Nature Medicine
4, 615 - 618 (1998)
doi:10.1038/nm0598-615
Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsisAbderrazzaq Belaaouaj1, Ronald McCarthy1, Mary Baumann1, Zhimin Gao2, Timothy J. Ley3, Soman N. Abraham2
& Steven D. Shapiro1, 4
1Respiratory & Critical Care and Cell Biology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA. sshapiro@imgate.wustl.edu
2Department of Pathology and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
3Bone Marrow Transplantation & Stem Cell Biology, Departments of Medicine, Genetics, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA
4Correspondence should be addressed to S.D.S. sshapiro@imgate.wustl.edu Neutrophil elastase (NE) is a potent serine proteinase1,2 whose expression is limited to a narrow window during myeloid development. In neutrophils, NE is stored in azurophil granules along with other serine proteinases3,4 (cathepsin C, proteinase 3 and azurocidin) at concentrations exceeding 5 mM (ref. 5). As a result of its capacity to efficiently degrade extracellular matrix, NE has been implicated in a variety of destructive diseases6. Indeed, while much interest has focused on the pathologic effects of this enzyme, little is known regarding its normal physiologic function(s). Because previous in vitro data have shown that NE exhibits antibacterial activity7−9, we investigated the role of NE in host defense against bacteria. Generating strains of mice deficient in NE (NE-/-) by targeted mutagenesis, we show that NE-/- mice are more susceptible than their normal littermates to sepsis and death following intraperitoneal infection with Cram negative (Klebsiella pneumoniae and Escherichia coli) but not Cram positive (Staphylococcus aureus) bacteria. Our data indicate that neutrophils migrate normally to sites of infection in the absence of NE, but that NE is required for maximal intracellular killing of Cram negative bacteria by neutrophils.
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