Cholinergic-Mediated Bronchoconstriction Induced by Prostaglandin D₂, Its Initial Metabolite 9α, 11β-PGF₂, and PGF_2αin Asthma

Abstract

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.

cDNA cloning, expression and characterization of human prostaglandin F synthase1

“…We also found that PGFS mRNA was expressed in PBL as well as lung. As PGD 2 is increased in alveolar lymphocytes as well as in macrophages, eosinophils and mast cells after a challenge with an inflammatory antigen [23–25], we examined the effect of Con A, which is considered to be a T lymphocyte‐specific mitogen [26], on expression of PGFS mRNA in PBL. As shown in Fig.…”

Mast cells in airway diseases and interstitial lung disease

“…Mast cell-derived mediators induce the classical features of the early asthmatic reaction in vivo , inducing bronchoconstriction, mucus secretion and mucosal oedema (for reviews see (Bradding and Cruse, 2008; Bradding et al, 2006; Brightling et al, 2003a; Moiseeva and Bradding, 2011)). For example, several studies have identified an increase in histamine, prostaglandin D 2 (PGD 2 ) and leukotriene C 4 (LTC 4 ) in the BAL fluid of asthma subjects following bronchial allergen challenge (Casale et al, 1987; Liu et al, 1991; Murray et al, 1986; Sedgwick et al, 1991; Wenzel et al, 1988; Wenzel et al, 1990; Wenzel et al, 1991) and that the early asthmatic reaction is significantly alleviated with the administration of potent selective inhibitors of histamine, LTC 4 and to a lesser extent PGD 2 (Beasley et al, 1987; Curzen et al, 1987; Findlay et al, 1992; Rafferty et al, 1987; Taylor et al, 1991). These mediators are most likely derived from mast cells in the bronchial mucosa because histamine, PGD 2 and LTC 4 are all released from human lung mast cells in vitro with remarkably similar kinetics to the allergen challenge studies (Schleimer et al, 1986).…”

Primary and Secondary Effector Cells in the Pathogenesis of Bronchial Asthma

“…Thus, at least some of the bronchoconstrictor activity of en dogenously generated PGD2 may result from the ac tion of one of its immediate metabolites. Using the potent and selective muscarinic cholinergic antagon ist, ipratropium bromide, administered by inhalation in a dose of 1 mg, we have shown that a significant proportion of bronchoconstriction mediated both by PGD2 and 9 a,1I/LPGF2 but not PGF2a occurs from stimulation of vagal reflexes in the airways [44].…”