Mice Lacking the Multidrug Resistance Protein 1 Are Resistant to Streptococcus pneumoniae- Induced Pneumonia

Abstract

Leukotrienes (LTs) are considered important for antibacterial defense in the lung. Multidrug resistance protein 1 (mrp1) is a transmembrane protein responsible for the cellular extrusion of LTC4. To determine the role of mrp1 in host defense against pneumonia, mrp1−/− and wild-type mice were intranasally inoculated with Streptococcus pneumoniae. mrp1−/− mice displayed a diminished outgrowth of pneumococci in lungs and a strongly reduced mortality. These findings were related to an effect of mrp1 on LT metabolism, because survival was similar in mrp1−/− and wild-type mice treated with the 5-lipoxygenase-activating protein inhibitor MK-886. Although LTC4 levels remained low in the bronchoalveolar lavage fluid of mrp1−/− mice, LTB4 concentrations were higher than in wild-type mice. These elevated LTB4 concentrations were important for the relative protection of mrp1−/− mice, because the LTB4 antagonist LTB4-dimethyl amide abolished their survival advantage. In vitro experiments suggested that the intracellullar accumulation of LTC4 in mrp1−/− mice results in product inhibition of LTC4-synthase, diminishing substrate competition between LTA4-hydrolase (which yields LTB4) and LTC4-synthase for the available LTA4. We conclude that mrp1−/− mice are resistant against pneumococcal pneumonia by a mechanism that involves increased release of LTB4. These results identify mrp1 as a novel target for adjunctive therapy in pneumonia.