Correlation between the Prostaglandin D2/E2 Ratio in Nasal Polyps and the Recalcitrant Pathophysiology of Chronic Rhinosinusitis Associated with Bronchial Asthma

Yoshimura, Tsuyoshi; Yoshikawa, Mamoru; Otori, Nobuyoshi; Haruna, Shinichi; Moriyama, Hiroshi

doi:10.2332/allergolint.o-08-545

Cited by 69 publications

(44 citation statements)

References 36 publications

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“…Nasal polyps from subjects with AERD show reduced expression of COX-2 mRNA (32) and hypermethylation of the PGE 2 synthase (PTGES) gene (33), and contain less PGE 2 than nasal polyps from aspirin-tolerant controls (34). Although these findings suggest impaired up-regulation of PGE 2 synthesis with inflammation, their causality in AERD is unproven.…”

mentioning

confidence: 71%

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

Liu

Laidlaw

Katz

et al. 2013

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

106

105

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Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, tissue eosinophilia, overproduction of cysteinyl leukotrienes (cysLTs), and respiratory reactions to nonselective cyclooxygenase (COX) inhibitors. Ex vivo studies suggest that functional abnormalities of the COX-2/microsomal prostaglandin (PG)E 2 synthase-1 system may underlie AERD. We demonstrate that microsomal PGE 2 synthase-1 null mice develop a remarkably AERD-like phenotype in a model of eosinophilic pulmonary inflammation. Lysine aspirin (Lys-ASA)-challenged PGE 2 synthase-1 null mice exhibit sustained increases in airway resistance, along with lung mast cell (MC) activation and cysLT overproduction. A stable PGE 2 analog and a selective E prostanoid (EP) 2 receptor agonist blocked the responses to Lys-ASA by ∼90%; EP 3 and EP 4 agonists were also active. The increases in airway resistance and MC products were blocked by antagonists of the type 1 cysLT receptor or 5-lipoxygenase, implying that bronchoconstriction and MC activation were both cysLT dependent. Lys-ASA-induced cysLT generation and MC activation depended on platelet-adherent granulocytes and T-prostanoid (TP) receptors. Thus, lesions that impair the inducible generation of PGE 2 remove control of platelet/granulocyte interactions and TP-receptor-dependent cysLT production, permitting MC activation in response to COX-1 inhibition. The findings suggest applications of antiplatelet drugs or TP receptor antagonists for the treatment of AERD.A spirin-exacerbated respiratory disease (AERD) affects 5-10% of all adults with asthma (1-3), ∼30% with severe asthma (4), and ∼40% with refractory chronic hyperplastic sinusitis (5). It involves severe eosinophilic respiratory tract inflammation and is defined by bronchoconstriction following the ingestion of nonselective COX inhibitors (6). Cysteinyl leukotrienes (cysLTs) (LTC 4 , LTD 4 , and LTE 4 ) drive these reactions, as well as some of the chronic features of AERD (7,8). CysLTs derive from arachidonic acid metabolized by 5-lipoxygenase (5-LO) to LTA 4 , conjugated to reduced glutathione by leukotriene C 4 synthase (LTC 4 S) to LTC 4 in mast cells (MCs), eosinophils, basophils, macrophages, and granulocyte-platelet complexes (9). After export, LTC 4 is converted sequentially to LTD 4 and LTE 4 . CysLTs induce bronchoconstriction (10, 11), tissue eosinophilia (12), and remodeling (13) through G-protein-coupled receptors (GPCRs) expressed by structural and hematopoietic cells (14-16). Individuals with AERD display higher urinary levels of LTE 4 than do aspirin-tolerant asthmatic (ATA) control subjects (17). Reactions to aspirin or other nonselective COX inhibitors are accompanied by marked further increases in urinary levels of LTE 4 and can be blocked by pretreatment with the 5-LO inhibitor zileuton or with antagonists of the type 1 receptor for cysLTs (CysLT 1 R) (18,19). The dependency on COX products to maintain homeostasis over 5-LO activity is a unique feature of AERD. Remarkably, subjects with AERD can tolerate selective ant...

