Decreased lung ischemia-reperfusion injury in rats after preoperative administration of cyclosporine and tacrolimus

Abstract

Cyclosporine and tacrolimus treatment before reperfusion was protective against lung ischemia-reperfusion injury in rats. The mechanism of these protective effects may involve the inhibition of nuclear factor kappaB, a central transcription factor mediating inflammatory injury. The decreased expression of cytokine messenger RNA indicates that both cyclosporine and tacrolimus may exert their protective effects at the pretranscriptional level.

Effects of tacrolimus on ischemia-reperfusion injury

“…Therefore, the demonstrated ability of tacrolimus to suppress cytokine release and adhesion molecule expression results in reduction of PMN infiltration and activation. 48,67,74 As such, tacrolimus pretreatment has reduced PMN infiltration into tissues exposed to I-R in small-bowel and liver models. 94,95 Beyond interrupting PMN activation by suppressing communication molecules, tacrolimus appears to show inhibitory actions specific to the PMN.…”

“…85 In parallel, tacrolimus has been documented to block early activation of NF-B. 65,74,75 In a rat lung model of I-R injury, NF-B inactivation by low-dose tacrolimus (0.2 mg/kg) resulted in reduction in IL-1, IL-2, IL-3, IL-5, TNF-␣, and IFN-␥ levels, resulting in improved endothelial continuity, suppressed inflammation on reperfusion, and reduced tissue damage from I-R insults. 74 Unfortunately, an implication of NF-B inactivation accounting entirely for the tacrolimus effect on acute inflammation would be gross oversimplification.…”

“…107 Although not specifically studied, this mechanism is a possible means for tacrolimus to inhibit apoptosis, being a well-documented inhibitor of TNF-␣. 44,[71][72][73][74] Inhibition of calcineurin-mediated dephosphorylation of NOS causes decreased NOS activity. 107 Recent studies in a cancer model have shown inducible NOS activity to correlate directly with apoptosis.…”

“…This ubiquitous transcription factor mediates early gene expression of cytokines, chemokines, growth factors, immunoreceptors, and cell adhesion molecules during I-R injury. 65,[74][75][76][77][78][79][80][81][82][83][84] Selective blockade of NF-B with proline dithiocarbamate during the early phase of reperfusion resulted in remarkable tissue protection after severe ischemic stress. 85 In parallel, tacrolimus has been documented to block early activation of NF-B.…”

Pulmonary Transplantation and Ischemia-Reperfusion Injury

“…Thus, a decrease in NF-κB activity, due to prevention of IκB degradation by pharmacological agents, leads to the attenuation of pro-inflammatory cytokine activation thereby leading to protection after lung IR. Inhibition of NF-κB via pharmacological agents like cyclosporine A or tacrolimus has been shown to offer protection from lung IR injury (Krishnadasan, et al, 2002). Treatment with pyrrolidine dithiocarbonate (another NF-κB inhibitor) has also been shown to improve lung function and attenuate lung IR injury in a porcine lung transplantation model (Ross, et al, 2000).…”