title: LOX-1 deletion improves neutrophil responses, enhances bacterial clearance, and reduces lung injury in a murine polymicrobial sepsis model.
abstract: Inflammatory tissue injury and immunosuppression are the major causes of death in sepsis. Novel therapeutic targets that can prevent excessive inflammation and improve immune responses during sepsis could be critical for treatment of this devastating disease. LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a membrane protein expressed in endothelial cells, has been known to mediate vascular inflammation. In the present study, we demonstrated that LOX-1 deletion markedly improved the survival rate in a murine model of polymicrobial sepsis. Wild-type (LOX-1(+/+)) and LOX-1 knockout (LOX-1(-/-)) mice were subjected to cecal ligation and puncture (CLP) to induce sepsis. LOX-1 deletion significantly reduced systemic inflammation and inflammatory lung injury during sepsis, together with decreased production of proinflammatory cytokines and reduced lung edema formation. Furthermore, LOX-1 deletion improved host immune responses after the induction of sepsis, as indicated by enhanced bacterial clearance. Interestingly, we were able to demonstrate that LOX-1 is expressed in neutrophils. LOX-1 deletion prevented neutrophil overreaction and increased neutrophil recruitment to infection sites after sepsis induction, contributing at least partly to increased immune responses in LOX-1 knockout mice. Our study results indicate that LOX-1 is an important mediator of inflammation and neutrophil dysfunction in sepsis.
authors.affiliation: Texas Lung Injury Institute, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Texas 75708, USA.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Wu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawamura
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kurdowska
authors.forename: Hong-Long
authors.initials: HL
authors.lastname: Ji
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
mesh_terms: D000818:Animals; D002432:Cecum / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000166:cytology; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D055370:Lung Injury / Q000276:immunology* / Q000382:microbiology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology; D015398:Signal Transduction; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008565:Membrane Proteins; C495138:Olr1 protein, mouse; D023063:Receptors, Interleukin-8B; D051127:Scavenger Receptors, Class E; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases