Bb. Chorinchath et al., AGE-ASSOCIATED DIFFERENCES IN TNF-ALPHA AND NITRIC-OXIDE PRODUCTION IN ENDOTOXIC MICE, The Journal of immunology, 156(4), 1996, pp. 1525-1530
Gram-negative bacterial infection is a common cause of septic shock in
the older population in the U.S. We employed an experimental model of
sepsis to study the cause of increased lethality due to LPS in older
animals. Three ages of male B6JC3J/Nia mice, young (2 mo old), mature
(12 mo old), and senescent (24 mo old), were treated with bacterial LP
S, and the older mice were found to be 10 times more sensitive to LPS
lethality. Increased sensitivity to LPS in senescent mice correlated w
ith significantly elevated plasma TNF-alpha and nitric oxide levels. A
bs to TNF-alpha afforded aged animals passive protection against a sup
ralethal dose of LPS, establishing a central role for TNF in the incre
ased sensitivity to LPS seen in the aged animals. Other cytokines, suc
h as IL-1 and IFN-gamma, appeared secondary to TNF and nitric oxide in
the age-associated sensitivity to LPS. Plasma corticosterone levels w
ere increased by LPS at a time when maximal levels of plasma TNF-alpha
were observed in both age groups, although the kinetics of hormone pr
oduction and the magnitude of TNF-alpha release varied among the age g
roups. Exogenously administered dexamethasone protected senescent anim
als given a high dose of LPS, by decreasing cytokine levels. The incre
ased sensitivity to LPS observed in aged animals, therefore, seems to
be due to excessive TNF and nitric oxide production, resulting from pe
rturbed endogenous hormonal control of cytokine production.