9 alpha,11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways.

Abstract

Prostaglandin (PG) D2, the predominant prostanoid released from activated mast cells in humans is initially metabolized by reduction of the C-1l keto function to yield 9a,11,6-PGF2. In this study the airway effects of 9a,11t-PGF2 were compared with those of its epimer 9a,11a-PGF2 (PGF2.) and PGD2.9a,11( -PGF2 was a potent contractile agonist of isolated guinea pig trachea and 4-mm human airways in vitro; the potencies of the PMs relative to PGD2 (= 1.00) being 0.65 (NS) and 4.08-(P < 0.001) for 9a,11ft-PGF2, and 0.52 (P < 0.01) and 2.40 (P < 0.001) for PGF2., respectively. When inhaled by asthmatic subjects, 9a,1fj-PGF2 was a potent bronchoconstrictor agent, being approximately equipotent with PGD2 and 28-32 times more potent than histamine (P < 0.01). These studies suggest that 9a,11B-PGF2 is at least equipotent with PGD2 as a bronchoconstrictor agonist, and in being a major metabolite of PGD2, could contribute to the bronchoconstrictor effect of this mast cell-derived mediator in asthma.

Evidence of mast cell activation and leukotriene release after mannitol inhalation

“…As expected the nonasthmatic subjects did not have a reduction in FEV1 despite having significantly increased urinary levels of LTE 4 and 9a,11b-PGF 2 , which, as well as its parent compound PGD 2 , is a potent bronchoconstrictor [17]. The major difference between the response to inhaled mannitol in the two groups studied is most probably related to differences in airway responsiveness to the released mediators.…”

“…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].…”

Indomethacin inhibits eosinophil migration to prostaglandin D2: therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis

“…14 Prostaglandin D 2 shows a wide range of biological activities, including vasodilatation, bronchoconstriction, inhibition of platelet aggregation and regulation of the sleep-wake cycle. [14][15][16][17][18] A number of recent lines of evidence have indicated that PGD 2 is also involved in allergic inflammation. Mice that over-produce PGD 2 exhibit enhanced allergic lung inflammation with eosinophilia and Th2-type cytokine production.…”

BAY u3405 an antagonist of thromboxane A2‐ and prostaglandin D2‐induced bronchoconstriction in the guinea‐pig

“…The metabolite of PGD2 (9a, 1 1fJ-PGF2) also has potent contractile activity on human and guinea-pig airways in vitro (Featherstone et al, 1990) and by inhalation in man (Beasley et al, 1987). In asthmatics, inhaled PGD2 is 10-30 times more potent than histamine and causes bronchoconstriction and coughing at approximately a 100 fold lower concentration than in normal subjects exemplifying the 'bronchial hyperresponsiveness' characteristic of this disease (Hardy et al, 1984).…”