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Mice lacking the multidrug resistance protein 1 are resistant to Streptococcus pneumoniae-induced pneumonia
M J Schultz1, J Wijnholds, M P Peppelenbosch
1Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.j.schultz@amc.uva.nl
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 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.
Insights
Mice lacking multidrug resistance protein 1 (mrp1) showed increased resistance to pneumococcal pneumonia. This protection is linked to altered leukotriene metabolism, specifically higher levels of LTB(4), suggesting mrp1 as a therapeutic target.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- Leukotrienes (LTs) play a role in lung antibacterial defense.
- Multidrug resistance protein 1 (mrp1) facilitates the cellular export of LTC(4).
Purpose of the Study:
- To investigate the role of mrp1 in host defense against Streptococcus pneumoniae pneumonia.
- To elucidate the mechanisms underlying mrp1's influence on lung immunity.
Main Methods:
- Comparison of mrp1(-/-) and wild-type mice infected with Streptococcus pneumoniae.
- Assessment of bacterial load, mortality, and leukotriene levels (LTC(4), LTB(4)).
- Pharmacological inhibition of 5-lipoxygenase-activating protein and LTB(4) antagonism.
Main Results:
- mrp1(-/-) mice exhibited reduced bacterial outgrowth and mortality compared to wild-type mice.
- Survival in mrp1(-/-) mice was similar to wild-type mice when treated with a 5-lipoxygenase inhibitor.
- Elevated LTB(4) levels in mrp1(-/-) mice correlated with their enhanced survival, which was abrogated by an LTB(4) antagonist.
- In vitro studies indicated that intracellular LTC(4) accumulation in mrp1(-/-) cells inhibits LTC(4)-synthase, favoring LTB(4) production.
Conclusions:
- mrp1 deficiency confers resistance to pneumococcal pneumonia through a mechanism involving increased LTB(4) release.
- Altered leukotriene metabolism, specifically enhanced LTB(4) production, is key to this protective effect.
- mrp1 represents a potential novel target for adjunctive therapies in pneumonia treatment.