reduction in FEV1 was 1.0¡0.5% after inhaling 635 mg of mannitol. Although smaller than in the asthmatics, significant increases of urinary 9a,11b-PGF 2 (68.4¡6.9 versus 56.0¡5.8 ng?mmol creatinine -1 ) and LTE 4 (58.5¡5.3 versus 43.0¡3.3 ng?mmol creatinine -1 ) were observed in the nonasthmatic subjects. There was also a small increase in urinary excretion of N t -methylhistamine in the nonasthmatics, but not in the asthmatics.The increased urinary levels of 9a,11b-prostaglandin F 2 support mast cell activation with release of mediators following inhalation of mannitol. Increased bronchial responsiveness to the released mediators could explain the exclusive bronchoconstriction in asthmatic subjects. Eur Respir J 2003; 22: 491-496.

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Section: Discussionmentioning

confidence: 99%

Evidence of mast cell activation and leukotriene release after mannitol inhalation

Brannan

Gulliksson²,

Anderson³

et al. 2003

Eur Respir J

151

108

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“…These inflammatory cytokines have been shown to be present in increased quantities in bronchoalveolar lavage samples from patients with inflammatory lung diseases such as asthma [37,38]. If COX 2 is induced in inflammatory lung disease it may therefore be possible to use COX 2 selective inhibitors to selectively reduce the secretion of pro-inflammatory prostanoids, such as PGD 2 and PGF 2 a, without inhibiting the secretion of "housekeeping" prostanoids generated by COX 1.…”

Section: Discussionmentioning

confidence: 99%

Selectivity of cyclo-oxygenase inhibitors in human pulmonary epithelial and smooth muscle cells

Range¹,

Pang²,

Holland³

et al. 2000

Eur Respir J

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Selectivity of cyclo-oxygenase inhibitors in human pulmonary epithelial and smooth muscle cells. S.P. Range, L. Pang, E. Holland, A.J. Knox. #ERS Journals Ltd 2000. ABSTRACT: Cyclo-oxygenase (COX) inhibitors may have a role in reducing inflammation in asthma and other pulmonary diseases. COX inhibitors have different selectivities for the two COX isoenzymes (COX 1 and COX 2) which vary between purified enzyme and intact cell preparations. The relative selectivity of COX inhibitors has not been studied in human airway cells.A number of COX inhibitors in cultured human airway cells were compared which exclusively express either COX 1 (primary degree cultured human airway smooth muscle (HASM) cells) or COX 2 (A549 pulmonary epithelial cell-line) as measured by Western blotting. COX activity was assayed by prostaglandin (PG)E 2 production following 30 min incubation with 5 mM arachidonic acid.COX activity in both cell types was similar; HASM cells 92. -5 M for aspirin. Sodium valerate had no effect in either HASM or A549 cells. The COX 2:COX 1 selectivity ratio (COX 2 IC50/COX 1 IC50) was <0.0001 for nimesulide, 0.001 for NS398, 0.03 for flurbiprofen and 1.9 for indomethacin.In conclusion the present study has shown that cyclo-oxygenase inhibitors have a range of selectivities for cyclo-oxygenase 1 and cyclo-oxygenase 2 in intact human airway cells. The relative cyclo-oxygenase 2 selectivity of N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulphonamide and nimesulide may have implications for the treatment of asthma and other inflammatory pulmonary diseases. Recent studies have suggested that cyclo-oxygenase (COX) products may be involved in the pathophysiology of several pulmonary diseases: COX products have been implicated in the inflammation found in asthmatic airways, with different COX products exerting differential effects in different situations in vivo [1±3]. Inhaled indomethacin and aspirin protect against indirect bronchoconstrictor challenges in asthma [4,5] suggesting that release of constrictor prostaglandins such as prostaglandin (PG)D 2 and PGF 2a may contribute to the mechanisms of action of these stimuli. Under different circumstances COX products may have a protective role. PGE 2 has been shown to have a potential bronchoprotective role both in vitro [6,7] and in vivo [8,9]. Studies showing that oral indomethacin inhibits refractoriness to repeated bronchoconstriction challenge suggest that endogenous PGE 2 may be involved in this protective response [10,11]. A small number of patients with asthma exhibit aspirin sensitivity, whereby oral aspirin and other COX inhibitors produce bronchochoconstriction. This bronchoconstriction can be prevented by inhalation of PGE 2 [12,13]. Collectively these studies implicate COX products in several aspects of asthma pathophysiology, but it is clear that the responses to COX inhibition depend on the inhibitor studied, the route of administration, the circumstances of use and the type of patients studied. Studies in cultured airway smooth muscle cells in vitro have sug...

