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Shock. 2002 Oct;18(4):348-54. doi: 10.1097/00024382-200210000-00010.

Age-associated loss of immunomodulatory protection by granulocyte-colony stimulating factor in endotoxic rats.

Shock (Augusta, Ga.)

Brigitte Vollmar, Sascha Pradarutti, Ruth M Nickels, Michael D Menger

Affiliations

  1. Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany.

PMID: 12392279 DOI: 10.1097/00024382-200210000-00010

Abstract

Elderly patients have a higher incidence of morbidity and mortality due to infectious diseases. Because most immune functions in the elderly differ compared with those in younger subjects, we studied the effect of the immunomodulating agent G-CSF on endotoxic liver injury and cytokine release in an aging animal model of acute sepsis. Young (3-month-old), mature (12-month-old), and senescent (24-month-old) male Sprague-Dawley rats (n = 6 each) were treated with bacterial endotoxin for 6 h. Age-matched groups of animals (n = 6 each) received G-CSF (200 microg/kg i.v.) 1 h prior to endotoxin. LPS-induced hepatic toxicity, as assessed in vivo by nutritive perfusion failure, intravascular leukocyte accumulation, biliary excretion dysfunction, and liver enzyme release, was significantly more pronounced in mature and old animals when compared with young animals. Concomitantly, mature but, in particular, senescent endotoxic animals exhibited 2- to 14-fold higher plasma levels of TNF-alpha, IL-1beta, IL-6, IL-10, and Rantes than young endotoxic rats. The percentage of G-CSF receptor surface expression on neutrophils did not significantly differ between young, mature, and senescent animals (36%-46%) and was found comparably down-regulated at 6 h after LPS exposure (15%-19%). Kupffer cell activation, i.e., clearance of intravascularly applied fluorescent latex beads, did not differ between the LPS-exposed age groups. G-CSF dampened LPS-induced Kupffer cell activation, and significantly reduced plasma cytokine levels in young and mature, but not in senescent animals. Thereby, G-CSF caused attenuation of hepatic tissue injury in all except the senescent endotoxic animals. In summary, our results show an age-dependent increase in hepatic LPS toxicity. Because flow cytometric analysis of G-CSF receptor expression disproved that cytokinemia-induced down-regulation of G-CSF receptors might account for the unresponsiveness to G-CSF in the senescent animals, other homeostatic regulatory mechanisms appear to undergo changes with age that bring out a disrupted balance between inflammatory cytokines with unresponsiveness to G-CSF and, thus, compromised host defense mechanisms in the elderly.

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