title: Distinct roles of pattern recognition receptors CD14 and Toll-like receptor 4 in acute lung injury.
abstract: Acute lung injury (ALI) induced by lipopolysaccharide (LPS) is a major cause of mortality among humans. ALI is characterized by microvascular protein leakage, neutrophil influx, and expression of proinflammatory mediators, followed by severe lung damage. LPS binding to its receptors is the crucial step in the causation of these multistep events. LPS binding and signaling involves CD14 and Toll-like receptor 4 (TLR4). However, the relative contributions of CD14 and TLR4 in the induction of ALI and their therapeutic potentials are not clear in vivo. Therefore, the aim of the present study was to compare the roles of CD14 and TLR4 in LPS-induced ALI to determine which of these molecules is the more critical target for attenuating ALI in a mouse model. Our results show that CD14 and TLR4 are necessary for low-dose (300-microg/ml) LPS-induced microvascular leakage, NF-kappaB activation, neutrophil influx, cytokine and chemokine (KC, macrophage inflammatory protein 2, tumor necrosis factor alpha, interleukin-6) expression, and subsequent lung damage. On the other hand, when a 10-fold-higher dose of LPS (3 mg/ml) was used, these responses were only partially dependent on CD14 and they were totally dependent on TLR4. The CD14-independent LPS response was dependent on CD11b. A TLR4 blocking antibody abolished microvascular leakage, neutrophil accumulation, cytokine responses, and lung pathology with a low dose of LPS but only attenuated the responses with a high dose of LPS. These data are the first to demonstrate that LPS-induced CD14-dependent and -independent (CD11b-dependent) signaling pathways in the lung are entirely dependent on TLR4 and that blocking TLR4 might be beneficial in lung diseases caused by LPS from gram-negative pathogens.
authors.affiliation: Division of Respiratory Infections, Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson St., Neustadt D-403, Denver, CO 80206, USA. JeyaseelanS@NJC.org
authors.forename: Samithamby
authors.initials: S
authors.lastname: Jeyaseelan
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
authors.forename: Scott K
authors.initials: SK
authors.lastname: Young
authors.forename: Mason W
authors.initials: MW
authors.lastname: Freeman
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli / Q000472:pathogenicity*; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000633:toxicity*; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000276:immunology* / Q000503:physiopathology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
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