Characterization of an elastase-induced emphysema model in immune-deficient rats.

Abstract

Emphysema affects millions of patients worldwide. Cell transplantation and tissue engineering are promising approaches for the regeneration of gas exchange tissue in vivo. A reproducible and resource-efficient animal model with relevant pathological and physiological features is critical to assess efficacy of novel therapies. Here, we share a method for rapid development of emphysema in an adaptive immune-deficient rat with <5% mortality, which is ideal for high-throughput human cell-based experimentation. Porcine pancreatic elastase (PPE) was intratracheally administered to male RNU rats. Rats were monitored for 21 days after which subjects underwent lung computed tomography (CT) scans. Rats were then weighed, intubated and mechanically ventilated to measure dynamic compliance. After sacrifice, lungs were fixed, and histological sections were quantitatively assessed for emphysematous changes. A single instillation of elastase was enough to produce anatomic and physiological evidence of emphysema. Weight change for doses of 16 and 32 units PPE/100 g were significantly lower than controls (P = 0.028 and P = 0.043, respectively). Compliance values for doses of 16 and 32 units PPE/100 g were significantly higher than controls (P = 0.037 and P = 0.006, respectively). Lung hyperlucency was confirmed by CT with mean Hounsfield units for a dose of 32 units PPE/100 g being significantly lower than controls (P < 0.001). The mean linear intersect for doses of 16 and 32 units PPE/100 g were significantly higher than controls (both P < 0.001). All reported P-values are one-sided. We present an efficient method for emphysema development in immune-deficient rats as a tool to evaluate human biological therapeutics. Changes in dynamic compliance, histology and cross-sectional imaging recapitulate human emphysema.