RGD Reference Report - Distinct roles of pattern recognition receptors CD14 and Toll-like receptor 4 in acute lung injury. - Rat Genome Database

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Distinct roles of pattern recognition receptors CD14 and Toll-like receptor 4 in acute lung injury.

Authors: Jeyaseelan, S  Chu, HW  Young, SK  Freeman, MW  Worthen, GS 
Citation: Jeyaseelan S, etal., Infect Immun. 2005 Mar;73(3):1754-63.
RGD ID: 4144789
Pubmed: PMID:15731076   (View Abstract at PubMed)
PMCID: PMC1064978   (View Article at PubMed Central)
DOI: DOI:10.1128/IAI.73.3.1754-1763.2005   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
lung disease  ISOCd14 (Mus musculus)4144789; 4144789acute lung injuryRGD 
lung disease  IMP 4144789; 4144789acute lung injuryRGD 
lung disease  ISOTlr4 (Mus musculus)4144789; 4144789acute lung injuryRGD 

Objects Annotated

Genes (Rattus norvegicus)
Cd14  (CD14 molecule)
Tlr4  (toll-like receptor 4)

Genes (Mus musculus)
Cd14  (CD14 antigen)
Tlr4  (toll-like receptor 4)

Genes (Homo sapiens)
CD14  (CD14 molecule)
TLR4  (toll like receptor 4)


Additional Information