Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

Abstract

Cardiopulmonary bypass (CPB) with moderate hypothermic cardiac arrest (MHCA) is essential for prolonged complex procedures in cardiac surgery and is associated with postoperative complications. Although cytokine release provoked through MHCA under CPB plays a pivotal role in postoperative organ damage, the pathomechanisms are unclear. Here, we investigated the cytokine release pattern and histological organ damage after MHCA using a recently described mouse CPB model. Eight BALB/c mice underwent 60 minutes of circulatory arrest under CPB, were successively rewarmed and reperfused. Blood cytokine concentrations and liver and kidney function parameters were measured and histological changes to these organs were compared to control animals. Our results showed a marked increase in proinflammatory cytokines and histological changes in the kidney, lung, and liver after CPB. Furthermore, clinical chemistry showed signs of hemolysis and acute kidney injury. These results suggest early onset of solid organ injury which correlates with increased leukocyte infiltration. A better understanding of the interplay between pro-inflammatory cytokine activation and solid organ injury in this model of CBP with MHCA will inform strategies to reduce organ damage during cardiac surgeries in the clinic.

Shear stress associated with cardiopulmonary bypass induces expression of inflammatory cytokines and necroptosis in monocytes

“…We also found that activation of TLR signaling in myeloid cells was initially suppressed but later increased at 8h after surgery, agreeing with a previous report (21). Other major pathways activated by CPB were early cell proliferation, likely due to the margination of leukocytes and their precursors from bone marrow (22); post-CPB leukocyte migration as reported in the literature (15,16).…”

“…The mechanism of how systemic inflammation leads to organ damage is unclear. Evidence of CPB-activated leukocytes transmigrating and infiltrating into tissues is substantial in the literature (14)(15)(16) and our results further corroborate that CPB-activated THP-1 cells rapidly upregulated adhesion and migration markers after shear. ~24.7% of the sheared monocytes later differentiated into macrophages; and together with the live inflammatory monocytes, they secrete cytokines, chemokines, and other damaging soluble factors to the surrounding tissues.…”

“…One leading hypothesis is that CPB activates inflammatory leukocytes that then extravasate and infiltrate into different organs after CPB, causing organ dysfunction. CPB has been shown to induce leukocyte adhesion and transmigration in patients after surgery ( 14 ); the accumulation of leukocytes in various organs after surgery has also been confirmed in CPB animal models ( 15 , 16 ). The question then becomes how infiltrated leukocytes cause damage.…”

Four hours of veno-venous extracorporeal membrane oxygenation using bi-caval cannulation affects kidney function and induces moderate lung damage in a mouse model

“…Clinical chemistry was done using an Olympus analyzer (AU 400) according to the manufacturer's instructions to evaluate liver enzymes (glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT)) and kidney function (creatinine, urea) after vv-ECMO. All values were corrected for hemodilution as previously described [13]. Furthermore, to evaluate hemolysis during the experiment, lactate dehydrogenase (LDH) values were compared between the start of the experiment and after 4 hours.…”

“…Twomicrometer paraffin sections were stained with periodic acid-Schiff (PAS) to evaluate kidney and liver morphology. Assessment of acute kidney injury (AKI) and liver damage was done using a method previously described [13].…”