Experimental Models of Ischemic Lung Damage for the Study of Therapeutic Reconditioning During Ex Vivo Lung Perfusion

BACKGROUND. Ex vivo lung perfusion (EVLP) may allow therapeutic reconditioning of damaged lung grafts before transplantation. This study aimed to develop relevant rat models of lung damage to study EVLP therapeutic reconditioning for possible translational applications. METHODS. Lungs from 31 rats were exposed to cold ischemia (CI) or warm ischemia (WI), inflated at various oxygen fractions (FiO(2)), followed by 3 h EVLP. Five groups were studied as follow: (1) C21 (control): 3 h CI (FiO(2) 0.21); (2) C50: 3 h CI (FiO(2) 0.5); (3) W21: 1 h WI, followed by 2 h CI (FiO(2) 0.21); (4) W50: 1 h WI, followed by 2 h CI (FiO(2) 0.5); and (5) W2h: 2 h WI, followed by 1 h CI (FiO(2) 0.21). Following 3 h EVLP, we measured static pulmonary compliance (SPC), pulmonary vascular resistance, lung weight gain (edema), oxygenation capacity (differential partial pressure of oxygen), and protein carbonyls in lung tissue (oxidative stress), as well as lactate dehydrogenase (LDH, lung injury), nitrotyrosine (nitro-oxidative stress), interleukin-6 (IL-6, inflammation), and proteins (permeability edema) in bronchoalveolar lavage (BAL). Perivascular edema was quantified by histology. RESULTS. No significant alterations were noted in C21 and C50 groups. W21 and W50 groups had reduced SPC and disclosed increased weight gain, BAL proteins, nitrotyrosine, and LDH. These changes were more severe in the W50 group, which also displayed greater oxidative stress. In contrast, both W21 and W50 showed comparable perivascular edema and BAL IL-6. In comparison with the other WI groups, W2h showed major weight gain, perivascular edema, SPC reduction, drop of differential partial pressure of oxygen, and massive increases of BAL LDH and proteins but comparable increase of IL-6 and biomarkers of oxidative stress. CONCLUSIONS. These models of lung damage of increasing severity might be helpful to evaluate new strategies for EVLP therapeutic reconditioning. A model combining 1 h WI and inflation at FiO(2) of 0.5 seems best suited for this purpose by reproducing major alterations of clinical lung ischemia-reperfusion injury.