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J Allergy Clin Immunol. 2014 Jun;133(6):1692-701.e3. doi: 10.1016/j.jaci.2013.12.1034. Epub 2014 Jan 31.

Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease.

Author information

1
Department of Medicine, Harvard Medical School, Boston, Mass; Division of Rheumatology, Immunology, and Allergy, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital, Boston, Mass.
2
Division of Rheumatology, Immunology, and Allergy, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital, Boston, Mass.
3
Department of Medicine, Harvard Medical School, Boston, Mass; Division of Rheumatology, Immunology, and Allergy, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: jboyce@rics.bwh.harvard.edu.

Abstract

BACKGROUND:

Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E(2) (PGE(2)) and the cyclic AMP-dependent protein kinase A (PKA).

OBJECTIVE:

To determine if PGE(2)-dependent control of LT production by granulocytes is dysregulated in AERD.

METHODS:

Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses.

RESULTS:

Granulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP(2) protein expression and PGE(2)-mediated cAMP accumulation, yet were resistant to PGE(2)-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE(2)-mediated suppression of LTB(4). The PKA inhibitor H89 potentiated LTB4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls.

CONCLUSIONS:

Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE(2), whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.

KEYWORDS:

AERD; Samter's triad; aspirin triad; aspirin-exacerbated respiratory disease; asthma; cyclic AMP; leukotriene; nonsteroidal anti-inflammatory drug; prostaglandin E(2); protein kinase A

PMID:
24486071
PMCID:
PMC4040319
DOI:
10.1016/j.jaci.2013.12.1034
[Indexed for MEDLINE]
Free PMC Article

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