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Aging-related hyperinflammation in endotoxemia is mediated by the alpha2A-adrenoceptor and CD14/TLR4 pathways.

Abstract：

AIMS:Sepsis is a major cause of morbidity and mortality in the elderly population. In prior studies, we have shown that in vivo, the inflammatory response in aged animals is exaggerated as compared to young animals and that this response likely accounts for the increased morbidity and mortality. Part of this uncontrolled inflammatory response in sepsis is due to the innate immune response. However, recent studies have shown that the pathogenesis of sepsis is much more complex. The adrenergic autonomic nervous system is now thought to play a key role in modulating the inflammatory response in sepsis. In this study, we hypothesize that not only is the innate immune response enhanced in response to lipopolysaccharide (LPS) in aged animals, but that the adrenergic nervous system also plays a role in the release of excess inflammatory cytokines. MAIN METHODS:Male Fischer-344 rats (young: 3 months; aged: 24 months) were used. Endotoxemia was induced by intravenous injection of lipopolysaccharide (LPS, 15 mg/kg BW). Splenic tissues were harvested and mRNA and protein were extracted. The protein expression of CD14 and TLR4, key mediators of LPS in the innate response, as well as alpha-2A adrenergic receptor (alpha(2A)-AR) and phosphodiesterase 4D (PDE4D), as the means by which the autonomic nervous system exerts its effects were analyzed. KEY FINDINGS:Splenic tissue concentrations of alpha(2A)-AR, PDE4D, CD14, and TLR4 were significantly increased in septic aged rats as compared to aged sham rats and septic young rats. The increased expression of alpha(2A)-AR in septic aged rats was further confirmed by immunohistochemical staining of splenic tissues. SIGNIFICANCE:These data support the hypothesis that not only is the innate immune response increased in aged animals during sepsis, but that there is also an upregulated response of the adrenergic autonomic nervous system that contributes to excess proinflammatory cytokine release.

journal_name

Life Sci

journal_title

Life sciences

authors

Leong J,Zhou M,Jacob A,Wang P

doi

10.1016/j.lfs.2010.03.009

subject

Has Abstract

pub_date

2010-05-08 00:00:00

pages

740-6

issue

19-20

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(10)00118-9

journal_volume

pub_type

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Aging-related hyperinflammation in endotoxemia is mediated by the alpha2A-adrenoceptor and CD14/TLR4 pathways.