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

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 6; pp. 1692 - 1701.e3
• Main Authors: Laidlaw, Tanya M., Cutler, Anya J., Kidder, Molly S., Liu, Tao, Cardet, Juan Carlos, Chhay, Heng, Feng, Chunli, Boyce, Joshua A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2014; Elsevier
• Subjects: Adult; AERD; Aged; Allergy and Immunology; Aspirin - adverse effects; aspirin triad; aspirin-exacerbated respiratory disease; asthma; Biological and medical sciences; Blood Platelets - immunology; Blood Platelets - metabolism; cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Dinoprostone - metabolism; Drug toxicity and drugs side effects treatment; Female; Granulocytes - immunology; Granulocytes - metabolism; Humans; Immunopathology; leukotriene; Leukotriene B4 - biosynthesis; Leukotrienes - metabolism; Male; Medical sciences; Middle Aged; Neutrophils - immunology; Neutrophils - metabolism; nonsteroidal anti-inflammatory drug; Pharmacology. Drug treatments; prostaglandin E2; protein kinase A; Receptors, Prostaglandin E, EP2 Subtype - agonists; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Respiratory Tract Diseases - chemically induced; Respiratory Tract Diseases - drug therapy; Respiratory Tract Diseases - immunology; Respiratory Tract Diseases - metabolism; Samter's triad; Toxicity: respiratory system, ent, stomatology; Young Adult; 5-LO; fMLP; leukotriene; aspirin-exacerbated respiratory disease; PKA; AERD; LT; asthma; EP; cAMP; LTC4S; Samter's triad; ATA; cysLT; aspirin triad; prostaglandin E2; myrPKI; PG; cyclic AMP; ADPβS; protein kinase A; nonsteroidal anti-inflammatory drug; Aspirin-tolerant asthma; Cysteinyl leukotriene; LTC 4S; Adenosine diphosphate 5′-[β-thio]diphosphate; Myristoylated peptide protein kinase A inhibitor; prostaglandin E 2; Prostaglandin; Leukotriene C 4 synthase; E prostanoid receptor; 5-Lipoxygenase; Formyl peptide; Cyclic adenosine monophosphate; Biological properties; Prostaglandin-endoperoxide synthase; Toxicity; Granulocyte; Prostaglandin E2; Acetylsalicylic acid; Immunology; Eicosanoid; prostaglandin E; Bronchus disease; Obstructive pulmonary disease; Salicylates; Human; Lung disease; Immunopathology; Pathophysiology; Enzyme; Respiratory disease; Arachidonic acid derivatives; Enzyme inhibitor; cAMP-dependent protein kinase; Antiplatelet agent; Asthma; Non steroidal antiinflammatory agent; Leukotriene; Analgesic; Antipyretic; Oxidoreductases
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.12.1034

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 E2 (PGE2) and the cyclic AMP-dependent protein kinase A (PKA). To determine if PGE2-dependent control of LT production by granulocytes is dysregulated in AERD. Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses. 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 EP2 protein expression and PGE2-mediated cAMP accumulation, yet were resistant to PGE2-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE2-mediated suppression of LTB4. 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. Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE2, whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.