Mice lacking the multidrug resistance protein 1 are resistant to Streptococcus pneumoniae-induced pneumonia

Leukotrienes (LTs) are considered important for antibacterial defense in th e lung. Multidrug resistance protein 1 (mrp1) is a transmembrane protein re sponsible for the cellular extrusion of LTC4. To determine the role of mrp1 in host defense against pneumonia, mrp1(-/-) and wild-type mice were intra nasally inoculated with Streptococcus pneumoniae. mrp1(-/-) mice displayed a diminished outgrowth of pneumococci in lungs and a strongly reduced morta lity. These findings were related to an effect of mrp1 on LT metabolism, be cause survival was similar in mrp1(-/-) and wild-type mice treated with the 5-lipoxygenase-activating protein inhibitor MK-886. Although LTC4 levels r emained low in the bronchoalveolar lavage fluid of mrp1(-/-) mice, LTB4 con centrations were higher than in wild-type mice. These elevated LTB4 concent rations were important for the relative protection of mrp1(-/-) mice, becau se the LTB4 antagonist LTB4-dimethyl amide abolished their survival advanta ge. In vitro experiments suggested that the intracellullar accumulation of LTC4 in mrp1(-/-) mice results in product inhibition of LTC4-synthase, dimi nishing substrate competition between LTA(4)-hydrolase (which yields LTB4) and LTC4-synthase for the available LTA(4). 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 fo r adjunctive therapy in pneumonia.