In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk.
Gram-negative bacteria release LPS, which activates Toll-like-receptor-4 (TLR4) in the host, initiating an inflammatory response to infection. Infection increases risk for thrombosis. Platelets contribute to defense from infection and to thrombosis. Experiments were designed to determine whether LPS, through TLR4 signaling, affects platelet phenotype. Platelet responses in wild-type (WT) mice and mice that lack the TLR4 gene (dTLR4) were compared following a single nonlethal injection of LPS (0.2 mg/kg iv). Compared with WT mice, mice without TLR4 had fewer circulating platelets with lower RNA content and were less responsive to thrombin-activated expression of P-selectin but were equally sensitive to aggregation or ATP secretion. One week following the LPS injection, the time it takes for the circulating platelet pool to turnover, the number of circulating platelets, thrombin-induced expression of P-selectin, and collagen-activated aggregation were increased comparably in both groups of mice. Therefore, the change of the platelet pool to an activated phenotype 1 wk after a single exposure to LPS appears to arise from a process that is independent of TLR4. The persistence of the effect 1 wk after the injection suggests that the changes reflect an action of LPS on megakaryocytes and their platelet progeny rather than on circulating platelets, which would have been cleared.
Jayachandran
Muthuvel
M
Department of Surgery, Mayo Clinic Rochester, 200 First St. SW, Rochester, MN 55905, USA.
Brunn
Gregory J
GJ
Karnicki
Krzysztof
K
Miller
Randall S
RS
Owen
Whyte G
WG
Miller
Virginia M
VM
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006490:Hemostatics / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D012307:Risk Factors; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D006490:Hemostatics; D008070:Lipopolysaccharides; D019007:P-Selectin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D013917:Thrombin