The Interleukin 4 Receptor-α Potentiates the Effect of Oncostatin M Receptor on the Release of FGF23 by Cardiomyocytes

Abstract

are combined, there are concerns regarding delays to institution of liver cold preservation. The aim of this study was to develop a combined DCD heart and liver retrieval protocol in a pig model with subsequent normothermic machine perfusion (NMP) of both organs to mitigate warm ischemic damage. Methods: Pigs (n= 12; 60-70 kg) were anesthetised. Baseline observations were recorded. After sternotomy, and laparotomy, ventilatory support was withdrawn to mimic DCD conditions. Death was defined as equalisation of central venous and mean arterial pressures. After a 5-minute standoff period, 1.5-2 L blood was collected from a right atrial cannula then a cardiac preservation flush (4°C) commenced via the proximal ascending aorta. The inferior vena cava was cut to vent the organs. The thoracic cavity was kept cold with saline ice slush. The heart was explanted and prepared on back-table for NMP. Liver preservation was begun immediately after blood collection by cold preservation solution flush via the infra-renal aorta and portal vein. The hepatic artery, portal vein and common bile duct were transected, and the liver explanted for back-table NMP preparation. Results: Warm ischaemic time (WIT) and back-table time (BTT) was 21 + 5 and 29 + 6 min for the heart; 20 + 6 (commencement of flush) and 33 + 19 min for the liver. The average blood volume collected was 1.6 L: 1:1 dilution with Krebs resulted in significant hemodilution (from 23 + 5% to 15 + 6%) and hypocalcemia (1.30 + 0.15 to 0.64 + 0.32 mM). This resulted in sub-optimal cardiac contractile recovery despite a favourable lactate profile. Liver enzyme release, bile production, and lactate and pH profiles were favourable during the first 4-6 hours of NMP but deteriorated thereafter. Conclusion: Heart and liver retrieval under standard DCD protocol is possible without excessively extending the WIT for either organ. However, there is insufficient donor blood to support NMP of both organs.

The Role of Oncostatin M and Its Receptor Complexes in Cardiomyocyte Protection, Regeneration, and Failure

“…Similar properties of OSM apply to IGF-1-treated cardiomyocytes [10]. Furthermore, integration of IL-4 receptor signals-which cause only minor changes in FGF23 secretionstrongly potentiate FGF23 release [110]. Another important feature of OSM is its ability to affect the myocardial environment by inducing the strong production and release of potent extracellular proteins (Table 1) such as TIMP-1, interleukin-6, and the regenerating islet-derived proteins (Reg1 and Reg3 chemokines) [9,11].…”

“…Moreover, OSMR signaling is likely to be even more complex, as it has been demonstrated that not only does the use of other activated receptors lead to the amplification of OSM signals but also that the OSMR is directly involved in unrelated receptor signaling cascades. In OSM-treated cardiomyocyte cultures, activation of the interleukin-4 receptor (IL-4R) strongly enhanced the release of FGF23, whereas the IL-4 receptor ligands IL-4 and IL-13 themselves did not trigger secretion [110]. FGF23 was initially identified as an endocrine hormone affecting mineral metabolism and decreasing phosphate reabsorption in the kidneys, but recent studies demonstrated its association with cardiac diseases [11,17].…”