Abstract
Patients with risks of ischemic injury, e.g. during circulatory arrest in cardiac surgery, or after resuscitation are subjected to therapeutic hypothermia. For aortic surgery, the body is traditionally cooled down to 18 °C and then rewarmed to body temperature. The role of hypothermia and the subsequent rewarming process on leukocyte-endothelial interactions and expression of junctional-adhesion-molecules is not clarified yet. Thus, we investigated in an in-vitro model the influence of temperature modulation during activation and transendothelial migration of leukocytes through human endothelial cells. Additionally, we investigated the expression of JAMs in the rewarming phase. Exposure to low temperatures alone during transmigration scarcely affects leukocyte extravasation, whereas hypothermia during treatment and transendothelial migration improves leukocyte-endothelial interactions. Rewarming causes a significant up-regulation of transmigration with falling temperatures. JAM-A is significantly modulated during rewarming. Our data suggest that transendothelial migration of leukocytes is not only modulated by cell-activation itself. Activation temperatures and the rewarming process are essential. Continued hypothermia significantly inhibits transendothelial migration, whereas the rewarming process enhances transmigration strongly. The expression of JAMs, especially JAM-A, is strongly modulated during the rewarming process. Endothelial protection prior to warm reperfusion and mild hypothermic conditions reducing the difference between hypothermia and rewarming temperatures should be considered.
Highlights
This range of temperatures should protect for ischemic events, and decrease the systemic inflammatory response
We investigated the expression of JAM-A and JAM-B on endothelial cells after post-hypothermic rewarming to clarify their role in this process
Transmigration of activated peripheral blood leukocytes (PBL) through non-activated Human microvascular endothelial cells-1 (HuMEC-1) under hypothermic conditions shows no significant changes with falling temperatures, whereas significant changes are noticeable compared to the control-group at 30 °C (p = < 0.0001) and 18 °C (p = 0.0207)
Summary
This range of temperatures should protect for ischemic events, and decrease the systemic inflammatory response. The production of adhesion molecules is modified during hypothermia and results in a decreased expression of ICAM-114, E-Selectin[15], VCAM and ELAM16. Experimental studies have demonstrated that post-hypothermic rewarming increases the production of pro-inflammatory cytokines like IL-618 or IL-819 and leads to an up-regulation of adhesion molecules, e.g. ICAM-1, E-Selectin and VCAM-120. While hypothermia has a protective effect upon inflammation and endothelial modulation, post-hypothermic rewarming could move the immune response towards an activating effect. This pro-inflammatory effect is clinically relevant, as it triggers endothelial leakage and post-ischemic tissue infiltration through transendothelial migration (TEM) of leukocytes, which may result in disadvantages for patients subject to deep hypothermia and posterior rewarming. We investigated the expression of JAM-A and JAM-B on endothelial cells after post-hypothermic rewarming to clarify their role in this process
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