HSP90 Inhibitor Improves Lung Protection in Porcine Model of Donation after Circulatory Arrest

Ann Thorac Surg. 2020 Jul 8;S0003-4975(20)31111-5. doi: 10.1016/j.athoracsur.2020.05.079. Online ahead of print.

Abstract

Background: Ischemia-reperfusion associated with prolonged warm ischemia during donation after circulatory death (DCD) induces acute lung injury. The objective was to combine ex-vivo lung perfusion (EVLP) and a heat shock protein-90 inhibitor (HSP90i) to recondition DCD organs and prevent primary graft dysfunction.

Methods: Pigs (55-65 kg) were anesthetized, ventilated, and hemodynamically monitored. Cardiac arrest was induced with KCl, and animals were left non-ventilated for two hours. Lungs were procured and perfused in an EVLP platform for four hours using a cellular perfusate. In the study group, the perfusate contained HSP90i and its transport vehicle (N=4). In the control group, the perfusate contained only the transport vehicle (N=4). Gas exchange, airway pressures, and compliance were measured. Pulmonary edema was assessed by bronchoscopy and weight measurement. Lung biopsies were obtained for histological analyses and protein expression measurements.

Results: The use of HSP90i reduced lung weight gain to 8.4±3.4% versus 26.6±6.2% in the control group (p<0.05). There was reduced edema formation. The PaO2/FiO2 ratio at the end of EVLP was 423±65 in the study group versus 339±25 mmHg in the control group, but this difference was not statistically significant. Lactate metabolism, pulmonary vascular resistance, and pulmonary arterial pressure improved during EVLP with the use of the HSP90i.

Conclusions: The use of HSP90i with EVLP improves the lung reconditioning process. Further research is required to confirm if these findings translate to benefit once transplanted and observed in-vivo. Successful pharmacological inhibitors may expand the donor pool in the context of DCD donors.