Reversal of Virus-Induced Alveolar Macrophage Bactericidal Dysfunction by Cyclooxygenase Inhibition In Vitro

Abstract

Virus infection of alveolar macrophages (AM) both in vivo and in vitro has been associated with a decreased ability of these cells to kill bacteria, together with enhanced production of metabolites of arachidonic acid. These metabolites, especially PGE2, may be inhibitory to some phagocyte functions. Primary cultures of bovine AM obtained by bronchoalveolar lavage of normal cattle were infected in vitro with parainfluenza-3 (PI3 virus) virus. Killing of Staphylococcus epidermidis by AM was determined on days 1-4 post-infection (p.i.) PI3 virus-infected AM killed significantly fewer bacteria on day 4 p.i. compared to uninfected controls (12.1 +/- 1.3% infected vs. 52.7 +/- 7.2% controls, P less than or equal to 0.05). Bacterial killing by virus-infected AM, but not control AM, was significantly enhanced on day 4 p.i. by addition of cyclooxygenase inhibitors 1 hr prior to bactericidal assay (28.0 +/- 4.5% indomethacin, 36.0 +/- 4.1% mefenamic acid, 38.6 +/- 7.3% piroxicam, 37.0 +/- 6.4% NDGA, 44.9 +/- 7.7% ETYA, P less than or equal to 0.05). Phagocytosis of opsonized sheep erythrocytes and superoxide generation by virus-infected AM were not significantly increased by cyclooxygenase inhibition. Phagosome-lysosome fusion was severely impaired in virus-infected AM. Pretreatment of virus-infected AM with indomethacin significantly enhanced the percentage of cell expressing fusion activity. This data suggests that in vitro bactericidal dysfunction associated with virus infection of AM is partially the result of enhanced production of prostaglandins or thromboxane by AM and/or an abnormal response to normal levels of endogenously produced cyclooxygenase metabolites. The data further indicate the presence of cyclooxygenase sensitive (phagosome-lysosome fusion) and insensitive (phagocytic) components of virus-induced bactericidal dysfunction in AM.

Critical Role of Prostaglandin E2 Overproduction in Impaired Pulmonary Host Response following Bone Marrow Transplantation

“…Surprisingly, indomethacin has no apparent effect on bacterial killing in control phagocytes (Fig. 6), which is in agreement with earlier work as well (48). The reasons for this discrepancy between phagocytosis and killing are unclear to us, and may simply reflect the fact that the phagocytosis assays are more sensitive than the bacterial killing assays.…”

Prostaglandin E2 Inhibits Alveolar Macrophage Phagocytosis through an E-Prostanoid 2 Receptor-Mediated Increase in Intracellular Cyclic AMP

“…The present study confirms that PGE 2 has important immunosuppressive effects on AM antimicrobial function (27,40,41) and enhances our understanding of the mechanisms whereby these effects occur. PGE 2 has previously been shown to either stimulate or inhibit the phagocytic capacity of monocytes/macrophages, with the majority of studies demonstrating inhibition (23)(24)(25)(26)(27)(28)(29).…”

Deletion of the Prostaglandin E2EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

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