Prostaglandin E<sub>2</sub> and cysteinyl leukotriene concentrations in sputum: association with asthma severity and eosinophilic inflammation

Aggarwal, Shashi; Moodley, Yuben; Thompson, Philip J.; Misso, N.L.A.

doi:10.1111/j.1365-2222.2009.03386.x

Cited by 74 publications

(49 citation statements)

References 40 publications

(60 reference statements)

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“…Therefore, the role of EP4 receptors in endothelial function awaits further investigation. In summary, increased levels and protective effects of PGE 2 in pulmonary inflammatory diseases have been described previously [14,46]. The accumulation of eosinophils in asthmatic airways greatly contributes to the outcome of the disease by releasing cytotoxic mediators, leading to airway remodeling and angiogenesis in the chronically inflamed pulmonary tissue [7].…”

Section: Discussionmentioning

confidence: 99%

“…While PGD 2, which is the predominant PG formed in mast cells, exerts proinflammatory effects by regulating the recruitment of eosino-phils, basophils, and Th2 lymphocytes to the sites of allergic inflammation [12], PGE 2 seems to attenuate inflammatory responses and reduce tissue injury in airways [13]. PGE 2 was found to exert bronchoprotective effects in patients with asthma [14]. In rats, the ovalbumin-induced early and late phase airway responses were inhibited by intratracheally administered PGE 2 [15].…”

Section: Introductionmentioning

confidence: 99%

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Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

et al. 2011

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Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE 2 and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE 2 and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxininduced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE 2 and the EP4 agonist prevented the activation and cell-surface clustering of b2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-a-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE 2 from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin-and TNF-a-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE 2 -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.Keywords: Adhesion . Endothelium . Eosinophils . Migration . Prostaglandins Supporting Information available online IntroductionEosinophil granulocytes are important effector cells in allergic inflammation and are recruited to the tissue by chemotactic signals [1][2][3][4][5]. The infiltrating eosinophils release several toxic and proinflammatory mediators which induce epithelial injury, airway hyper-responsiveness, and airway remodeling [6][7][8]. Therefore, eosinophils are regarded as potential therapeutic targets in allergic diseases and asthma [9].Prostaglandins (PGs) play diverse roles in inflammation, depending on the cellular context, the type of PG being released, and the differential expression of PG receptors [10,11]. While PGD 2, which is the predominant PG formed in mast cells, exerts proinflammatory effects by regulating the recruitment of eosino- Eur. J. Immunol. 2011. 41: 2379-2389 DOI 10.1002 Leukocyte signaling 2379 phils, basophils, and Th2 lymphocytes to the sites of allergic inflammation [12], PGE 2 seems to attenuate inflammatory responses and reduce tissue injury in airways [13]. PGE 2 was found to exert bronchoprotective effects in patients with asthma [14]. In rats, the ovalbumin-induced early and late phase airway responses were inhibited by intratracheally administered PGE 2 [15]. The activity of PGE 2 is mediated by four subtypes of E-type prostanoid receptors (EP), EP1, EP2, EP3, and EP4 [16]. These G protein-coupled receptors have distinct biological imprints depending on their affinity with...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

et al. 2011

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“…Consequently, TP-dependent effects become magnified in the setting of inflammation if the capacity to up-regulate PGE 2 generation (or to signal through EP receptors) is impaired. Deficient PGE 2 may potentiate AHR in the setting of eosinophilic inflammation (15,47). Defective COX-2-dependent production of PGE 2 and deficient expression of EP 2 receptors have both been documented in AERD (19,21,48), and might account for the marked eosinophilic airway inflammation and high basal levels of leukotriene E 4 typical of this syndrome.…”

Section: Pge 2 Deficiency Augments Icam-1-dependent Pulmonary Leukocytementioning

confidence: 99%

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

Liu

Laidlaw

Cheng

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…[52][53][54] Although it is reported that IL-13 inhibits PGE 2 synthetic pathways and decreases PGE 2 secretion in HBE cells, 55 a clinical study showed that cysLT and PGE 2 concentrations in sputum are higher in those with asthma than in control subjects. 56 PGE 2 also promotes cell growth in bronchial epithelial cells. 57 We showed that, consistent with this, PGE 2 secretion was increased during the cell growth and diff erentiation phase of HBE cells.…”

Section: Secretion In Goblet-enriched Cellsmentioning

confidence: 99%

Secretory Phospholipases A 2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

Tanabe

Shimokawaji

Kanoh

et al. 2015

Chest

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BACKGROUND: Secretory phospholipases A 2 (sPLA 2 ) initiate the biosynthesis of eicosanoids, are increased in the airways of people with severe asthma, and induce mucin hypersecretion. We used IL-13-transformed, highly enriched goblet cells and differentiated (ciliary cellenriched) human bronchial epithelial cell culture to evaluate the relative contribution of ciliated and goblet cells to airway sPLA 2 generation and response. We wished to determine the primary source(s) of sPLA 2 and leukotrienes in human airway epithelial cells.

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Prostaglandin E₂ and cysteinyl leukotriene concentrations in sputum: association with asthma severity and eosinophilic inflammation

Cited by 74 publications

References 40 publications

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

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

Secretory Phospholipases A 2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

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Prostaglandin E2 and cysteinyl leukotriene concentrations in sputum: association with asthma severity and eosinophilic inflammation

Cited by 74 publications

References 40 publications

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

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

Secretory Phospholipases A 2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

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Prostaglandin E₂ and cysteinyl leukotriene concentrations in sputum: association with asthma severity and eosinophilic inflammation

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