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Abstract 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 IL-1β. <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 and hepatotoxicity. <Moreover, the hypothesis that the gonadal hormonal state in male rats modulates the interaction of immunosuppressants with endotoxemia was also tested. 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). These 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. <These findings 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. <These findings implicate androgen and their receptors in the LPS/tacrolimus renal interaction. <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. <Either 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 responses. <7. The current study produces a number of novel and clinically relevant findings. < 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 current research. <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. |