Abstract
Ex vivo lung perfusion (EVLP) has been implemented to increase the number of donor lungs available for transplantation. The use of K(ATP) channel modulators during EVLP experiments may protect against lung ischemia-reperfusion injury and may inhibit the formation of reactive oxygen species. In a rat model of donation after circulatory death with 2 h warm ischemic time, we evaluated rat lungs for a 4-hour time in EVLP containing either mitochondrial-specific or plasma membrane and/or sarcolemmal-specific forms of K(ATP) channel modulators. Lung physiological data were recorded, and metabolic parameters were assessed. When compared to the control group, in the EVLP performed with diazoxide or 5-hydroxydecanoic acid (5-HD) we recorded significantly lower pulmonary vascular resistance and only in the diazoxide group recorded significant lung weight loss. In the perfusate of the 5-HD group, interleukin-1β and interleukin-1α were significantly lower when compared to the control group. Perfusate levels of calcium ions were significantly higher in both 5-HD and cromakalim groups, whereas the levels of calcium, potassium, chlorine and lactate were reduced in the diazoxide group, although not significantly when compared to the control. The use of a diazoxide mitochondrial-specific K(ATP) channel opener during EVLP improved lung physiological and metabolic parameters and reduced edema.
Highlights
Lung transplantation is the accepted treatment option for patients in endstage lung disease who are failing maximal medical therapy
As a starting point before applying a defined pharmacological concentration of K(ATP) channel modulators to the lung tissues during ex vivo lung perfusion (EVLP) experiments, we searched the literature for different K(ATP) channel modulators and their previously nontoxic concentration used in vivo and in vitro
We sought to inhibit the membrane hyperpolarization during reperfusion using a variety of K(ATP) channel modulators and designed our experiments with the blockers used as a control for the experiment performed with openers and selected modulators directed against either the mitochondrial-specific K(ATP) channels (DZ as an opener and 5-hydroxydecanoic acid (5-HD) as a blocker) or the plasma membrane and/or sarcolemmal-specific forms of the K(ATP) channel (CK as an opener and GL as a blocker)
Summary
Lung transplantation is the accepted treatment option for patients in endstage lung disease who are failing maximal medical therapy. It has been hypothesized that, after stopping the flow in the lung endothelium and during the graft preservation cold ischemic time, mechanosignaling cascades initiate an inhibiting response of the sodium Na+-K+ ATPase and various K+ channels. This biochemical cascade leads to Na+ influx with persistent cell membrane depolarization due to a decrease in intracellular K+ [10,11], and leads to an increase in reactive oxygen species (ROS) in the mitochondria [12] and to enhanced activity of ROS-producing enzymes [13]. Caspase-1 drives the processing of pro-IL-1β to IL-1β as well as that of pro-IL-18 to IL-18, with both of these cytokines being able to activate IL-6 and other pro-inflammatory cytokines [14,15]
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