Activation of angiotensin-converting enzyme 2 (ACE2) modulates lung mechanics in a brain death model and attenuates pulmonary edema after rat lung transplantation
Paolo Melo1, Natalia Nepomuceno1, Liliane Ruiz1, Vanessa Vilela1, Giovana Manzuti1, Karina Andrighetti 1, Emanuel Kennedy2, Marcelo Cypel3, Paulo Pêgo1.
1Laboratorio de pesquisa em cirurgia toracica, Instituto do Coração do Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, SP, BR, São Paulo, Brazil; 2Departamento de Ciencias da Saude, Universidade Federal Rural do Semi-Arido, Mossoro, Brazil; 3Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Canada
Toronto Lung Transplant Program. Programa de Pos Graduacao em Cirurgia Toracica e Cardiovascular - FMUSP.
Introduction: Lung transplantation is a therapeutic option established worldwide for end-stage lung diseases. However, as most donors evolve with brain death (BD), the donated lung may have been compromised. In view of the participation of the renin angiotensin system (RAS) and the use of angiotensin-converting enzyme 2 (ACE2) activators in several pathological processes, it was investigated how diminazene aceturate (DIZE), an ACE2 activator, modulates hemodynamic and blood gas changes, as well as lung function following transplantation in rats.
Method: Male Lewis rats were randomly distributed in the following experimental groups: intact, brain death (BD) and BD + diminazene aceturate (BD+DIZE). The last two groups were submitted to brain death process, treated with saline (0.9%) or DIZE (15 mg/kg-1) and kept on mechanical ventilation for 6 hours (donor). After this period, cardiopulmonary block extraction and left unilateral transplantation (LTx) with independent graft ventilation was performed, followed by 2h reperfusion. Hemodynamics (mean arterial pressure - MAP), blood gas analysis, lung mechanics, and pulmonary edema were evaluated. Results are presented as S.E.M. (ANOVA; Tukey; p<0.05). (Approval # CEUA/FMUSP - 1630/2021).
Results: The administration of DIZE, 3 hours after BD, prevented the increase in the MAP (210’ after BD-induction: BD – 110 ± 12 mmHg; n=5; BD+DIZE – 40 ± 12 mmHg; n=4 / p=0.0001) without associated blood gas and metabolic alterations. Changes in lung mechanics, such as decreased tissue damping (G) and histeresivity (n) followed by increased respiratory system compliance (Crs), were associated with BD+DIZE (G - 0,25 ± 0,03 cmH2O/mL; Crs - 0,71 ± 0,03 mL/cmH2O; n – 0,14 ± 0,008) compared to intact (G - 0,40 ± 0,02 cmH2O/mL, p = 0.01; Crs – 0,64 ± 0,01 mL/cmH2O, p = 0.02; n - 0,26 ± 0,01, p = 0.004) and BD groups (G – 0,41± 0,05 cmH2O/mL, p = 0.02; Crs – 0,61 ± 0,01 mL/cmH2O, p = 0.01; n - 0,25 ± 0,008, p = 0.01) (Figure 1). After LTx, MAP, gas exchange function, and lung mechanical parameters, were not different among the 3 groups (p>0.05). On the other hand, the DIZE treatment was capable to reduce wet-to-dry weight ratio (INTACT – 1,87 ± 0,13; BD – 2,59 ± 0,14; BD+DIZE – 1,93 ± 0,15 / p=0.01) (Figure 2).
Conclusion: Our data suggests that activation of ACE2 is able to modulate donor hemodynamic and lung mechanical parameters, probably reducing tissue resistance and improving airflow in the peripheral airways, converging to a decrease in ventilation heterogeneity in the sudden onset model of brain death. Our data also indicates that DIZE attenuates pulmonary edema on grafts from BD donors after lung transplantation.
Keywords: Diminazene aceturate. Renin-angiotensin system. Brain death. Lung mechanics. Lung transplantation.
CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico.
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