Persistent Inactivation of Macrophage Cyclooxygenase-2 in Mycobacterial Pulmonary Inflammation

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FONTE

American Thoracic Society

RESUMO

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)-α 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-α 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.

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