Organ-protective effects on the liver and kidney by minocycline in small piglets undergoing cardiopulonary bypass

Abstract

Cardiopulmonary bypass (CPB) often is required for the operative correction of congenital heart defects in small infants. Unfortunately, CPB is associated with injury of inner organs such as the brain, kidney, lung, and liver. Renal failure and increase in liver enzymes are typical side effects observed after CPB. Here, we investigate whether organ protection of the kidney and liver can be achieved with the application of minocycline, which is known-besides its anti-infective effects-to act as a poly-ADP-ribose-polymerase inhibitor. Twenty-nine 4-week-old Angler Sattelschwein-piglets (8-15 kg) were divided into four groups: control group (n = 8), CPB group (n = 9), minocycline-control group (n = 6), and the minocycline-CPB group (n = 6). CPB groups were thoracotomized and underwent CPB for 120 min (cross-clamp, 90 min; reperfusion, 30 min) followed by a 90-min recovery time. The control groups also were thoracotomized but not connected to CPB. The minocycline group received 4 mg/kg minocycline before and 2 mg/kg after CPB. In the kidneys, CPB histologically resulted in widening of Bowman's capsule, and-mainly in tubules-formation of poly-ADP-ribose, nitrosylation of tyrosine-residues, nuclear translocation of hypoxia-induced factor HIF-1α, and of apoptosis-inducing factor (AIF). In addition, we found significantly less ATP in the kidney and significantly increased plasma urea and creatinine. Similar but gradually attenuated changes were found in the liver together with significantly elevated de-Ritis coefficient. These changes in the kidney and liver were significantly diminished by minocycline (except AIF in the liver which was similar in all groups). In conclusion, CPB causes damage in the kidney and-to a lower degree-in the liver, which can be attenuated by minocycline.

Strategies for Pharmacological Organoprotection during Extracorporeal Circulation Targeting Ischemia-Reperfusion Injury

“…The same effect could be shown in liver, where minocycline significantly decreased hepatic TNFα and IL-1β expression and improved liver function (Li et al, 2015 ). The PARP-inhibitory effect of minocycline and its positive influence on cell apoptosis were also revealed in other studies and by our working group: piglets subjected to cardio-pulmonary bypass showed less organ dysfunction (hippocampus, liver, kidney) when minocycline was administered before bypass and during reperfusion (Tao et al, 2010 ; Dhein et al, 2015 ; Salameh et al, 2015 ).…”

Effects of minocycline on parameters of cardiovascular recovery after cardioplegic arrest in a rabbit Langendorff heart model

“…Specifically, AIF was significantly inhibited by minocycline in left ventricular endocardium. Similar effects of minocycline have been described for hippocampus tissue in a mouse model of experimental epilepsy and by the authors in a study on liver and kidneys of piglets undergoing cardio‐pulmonary bypass …”

“…Other studies have concluded that minocycline has positive effects on liver and kidney function during cardio-pulmonary bypass while in a model of myocardial infarction in diabetic rats this drug reduced infarct size in diabetic rats. 26,27 These results also suggest that under the stress of ischemia and reperfusion minocycline is able to protect vulnerable tissues.…”

“…Similar effects of minocycline have been described for hippocampus tissue in a mouse model of experimental epilepsy and by the authors in a study on liver and kidneys of piglets undergoing cardio-pulmonary bypass. 26,28 In both studies minocycline reduced mitochondrial AIF translocation.…”

Resolvin D1 mitigates energy metabolism disorder after ischemia–reperfusion of the rat lung

“…Extracorporeal circulation can cause damage to the internal organs, such as brain, kidney, lung, and liver. Dhein et al [ 42 ] revealed that extracorporeal circulation decreased the ATP content in kidney and liver, but minocycline could significantly increase the ATP level in organs and reduce the injuries of kidney and liver. The Na + –K + -ATPase, a kind of protease, is located in the membranes of the cells and organelles functioning in substance transport, energy conversion, information transmission, cell membrane integrity maintenance and tissue metabolism.…”