Physiological, Radiological and Morphological Characterization of Large Animal Pulmonary Ischemia-Reperfusion Injury

Abstract

<h3>Purpose</h3> Large animal models are essential to study ischemia-reperfusion injury (IRI) in lung transplantation (LTx). Despite a long history of animal models, clinically relevant injury markers are not well described. Also, the manifestation of lung IRI with different sets of parameters has not been investigated thoroughly. Therefore, we aimed to develop and describe a porcine pulmonary IRI model at a physiological, radiological and morphological level. <h3>Methods</h3> In a clamping group [CLA] the left lung (LL) of a domestic pig was clamped (3h) and reperfused (3h) in situ (n=9). During the last hour of reperfusion, contralateral right lung (RL) was clamped to force the entire pulmonary flow to the injured LL. This reflects an intra-operative step in sequential single LTx after reperfusion of the first lung. In a control group [CON] the animals were fully instrumented (n=6). Lung injury was assessed by continuous monitoring of lung compliance and intermittent calculation of Pa/FiO₂ ratio. After the experiments, wet to dry (W/D) ratio was calculated and an ex vivo lung computed tomography (CT) scan as well as histological assessment were performed. Data was analyzed in time using 2-way ANOVA test or student T-test. <h3>Results</h3> A reproducible injury pattern in [CLA] compared to [CON] was noticed. Physiological assessment showed decline in lung function (<i>Fig 1; A,B</i>). Severe LL injury in [CLA] was reflected by increase in W/D ratio, CT measured density (<i>Fig 1; C,D,G,H)</i> and translated into morphological assessment (<i>Fig 1; E,F).</i> <h3>Conclusion</h3> We report a unique model of porcine lung IRI with meticulous description of physiological, radiological and morphological parameters. We demonstrated that injury is consistent at all the levels of assessment, reflecting the clinical syndrome and definition of primary graft dysfunction (PGD) after LTx. This model allows to investigate PGD at a true pre-clinical level with the potential to translate treatment strategies rapidly into clinical practice.