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.
The kinetics and phenotype of T lymphocytes infiltrating the airways of guinea pigs undergoing late-phase asthmatic reactions (LAR) were studied with monoclonal antibodies, cytofluorimetry, and immunocytochemistry. Challenge of sensitized animals with aerosolized ovalbumin was followed by early (2 h) and late-phase (17 h) bronchoconstriction. The induction of hypersensitivity, by aerosolized antigen, was associated with an increase in mucosal T cell numbers, which consisted almost entirely of CD8+ T cells. Following allergen challenge of fully sensitized animals, a biphasic rise in total T cell (CD3+) numbers was observed in the bronchial mucosa, peaking at 17 and 48 h. A similar pattern of T cell accumulation was observed in the bronchial adventitia but with an extra early peak at 2 h. In contrast to the T cell influx of the sensitization phase, the postchallenge infiltrate consisted largely of CD3+, CD8- cells. Eosinophil numbers were elevated in both submucosa and adventitia, with a single broad peak between 17 and 48 h. T cell infiltration was compared with eosinophil accumulation; while correlations between T cell and eosinophil numbers varied over the 96 h of the experiment, strong associations were observed between CD8+ numbers and eosinophils in the adventitia at 6 h (r = 0.733, p less than 0.01) and between CD3+ numbers and eosinophils in the submucosa at 72 h (r = 0.88, p less than 0.001). No significant changes were detected in T cell or eosinophil numbers in the lung parenchyma. There was a postchallenge increase in eosinophils (but not T cells) in bronchoalveolar lavage (BAL).(ABSTRACT TRUNCATED AT 250 WORDS)
In this study, we have investigated the contribution of cholinergic-mediated bronchoconstriction in the airway response provoked by inhaled prostaglandin (PG)D2, its metabolite 9 alpha, 11 beta-PGF2, and PGF2 alpha, which are generated during mast cell activation in vivo and are potent bronchoconstrictor agonists in humans. The effect of prior inhalation of 1 mg ipratropium bromide (IB) on the bronchoconstrictor response to inhaled methacholine (MCh), PGD2, 9 alpha, 11 beta-PGF2, and PGF2 alpha was determined in 7 allergic asthmatic subjects by measuring changes in SGaw, FEV1, and Vmax30. Methacholine, PGD2, and 9 alpha, 11 beta-PGF2 caused concentration-related bronchoconstriction with PGD2 and 9 alpha, 11 beta-PGF2 being between 45 and 112 times more potent than MCh (p less than 0.05), depending on the method used to measure airway caliber. Preinhalation of IB displaced the concentration response curves to MCh between 69- and 196-fold to the right, and this was significantly greater than that observed with PGD2 (12- to 23-fold, p less than 0.02) and 9 alpha, 11 beta-PGF2 (12- to 22-fold, p less than 0.02). Ipratropium bromide inhibited the bronchoconstriction achieved with the highest concentration of agonist by 73 to 91% with MCh, 46 to 79% with PGD2, and 32 to 38% with 9 alpha, 11 beta-PGF2. Ipratropium bromide did not affect the bronchoconstriction pattern to inhaled PGF2 alpha, irrespective of the nature of the response. We conclude that although PGD2 and 9 alpha, 11 beta-PGF2 are potent contractile agonists of human smooth muscle in vitro, bronchoconstriction observed with these mediators in vivo results from a combination of both direct and cholinergic-mediated mechanisms.
Inhalation of ovalbumin by conscious, sensitized guinea pigs induced two phases of airway obstruction measured at 2 h (EAR) and at 17 h (LAR), respectively. In addition to causing airway obstruction, allergen challenge induced an accumulation in the bronchial lumen of eosinophil and neutrophil polymorphonuclear leukocytes at 17 h. Intraperitoneal injection of guinea pigs with a specific rabbit anti-guinea pig neutrophil serum 24 h before challenge reduced the number of circulating neutrophils by 94% and the airway neutrophilia after challenge by 90%, but it had no effect on the magnitude of either the EAR or the LAR. The observation that the LAR was not effected by neutropenia supports previous conclusions derived from experiments using the anti-allergic drugs, cromolyn sodium and nedocromil sodium, and the beta 2-adrenoceptor stimulant, albuterol, that, although there is a temporal relationship between neutrophil accumulation in the airways and the peak of the LAR, this polymorphonuclear leukocyte does not play a central role in the pathophysiologic processes that give rise to the late-phase response to guinea pig airways.
Summary In this double‐blind study we have investigated the vascular effects of prostaglandin, (PG) D2, in normal skin and compared these effects with histamine and the initial PGD2 metabolite 9α, 11β‐PGF2. In eight healthy subjects the vascular response to intradermal injections of histamine, PGD2, a combination of histamine and PGD2, and 9α, 11β‐PGF2, was assessed by measurement of the weal and flare area. Histamine caused dose‐related increases in weal area (P<0.01). The weal response due to PGD2 was greater than saline control only at a dose of 71.0 and 710 nmol (P<0.05). Because of the small size of the weal produced by PGD2 when compared with histamine, it was not possible to determine their relative potencies. Histamine and PGD2 caused dose‐related increases in flare area (P<0.05), and when compared at a response level of 10 cm2 and 15 cm2, histamine was 45 and 251 (P<0.01) times more potent than PGD2 in molar terms. Weal and flare responses due to 9α, 11β‐PGF2 were similar to those observed with the equimolar concentration of PGD2. The weal and flare responses when PGD2 and histamine when combined were not significantly different from that predicted by a purely additive effect. We conclude that histamine is likely to be an important mediator contributing towards increased vascular permeability and vasodilatation following immunological activation of skin mast cells in vivo, while PGD2 and its metabolite 9α, 11β‐PGF2 play only a minor role.
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