Cystic Fibrosis Gene Mutation (ΔF508) Is Associated with an Intrinsic Abnormality in Ca2+-Induced Arachidonic Acid Release by Epithelial Cells

ABSTRACT Pseudomonas aeruginosa, a gram-negative, facultative pathogen, causes severe and often even lethal infections in immunocompromised patients, as well as cystic fibrosis patients. We show here that a variety of P. aeruginosa strains activate phospholipase A2 (PLA2), cultured epithelial cells, and fibroblasts, resulting in increased intracellular and extracellular arachidonic acid release. The use of different PLA2 inhibitors revealed that P. aeruginosa-induced arachidonic acid release is mediated by activation of cytosolic PLA2 (cPLA2), whereas iPLA2 or sPLA2 do not seem to be involved in the response to P. aeruginosa. Likewise, the cPLA2-specific inhibitors MAFP and AACOCF3 prevented apoptosis of cultured epithelial cells upon P. aeruginosa infection, whereas inhibitors specific for iPLA2 or sPLA2 were without effect. The physiological significance of these findings is indicated by an inhibition of apoptosis in tracheal epithelial cells upon in vivo infection with P. aeruginosa. The data indicate that arachidonic acid generation by activation of cPLA2 during P. aeruginosa infection plays an important role in the induction of host cell death.

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Phospholipase Activation and Arachidonic Acid Release in Cultured Intestinal Epithelial Cells (INT 407)

Scandinavian Journal of Gastroenterology ◽

10.3109/00365528909093077 ◽

1989 ◽

Vol 24 (4) ◽

pp. 475-484 ◽

Cited By ~ 13

Author(s):

C. Gustafson ◽

C. Tagesson

Keyword(s):

Arachidonic Acid ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Arachidonic Acid Release ◽

Acid Release

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Rifampin Inhibits Prostaglandin E2 Production and Arachidonic Acid Release in Human Alveolar Epithelial Cells

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00985-07 ◽

2007 ◽

Vol 51 (12) ◽

pp. 4225-4230 ◽

Cited By ~ 10

Author(s):

Yael Yuhas ◽

Inbar Azoulay-Alfaguter ◽

Eva Berent ◽

Shai Ashkenazi

Keyword(s):

Arachidonic Acid ◽

Epithelial Cells ◽

Alveolar Epithelial Cells ◽

Arachidonic Acid Release ◽

Alveolar Epithelial ◽

Dependent Inhibition ◽

Dose Dependent Inhibition ◽

Acid Release ◽

Dose Dependent ◽

Human Alveolar Epithelial Cells

ABSTRACT Rifampin, a potent antimicrobial agent, is a major drug in the treatment of tuberculosis. There is evidence that rifampin also serves as an immunomodulator. Based on findings that arachidonic acid and its metabolites are involved in the pathogeneses of Mycobacterium tuberculosis infections, we investigated whether rifampin affects prostaglandin E2 (PGE2) production in human alveolar epithelial cells stimulated with interleukin-1β. Rifampin caused a dose-dependent inhibition of PGE2 production. At doses of 100, 50, and 25 μg/ml, it inhibited PGE2 production by 75%, 59%, and 45%, respectively (P < 0.001). Regarding the mechanism involved, rifampin caused a time- and dose-dependent inhibition of arachidonic acid release from the alveolar cells. At doses of 100, 50, 25, and 10 μg/ml, it significantly inhibited the release of arachidonic acid by 93%, 64%, 58%, and 35%, respectively (P < 0.001). Rifampin did not affect the phosphorylation of cytosolic phospholipase A2 or the expression of cyclooxygenase-2. The inhibition of PGE2, and presumably other arachidonic acid products, probably contributes to the efficacy of rifampin in the treatment of tuberculosis and may explain some of its adverse effects.

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