Prostaglandin E₂deficiency uncovers a dominant role for thromboxane A₂in house dust mite-induced allergic pulmonary inflammation

Abstract

Prostaglandin E 2 (PGE 2 ) is an abundant lipid inflammatory mediator with potent but incompletely understood anti-inflammatory actions in the lung. Deficient PGE 2 generation in the lung predisposes to airway hyperresponsiveness and aspirin intolerance in asthmatic individuals. PGE 2 -deficient ptges −/− mice develop exaggerated pulmonary eosinophilia and pulmonary arteriolar smoothmuscle hyperplasia compared with PGE 2 -sufficient controls when challenged intranasally with a house dust mite extract. We now demonstrate that both pulmonary eosinophilia and vascular remodeling in the setting of PGE 2 deficiency depend on thromboxane A 2 and signaling through the T prostanoid (TP) receptor. Deletion of TP receptors from ptges −/− mice reduces inflammation, vascular remodeling, cytokine generation, and airway reactivity to wild-type levels, with contributions from TP receptors localized to both hematopoietic cells and tissue. TP receptor signaling ex vivo is controlled heterologously by E prostanoid (EP) 1 and EP 2 receptor-dependent signaling pathways coupling to protein kinases C and A, respectively. TP-dependent up-regulation of intracellular adhesion molecule-1 expression is essential for the effects of PGE 2 deficiency. Thus, PGE 2 controls the strength of TP receptor signaling as a major bronchoprotective mechanism, carrying implications for the pathobiology and therapy of asthma.cyclooxygenase | EP receptors P rostaglandins (PGs) derive from the metabolism of arachidonic acid by cyclooxygenase (COX)-1 and COX-2 (1). COX-derived PGH 2 is converted to one of five PGs [PGD 2 , PGE 2 , PGF 2 α, PGI 2 , or thromboxane A 2 (TXA 2 )] by distinct terminal synthases. Specific G protein-coupled receptors (2) mediate the effects of PGs in vivo, including roles in regulation of vascular tone, hemostasis, hematopoiesis, epithelial cell turnover, cancer, and inflammation (1). Although COX inhibitors control inflammatory pain (3) and may prevent vascular disease and certain cancers (1), these reagents can also interfere with the production of PGs needed for homeostatic functions and cause unwanted side effects (1, 4). PGE 2 is one of the most functionally versatile PGs. Three terminal synthases can convert PGH 2 to PGE 2 (5-7). Of these, microsomal PGE 2 synthase (mPGES)-1 is the dominant enzyme responsible for converting COX-2-derived PGH 2 to PGE 2 during inflammation (8). Four E prostanoid (EP) receptors (9) mediate the effects of PGE 2 . PGE 2 is pathogenetic in models of autoimmune diseases (10) and inflammatory arthritis (8), but is bronchoprotective (11) and anti-inflammatory (12, 13) in certain models of allergic lung disease. In patients with atopic asthma, inhalation of PGE 2 blocks bronchoconstriction in response to challenge with inhaled specific allergen (14) and attenuates the recruitment of eosinophils and basophils to the airway. Reduced PGE 2 levels in the setting of sputum eosinophilia correlate with airway hyperresponsiveness (AHR) (15), a cardinal feature of asthma. Aspirin-exacerbated respiratory disea...

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

“…4C). Short-term TP receptor blockade had no effect on histologic indices of inflammation, whereas tpr deletion markedly impaired the development of these features as in our previous study (28). Discussion AERD accounts disproportionately for severe asthma and chronic rhinosinusitis (3,4).…”

“…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.…”

“…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.…”

“…PKA also phosphorylates and desensitizes the T-prostanoid (TP) receptor (28). Inhaled PGE 2 blocks both bronchoconstriction and increases in urinary LTE 4 that occur with aspirin challenge of subjects with AERD (29).…”

The role of heat shock proteins in inflammatory injury induced by cold stress in chicken hearts

“…COX-2 inhibitors reduce mucosal damage, which further indicates the role of prostaglandins in tissue damage and inflammation reactions (Zheng et al 2012). PTGES catalyzes the isomerization of PGH2 to PGE2, and the latter plays an important role in inflammation (Liu et al 2012a), cell growth, and transformation (Sasaki et al 2012). In the current study, we found that the NF-κB, iNOS, and TNF-α mRNA levels of heart tissue were significantly increased (P < 0.05) in stress groups.…”