Abstract
Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling within the lung. Clinical computed tomography (CT) scans are routinely used to aid in PAH diagnosis. Animal models, including the Sugen-hypoxic rat model (SU/hyp), of PAH closely mimic human PAH development. We have previously used micro-computed tomography (microCT) to find extensive right lung vascular remodeling in the SU/hyp. We hypothesized that the individual right lung lobes may not contribute equally to overall lung vascular remodeling. Sprague-Dawley rats were subjected to a subcutaneous injection of vascular endothelial growth factor receptor blocker (Sugen 5416) and subsequently exposed to chronic hypoxic conditions (10% O2) for three weeks. Following perfusion of the lung vasculature with an opaque resin (Microfil), the right lung lobes were microCT-imaged with a 10-µm voxel resolution and 3D morphometry analysis was performed separately on each lobe. As expected, we found a significantly lower ratio of vascular volume to total lobe volume in the SU/hyp compared with the control, but only in the distal lobes (inferior: 0.23 [0.21–0.30] versus 0.35 [0.27–0.43], P = 0.02; accessory: 0.27 [0.25–0.33] versus 0.37 [0.29–0.43], P = 0.06). Overall, we observed significantly fewer continuous blood vessels and reduced vascular density while having greater vascular lumen diameters in the distal lobes of both groups (P < 0.05). In addition, the vascular separation within the SU/hyp lobes and the vascular surface area to volume ratio were significantly greater in the SU/hyp lobes compared with controls (P < 0.03). Results for the examined parameters support the overall extensive vascular remodeling in the SU/hyp model and suggest this may be lobe-dependent.
Highlights
Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling within the lung
The distal lobes influence the ratio of vascular volume to tissue volume The ratio of lobe-specific vascular volume to lobe-specific lung tissue volume between groups revealed no differences between the control and SU/hyp lobes 1 and 2, but a significantly greater ratio for control lobe 3 and the same trend for lobe 4 when compared with the SU/hyp lobes (P 1⁄4 0.02 and 0.06, respectively)
No significant differences were found between lobes within each treatment group (Fig. 2a), which would indicate that the vascular volume of each lobe within the respective treatment group is being affected
Summary
Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling within the lung. Clinical CT measures have been used to show differences in lung vascular volumes and patterns in smokers,[1] those with emphysema,[2] and chronic obstructive pulmonary disease (COPD).[3] More recently, clinical CT scans were evaluated to quantify morphological biomarkers for diagnostic, phenotyping, and prognostic purposes in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH). Several animal models of PAH exist; the Sugen-hypoxic (SU/hyp) rat model develops human-like plexiform lesions, which do not revert back to normal upon removal from hypoxic conditions.[5] We have previously found evidence of extensive right lung vascular remodeling in the late stage SU/hyp rat model using micro-computed tomography (microCT).[6] As a follow-up of this work, we hypothesized that individual lung lobes (1 1⁄4 superior, 2 1⁄4 middle, 3 1⁄4 inferior, or 4 1⁄4 accessory) may not contribute to overall lung vasculature differences observed in the SU/hyp model of PAH
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