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mentioning

confidence: 71%

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

Liu

Laidlaw

Katz

et al. 2013

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

106

105

View full text Add to dashboard Cite

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“…However, the precise identity of the products and the causative mechanism(s) by which they induce MC activation are unclear, and there is no explanation for why this mechanism is unique to AERD. of PGE 2 (22), reduced expression of EP 2 receptors by MCs and other tissue leukocytes (6,23), and diminished function of PKA (24) are all reported in association with AERD. Mice that are selectively PGE 2 -deficient due to targeted deletion of microsomal PGE 2 synthase (ptges −/− mice) develop a phenotype strikingly similar to AERD when challenged with lysine aspirin (Lys-ASA) following a period of exposure to an extract (Df) from the house dust mite Dermatophagoides farinae to elicit airway inflammation (25).…”

Section: Introductionmentioning

confidence: 99%

Aspirin Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway

Liu

Kanaoka

Barrett

et al. 2016

Journal of Allergy and Clinical Immunology

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Aspirin exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways, involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic prostaglandin (PG)E 2 . The mechanistic basis for MC activation in this disorder is unknown. We now demonstrate that patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared to polyps from aspirin tolerant (AT) controls. The murine model of AERD, generated by dust mite priming of mice lacking microsomal PGE 2 synthase (ptges −/− mice), shows a similar upregulation of IL-33 protein in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of LTC 4 synthase (LTC 4 S), the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges −/− lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite-primed ptges −/− mice with lysine aspirin (Lys-ASA) induce IL-33-dependent MC activation and bronchoconstriction. Thus, IL-33 is a component of a cysLT-driven innate type 2 immune response that drives pathogenic MC activation and contributes substantially to AERD pathogenesis.

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“…In comparison, the levels of PGE 2 and its metabolites were slightly elevated but not significantly different in the CRS group. Thus, PGD 2 may be a potential candidate mediator implicated in NK cell dysfunction in CRS, compatible with an elevated expression of PGDS and production of PGD 2 in CRS 17,18 . PGD 2 attenuates NK cell effector functions.…”

Section: Nk Cells Regulate Eosinophilic Inflammation In a Murine Modementioning

confidence: 83%

Natural Killer Cells Regulate Eosinophilic Inflammation in Chronic Rhinosinusitis

Kim

Jang

2015

Journal of Allergy and Clinical Immunology

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Eosinophils play a major pathologic role in the pathogenesis of diverse inflammatory diseases including chronic rhinosinusitis (CRS). Dysregulated production of prostaglandin (PG), particularly PGD 2 , is considered to be an important contributing factor to eosinophilic inflammation in CRS primarily through proinflammatory and chemotactic effects on eosinophils. Here, we provide evidence that PGD 2 can promote eosinophilic inflammation through a suppression of Natural killer (NK) cell effector function and NK cell-mediated eosinophil regulation. Eosinophil apoptosis mediated by NK cells was significantly decreased in CRS patients compared with healthy controls. This decrease was associated with NK cell dysfunction and eosinophilic inflammation. Tissue eosinophils were positively correlated with blood eosinophils in CRS patients. In a murine model of CRS, NK cell depletion caused an exacerbation of blood eosinophilia and eosinophilic inflammation in the sinonasal tissue. PGD 2 and its metabolite, but not PGE 2 and a panel of cytokines including TGF-β, were increased in CRS patients compared with controls. Effector functions of NK cells were potently suppressed by PGD 2 -dependent, rather than PGE 2 -dependent, pathway in controls and CRS patients. Thus, our results suggest decreased NK cell-mediated eosinophil regulation, possibly through an increased level of PGD 2 , as a previously unrecognized link between PG dysregulation and eosinophilic inflammation in CRS.

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Correlation between the Prostaglandin D2/E2 Ratio in Nasal Polyps and the Recalcitrant Pathophysiology of Chronic Rhinosinusitis Associated with Bronchial Asthma

Abstract: It has previously been reported that CRS complicated by AIA is most likely to be characterized by repeated remissions and relapses, and is thus the most intractable. We may therefore say that the PGD(2)/PGE(2) ratio reflects the intractable nature of CRS.

Cited by 69 publications

References 36 publications

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

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

Aspirin Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway

Natural Killer Cells Regulate Eosinophilic Inflammation in Chronic Rhinosinusitis

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Correlation between the Prostaglandin D2/E2 Ratio in Nasal Polyps and the Recalcitrant Pathophysiology of Chronic Rhinosinusitis Associated with Bronchial Asthma

Abstract: It has previously been reported that CRS complicated by AIA is most likely to be characterized by repeated remissions and relapses, and is thus the most intractable. We may therefore say that the PGD(2)/PGE(2) ratio reflects the intractable nature of CRS.

Cited by 69 publications

References 36 publications

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

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

Aspirin Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway

Natural Killer Cells Regulate Eosinophilic Inflammation in Chronic Rhinosinusitis

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

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