RGD Reference Report - Mice lacking the multidrug resistance protein 1 are resistant to Streptococcus pneumoniae-induced pneumonia. - Rat Genome Database

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

Authors: Schultz, MJ  Wijnholds, J  Peppelenbosch, MP  Vervoordeldonk, MJ  Speelman, P  Van Deventer, SJ  Borst, P  Van der Poll, T 
Citation: Schultz MJ, etal., J Immunol. 2001 Mar 15;166(6):4059-64.
RGD ID: 5128828
Pubmed: PMID:11238654   (View Abstract at PubMed)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
bacterial pneumonia  ISOAbcc1 (Mus musculus)5128828; 5128828 RGD 
bacterial pneumonia  IMP 5128828 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abcc1  (ATP binding cassette subfamily C member 1)

Genes (Mus musculus)
Abcc1  (ATP-binding cassette, sub-family C member 1)

Genes (Homo sapiens)
ABCC1  (ATP binding cassette subfamily C member 1 (ABCC1 blood group))


Additional Information