The single injection of vascular endothelial growth factor receptor (VEGFr) antagonist SU5416 and chronic exposure to hypoxia in rats (SuHx) leads to severe pulmonary arterial hypertension (PAH). The aim of the study was to characterize the lung morphology in SuHx rats by noninvasive microscopic computed tomography (microCT).
The Wistar-Kyoto rats were injected subcutaneously with the VEGF-receptor inhibitor SU5416 (20 mg/kg body weight) and were then exposed to chronic hypoxia (10% oxygen) for 21 days (SuHx) followed by normoxia for an additional two weeks. Microscopic computed tomography (microCT), hemodynamics and heart hypertrophy were assessed 35 days after SU5416 or saline injection. Lung segmentation and quantitative analysis of the lung volume, CT density, functional residual capacity (FRC) were performed. Lungs airspace percentage, septal wall thickness and mean linear intercept (MLI) were assessed on H&E stained slides using uniform random sampling and alveolar morphometry software.
The combination of SU5416 and chronic exposure to hypoxic conditions resulted in severe PAH. The examination of 3D images obtained during in vivo microCT imaging of SuHx rats revealed decreased lungs CT density in rats with PAH in comparison with normoxic control (p=0.001). Moreover, FRC and air to tissue compartments volume ratio significantly increased in the SuHx animals in comparison with control rats (for both p=0.001), indicating presence of pulmonary emphysema in PH animals. All of these findings were validated by histological analysis of the lung tissues, demonstrating significantly greater mean linear intercept (MLI) and lung airspace values in the SU5416-treated rat lungs in comparison with normoxic control rats.
This is the first study demonstrating presence of pulmonary emphysema in rats subjected to SU5416 and hypoxia by high-resolution microCT