Ketoconazole inhibits alveolar macrophage production of inflammatory mediators involved in acute lung injury (adult respiratory distress syndrome).
BACKGROUND
Acute inflammatory lung injury (adult respiratory distress syndrome [ARDS]) causes significant morbidity and death in surgical patients. The alveolar macrophage elaborates proinflammatory mediators implicated in acute pulmonary injury. The macrophage products, leukotriene B4 (LTB4), thromboxane A2 (TXA2), and procoagulant activity (PCA), initiate inflammatory cascades that lead to microvascular thrombosis and neutrophil infiltration, two common features of ARDS. One potential method of preventing or attenuating lung injury is to inhibit the production of inflammatory mediators. Preliminary studies indicate that ketoconazole, known primarily for its antifungal properties, may prevent ARDS.


METHODS
LTB4, TXB2, and PCA production by rabbit alveolar macrophages was measured after treatment with endotoxin or Ca ionophore and ketoconazole or selective 5-lipoxygenase (MK 886) and thromboxane synthetase (imidazole) inhibitors.


RESULTS
Ketoconazole significantly inhibits alveolar macrophage production of LTB4, TXB2, and PCA. Ketoconazole inhibition of PCA is independent of effects on 5-lipoxygenase and thromboxane synthetase.


CONCLUSIONS
Ketoconazole inhibition of alveolar macrophage proinflammatory mediators may be of benefit in preventing ARDS by minimizing neutrophil infiltration and microvascular thrombosis. Inhibition of 5-lipoxygenase and thromboxane synthetase, without affecting cyclooxygenase, may offer a selective advantage by allowing production of other homeostatic eicosanoids.
Williams
J G
JG
Department of Surgery, University of Washington School of Medicine, Seattle, Wash.
Maier
R V
RV
D000818:Animals; D001779:Blood Coagulation Factors / Q000037:antagonists & inhibitors*; D007654:Ketoconazole / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000378:metabolism*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D001779:Blood Coagulation Factors; C045072:macrophage procoagulant activity; D007975:Leukotriene B4; D013928:Thromboxane A2; D007654:Ketoconazole