Mice lacking the multidrug resistance protein 1 are resistant to Streptococcus pneumoniae-induced pneumonia.
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 LTC(4). 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 LTC(4) levels remained low in the bronchoalveolar lavage fluid of mrp1(-/-) mice, LTB(4) concentrations were higher than in wild-type mice. These elevated LTB(4) concentrations were important for the relative protection of mrp1(-/-) mice, because the LTB(4) antagonist LTB(4)-dimethyl amide abolished their survival advantage. In vitro experiments suggested that the intracellullar accumulation of LTC(4) in mrp1(-/-) mice results in product inhibition of LTC(4)-synthase, diminishing substrate competition between LTA(4)-hydrolase (which yields LTB(4)) and LTC(4)-synthase for the available LTA(4). We conclude that mrp1(-/-) mice are resistant against pneumococcal pneumonia by a mechanism that involves increased release of LTB(4). These results identify mrp1 as a novel target for adjunctive therapy in pneumonia.
Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.j.schultz@amc.uva.nl
M J
MJ
Schultz
J
J
Wijnholds
M P
MP
Peppelenbosch
M J
MJ
Vervoordeldonk
P
P
Speelman
S J
SJ
van Deventer
P
P
Borst
T
T
van der Poll
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007211:Indoles / Q000008:administration & dosage; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D007274:Injections, Intraperitoneal; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011018:Pneumonia, Pneumococcal / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D002722:Chlorobenzenes
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007211:Indoles; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes