Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease.
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.
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.
Tanya M
TM
Laidlaw
Division of Rheumatology, Immunology, and Allergy, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital, Boston, Mass.
Anya J
AJ
Cutler
Division of Rheumatology, Immunology, and Allergy, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital, Boston, Mass.
Molly S
MS
Kidder
Division of Rheumatology, Immunology, and Allergy, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital, Boston, Mass.
Tao
T
Liu
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.
Juan Carlos
JC
Cardet
Division of Rheumatology, Immunology, and Allergy, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital, Boston, Mass.
Heng
H
Chhay
Division of Rheumatology, Immunology, and Allergy, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital, Boston, Mass.
Chunli
C
Feng
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.
Joshua A
JA
Boyce
D000328:Adult; D000368:Aged; D001241:Aspirin / Q000009:adverse effects; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000378:metabolism; D012140:Respiratory Tract Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D055815:Young Adult
D015289:Leukotrienes; D058307:Receptors, Prostaglandin E, EP2 Subtype; D007975:Leukotriene B4; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D001241:Aspirin
AERD; Samter's triad; aspirin triad; aspirin-exacerbated respiratory disease; asthma; cyclic AMP; leukotriene; nonsteroidal anti-inflammatory drug; prostaglandin E(2); protein kinase A