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“…DP receptor agonists stimulate chloride secretion in canine tracheal epithelial cells (Liu et al, 1996a). In addition, bronchoconstriction is caused by DP receptor activation and this e ect appears to be involved in asthmatic complications (Johnston et al, 1995). Agents from this prostanoid receptor class have also been shown to lower intraocular pressure (IOP) (Matsugi et al, 1995;Camras & Alm, 1997).…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin DP receptors positively coupled to adenylyl cyclase in embryonic bovine tracheal (EBTr) cells: pharmacological characterization using agonists and antagonists

Crider

Griffin

Sharif

1999

British J Pharmacology

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1 Various prostaglandin agonists representing various classes of receptor subtypes were evaluated for their ability to stimulate adenylyl cyclase via the endogenous DP receptor in embryonic bovine tracheal (EBTr) cells. Two antagonists were used to block the agonist-induced cyclic AMP production. 2 ZK118182 (EC 50 =16+4 nM), RS-93520 (EC 50 =23+4 nM), SQ27986 (EC 50 =33+9 nM), ZK110841 (EC 50 =33+5 nM), BW245C (EC 50 =59+19 nM) and PGD 2 (EC 50 =101+10 nM) (n=4 ± 70) were the most potent agonists. Whilst most compounds were full agonists (E max =100% relative to PGD 2 ), BW245C was signi®cantly more e cacious than PGD 2 (E max =121+3%; P50.001) and RS-93520 appeared to be a partial agonist (E max =64+9%; P50.001).3 Agonists from the EP (e.g. enprostil; misoprostol; butaprost), FP (e.g. cloprostenol;¯uprostenol; PHXA85), IP (iloprost; PGI 2 ) and TP (U46619) prostanoid receptor classes were weak agonists or inactive in the EBTr cell assay system. 4 The DP-receptor antagonist, BWA868C, showed a competitive antagonist pro®le with pA 2 values of 8.00+0.02 and 8.14+0.13 in Schild analyses with two structurally di erent agonists, BW245C and ZK118182, respectively (n=3). AH6809, another purported DP-receptor antagonist, weakly inhibited PGD 2 -and ZK118182-induced cyclic AMP production (K i s=808+193 nM and 782+178 nM, respectively). 5 The current studies have characterized the DP receptor positively coupled to adenylyl cyclase in EBTr cells using a wide range of agonist and antagonist prostaglandins. These data support the utility of the EBTr cell line as a useful tool for the evaluation of DP receptor agonists and antagonists and for pro®ling other classes of prostaglandins. Keywords: Prostaglandin; DP receptor; EBTr cells; BW245C; BWA868C; AH6809; ZK118182; RS93520; cyclic AMP; adenylyl cyclaseAbbreviations: EC 50 , concentration of agonist required to produce 50% of the maximal response (potency); E max , per cent of the maximal response (intrinsic activity; e cacy); IC 50 , concentration of inhibitor required to produce 50% of the maximal inhibition; K i , concentration of inhibitor required to produce 50% of the maximal inhibition at equilibrium; pA 2 , equilibrium dissociation constant of the antagonist; RIA, radioimmunoassay

show abstract

Prostaglandin D2-induced bronchoconstriction is mediated only in part by the thromboxane prostanoid receptor

Cited by 74 publications

References 18 publications

Evidence of mast cell activation and leukotriene release after mannitol inhalation

Evidence of mast cell activation and leukotriene release after mannitol inhalation

Selectivity of cyclo-oxygenase inhibitors in human pulmonary epithelial and smooth muscle cells

Prostaglandin DP receptors positively coupled to adenylyl cyclase in embryonic bovine tracheal (EBTr) cells: pharmacological characterization using agonists and antagonists

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