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Endotoxic shock is associated with major complications such as renal cardiovascular and hepatic abnormalities, which contribute to the high morbidity and mortality rates.
These devastating actions of endotoxemia have been linked to the excessive generation of pro-inflammatory cytokines such as TNF-α, IL-6, and
<Recent reports have shown that some immunosuppressants like
cyclosporine protect against inflammatory and cardiovascular derangements
evoked by endotoxemia.
<The main objectives of the present study were to investigate whether calcineurin-dependent (cyclosporine and tacrolimus) and -
independent(sirolimus) immunosuppressants interact differently with end organ
damage associated with the endotoxic insult such as nephrotoxicity, cardiotoxicity
<Moreover, the hypothesis that the gonadal hormonal state in
male rats modulates the interaction of immunosuppressants with endotoxemia was
Accordingly, pharmacologic, biochemical, histopathologic, and protein
expression studies were employed to determine the individual and combined
effects of LPS and immunosuppressants on renal, hepatic, and cardiac profiles.
<The possible modulatory effects of androgen on the evoked responses were
assessed by determining the influences of bilateral castration or androgen receptor
blockade by flutamide on these interactions.
<A summary of novel findings and
conclusions of the study is outlined below.
<1. The 6-hr treatment of rats with LPS triggered a clear inflammatory
response as denoted by ELISA determinations (elevations of serum TNFα
and MPO) and Western blotting studies (increased protein expressions of
renal TLR-4, MCP-1 and NOX-2).
<2. Histopathological studies demonstrated that the inflammatory response to
endotoxemia was accompanied by signs of nephrotoxicity (dilated
proximal & distal tubules, extensive cytoplasmic vacuolation and hydropic
swelling) and hepatotoxicity (lytic necrosis, vascular congestion, venous
thrombosis, Kupffer cell hyperplasia, and parenchymal neutrophils).
end organ damages were confirmed by elevations in serum biomarkers of
kidney (BUN and creatininie) and liver function (sGOT and sGPT).
By contrast, no functional (serum CPK) or histopathological evidence of
cardiotoxicity was manifest in endotoxic rats.
3. The effects of immunosuppressants on LPS toxicity varied and depended
on the particular type of immunosuppressant drug and type of end organ.
<Functional and histopathological manifestations of LPS nephrotoxicity
were abrogated by sirolimus and intensified by cyclosporine or tacrolimus.
<A similar pattern was observed with the LPS-induced increases in renal
protein expressions of inflammatory (TLR-4 and MCP-) and oxidative
(NOX-2), which were eliminated by sirolimus and potentiated after
calcineurin inhibition by cyclosporine.
<This is further confirmed by the
observation that substantially higher rises in serum levels of TNFα and
MPO were observed in LPS/tacrolimus-treated rats.
highlight an important role for calcineurin inhibition in the cyclosporine or
tacrolimus exacerbation of LPS inflammation and nephrotoxicity.
4. Testosterone bioavailability is
essential for the elicitation of the
exaggerated nephrotoxicity caused by tacrolimus in endotoxic rats.
<Potentiated functional and histopathological, and inflammatory (serum
TNFα and MPO) signs of nephrotoxicity in tacrolimus-treated endotoxic
rats disappeared in castrated rats or in flutamide-treated intact rats.
findings implicate androgen and their receptors in the LPS/tacrolimus
<5. Unlike nephrotoxicity, the presumed advantageous effect of calcineurin
inhibition against toxic manifestations of LPS was not demonstrated in
case of LPS hepatotoxicity.
Indeed, the significant increases in serum
sGOT and sGPT and hepatic histopathological damage caused by LPS
were diminished in rats pretreated with cyclosporine or sirolimus, but
were maintained or even worsened in presence of tacrolimus.<This
discrepancy implies that tacrolimus might interact with cellular processes
other than calcineurin to potentiate LPS hepatotoxicity.
<6. The utilization of bilateral castration or androgen receptor blockade by
flutamide suggests crucial roles for androgenic hormones and receptors in
the hepatic responses to LPS and its interaction with tacrolimus.
maneuver reduced the rises in serum levels of sGOT and sGPT and
concomitant structural damage in hepatic tissues caused by LPS or its
combination with tacrolimus.
<Notably, some of the responses to these
insults especially the histopathological damages largely remained in
castrated or flutamide-treated preparations, which possibly indicate the
involvement of non-androgenic pathways in the elicitation of these
<7. The current study produces a number of novel and clinically relevant
< Among all three immunosuppressants, sirolimus appeared to the
most advantageous because it greatly compromised both nephrotoxic and
hepatotoxic manifestations of endotoxemia.
<Moreover, strategies that
reduce testosterone availability or cause androgen receptor hyporeactivity
might help in offsetting the end organ damage caused by endotoxemia.
<Three abstracts have been prepared from the data collected from the
<As shown below, these abstracts have been submitted and accepted for presentation in the Experimental Biology meeting that will be held
this year in San Diego, USA (April 4-7, EB2020).
Remarkably, based on an
official invitation from the American Society for Pharmacology and Experimental
Therapeutics (ASPET), the first abstract will be presented orally as a part of
ASPET Daily Datablitz.