Prostaglandin E2 Exerts Homeostatic Regulation of Pulmonary Vascular Remodeling in Allergic Airway Inflammation

Abstract

Nonselective inhibition of PG synthesis augments inflammation in mouse models of airway disease, but the roles of individual PGs are not completely clarified. To investigate the role of PGE2 in a mouse model of airway inflammation induced by a natural allergen, we used mice lacking the critical terminal synthetic enzyme, microsomal PGE2 synthase (mPGES)-1. Mice lacking mPGES-1 (ptges−/− mice) and wild-type C57BL/6 controls were challenged intranasally with low doses of an extract derived from the house dust mite Dermatophagoides farinae (Der f). The levels of PGE2 in the bronchoalveolar lavage fluids of Der f-treated ptges−/− mice were ~80% lower than the levels in wild-type controls. Der f-induced bronchovascular eosinophilia was modestly enhanced in the ptges−/− mice. Both Der f-treated strains showed similar increases in serum IgE and IgG1, as well as comparable levels of Th1, Th2, and Th17 cytokine production by Der f-stimulated spleen cells. These findings indicated that mPGES-1-derived PGE2 was not required for allergen sensitization or development of effector T cell responses. Unexpectedly, the numbers of vascular smooth muscle cells and the thickness of intrapulmonary vessels were both markedly increased in the Der f-treated ptges−/− mice. These vascular changes were suppressed by the administration of the stable PGE2 analog 16, 16-dimethyl PGE2, or of selective agonists of the E-prostanoid (EP) 1, EP2, and EP3 receptors, respectively, for PGE2. Thus, mPGES-1 and its product, PGE2, protect the pulmonary vasculature from remodeling during allergen-induced pulmonary inflammation, and these effects may be mediated by more than one EP receptor.

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

“…Df was from Greer Laboratories (XPB81D3A25) (35). Selective agonists of the EP 1 (DI-004), EP 2 (AE1-259-01), EP 3 (AE-248), and EP 4 (AE-329) receptors were from ONO Pharmaceuticals (67).…”

“…Ptges −/− mice develop marked eosinophildominated bronchovascular cellular infiltrates (>75% of BAL fluid cells) with lesser numbers of neutrophils (28,35). AERD is also associated with marked eosinophilia of the respiratory mucosa (44), often without evidence of sensitization to allergens.…”

“…EP 3 and EP 4 agonists were also active. In our previous studies, the long-term intranasal administrations of the EP 2 or EP 3 agonists suppressed Df-induced pulmonary eosinophilia in the ptges −/− mice with equal efficacy (35). Deletion of EP 2 receptors mirrored the increase in Dfinduced inflammation and remodeling of the pulmonary vasculature (Fig.…”

“…Mice lacking mPGES-1 (ptges −/− mice) treated intranasally (i.n.) with an extract (Df) from the dust mite Dermatophagoides farinae develop marked eosinophilic bronchovascular inflammation compared with wild-type control animals (28,35). Df-treated ptges −/− mice exhibit airflow obstruction, cysLT production, and lung MC activation in response to aspirin.…”

Analysis of Two Major Intracellular Phospholipases A2 (PLA2) in Mast Cells Reveals Crucial Contribution of Cytosolic PLA2α, Not Ca2+-independent PLA2β, to Lipid Mobilization in Proximal Mast Cells and Distal Fibroblasts

“…Although the molecular mechanism underlying the anti-anaphylactic action of PGE 2 in vivo has not yet been fully understood, it appears to be mediated by the PGE receptor EP3, because its absence also results in exacerbated allergic reactions in mice (31). Reportedly, the deficiency of mPGES-1 also leads to augmented asthmatic airway inflammation, which could be explained by profound alteration in vascular remodeling (32). Thus, the augmented PCA reaction in Ptges Ϫ/Ϫ mice observed in our study might also rely on a similar vascular mechanism.…”