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Persistent Inactivation of Macrophage Cyclooxygenase-2 in Mycobacterial Pulmonary Inflammation

¹ College of Biomedical Sciences, Florida Atlantic University, Boca Raton, Florida; ² Wake Forest University School of Medicine, Caswell Beach, North Carolina; and ³ Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina

Correspondence and requests for reprints should be addressed to Yoshimi Shibata, Ph.D., College of Biomedical Sciences, Florida Atlantic University, 777 Glades Rd, PO Box 3091, Boca Raton, FL 33431-0991. E-mail: yshibata{at}fau.edu

The induction of cyclooxygenase-2 (COX-2) in tissue macrophages (M) increases prostaglandin E₂ (PGE₂) release, potentially down-regulating granulomatous inflammation. In response to Mycobacteria, local M express COX-2, which is either nuclear envelope (NE)-associated or NE-dissociated. Persistent mycobacterial pulmonary inflammation is characterized by alveolar M expressing NE-dissociated (inactive) COX-2 without release of PGE₂. In this study, we examined COX-2 in alveolar M after intranasal exposure to heat-killed Mycobacterium bovis BCG (HK-BCG). After administration, whole lungs of C57Bl/6 mice were lavaged with saline; COX-2 expression and PGE₂ release by alveolar M and tumor necrosis factor (TNF)- and nitric oxide levels in the lung lavage were monitored. Normal alveolar M had undetectable levels of COX-2 on Western blots. However, 1 day after intranasal administration, almost all alveolar M had phagocytosed HK-BCG and expressed NE-dissociated COX-2 without any increase in the release of PGE₂. At 28 days after intranasal administration, 68% of alveolar M still contained both BCG and the NE-dissociated form of COX-2. NE-associated (active) COX-2 was not observed in alveolar M. In contrast, 7 days after intraperitoneal injection of HK-BCG, peritoneal M containing HK-BCG were no longer detected. At 28 days after intranasal administration, TNF- and nitrite levels in the lung lavage fluid were significantly higher than those in controls. Our results indicate that mycobacterial pulmonary inflammation is associated with suppressed PGE₂ production by alveolar M, with expression of COX-2 dissociated from the NE.

Key Words: alveolar macrophages • PGE₂ • COX-2 • mycobacteria

CLINICAL RELEVANCE This study investigates the pathophysiology associated with mycobacterial pulmonary inflammation. A novel aspect of alveolar macrophage activation by mycobacteria is the persistent presence of inactive cyclooxygenase isoforms with suppression of prostaglandin E2 production.