The Ex-Vivo Isolated, Perfused Human Lung Model: Description and Potential Applications

Abstract

An ex-vivo isolated, perfused, and ventilated human lung (IPHL) model is well suited for many kinds of physiological, pharmacological, and surgical studies, when the physiological and biochemical conditions in the lung can be maintained near to those in vivo. The aim of this work was to develop such a model. The lung preparations used were available after resection because of bronchial carcinoma. Since the tumor remains intact in these anatomical preparations, this model is particularly suitable for investigation of the pharmacokinetics and effects of anticancer agents. Carrying out a series of 52 IPHL experiments (with 11 whole-lung preparations and 41 lobe preparations), we have established an IPHL model which allows extracorporeal perfusion and ventilation of the resected lungs in physiological conditions for 2-3 hours. The net weight gain during the experiment, wet-to-dry weight ratio for lung tissue, angiography of the pulmonary artery, pulmonary vascular resistance, color and fluorescence of the lung surface, and alveolar gas diffusion into the perfusate proved to be useful parameters to assess the stability of the preparations and the quality of the experiments. To confirm that an intraparenchymal tumor was perfused via the pulmonary artery, methods to detect avidin and dextran-biotin in tumor tissue after administration into the perfusion solution were employed. Histological examination of bronchial as well as tumor tissue, a computerized histoanalyzation, and a tumor grading program demonstrated that IPHL experiments did not interfere with the grading and staging of the tumors-an important ethical precondition for the use of human preparations in an extracorporeal perfusion model.

Dose Optimization of a Doxorubicin Prodrug (HMR 1826) in Isolated Perfused Human Lungs: Low Tumor pH Promotes Prodrug Activation by β-Glucuronidase

“…The mean (ϮS.D., n) net weight gain due to the formation of edema during isolated lung perfusion was 22% (Ϯ16.8%, n ϭ 22) with no differences between subgroups. Net weight gain did not exceed 66%, which was the predefined acceptance criterion (Linder et al, 1996). Histological examinations of the samples did not reveal any damage of the endothelial cells.…”

“…All samples included fulfilled the previously outlined evaluation criteria for the stability of the lung preparations during perfusion and the quality of the perfusion experiments (Linder et al, 1996). The mean (ϮS.D., n) net weight gain due to the formation of edema during isolated lung perfusion was 22% (Ϯ16.8%, n ϭ 22) with no differences between subgroups.…”

“…The lobe preparations were perfused ex vivo for 150 min as described previously (Linder et al, 1996;Mü rdter et al, 1997). In brief, immediately after lung resection, the arteries were cannulated and the bronchus was connected to a bronchial tube.…”

“…To facilitate prediction of the optimal dose of HMR 1826 in treatment of lung carcinoma, we investigated the effect of circulating HMR 1826 prodrug concentration on the intratumoral concentrations of active doxorubicin using the isolated perfused human lung model (Linder et al, 1996). In addition, we carried out tissue pH measurements and enzyme kinetic in vitro experiments to investigate the relationship between tissue pH and the ␤-glucuronidase-mediated activation of HMR 1826.…”

“…Because, in contrast to cyclophosphamide, bioactivation of HMR 1826 takes place in the tumor, pharmacokinetic studies aimed at dose optimization of HMR 1826 should be based on characterization of its intratumoral pharmacokinetics. Inasmuch as it is exceedingly difficult to measure intratumoral concentrations of drugs in vivo, we used the isolated human lung perfusion model (Linder et al, 1996) to characterize the tissue pharmacokinetics of HMR 1826 at different circulating concentrations of HMR 1826.…”