Continuous, Automated Breathing Rate and Body Motion Monitoring of Rats With Paraquat-Induced Progressive Lung Injury.

Szczepan W Baran,Laura R Schaevitz,Maria A Lim,Dana B Walker,Shiva K Shanmukhappa,Ashwini Mathur,Ayan Das Gupta,David J Rowlands

doi:10.3389/fphys.2020.569001

Szczepan W Baran, Laura R Schaevitz + Show 6 more

Open Access

https://doi.org/10.3389/fphys.2020.569001

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Abstract

Assessments of respiratory response and animal activity are useful endpoints in drug pharmacology and safety research. We investigated whether continuous, direct monitoring of breathing rate and body motion in animals in the home cage using the Vum Digital Smart House can complement standard measurements in enabling more granular detection of the onset and severity of physiologic events related to lung injury in a well-established rodent model of paraquat (PQ) toxicity. In rats administered PQ, breathing rate was significantly elevated while body motion was significantly reduced following dosing and extending throughout the 14-day study duration for breathing rate and at least 5 days for both nighttime and daytime body motion. Time course differences in these endpoints in response to the potential ameliorative test article bardoxolone were also readily detected. More complete than standard in-life measurements, breathing rate and body motion tracked injury progression continuously over the full study time period and aligned with, and informed on interval changes in clinical pathology. In addition, breathing rates correlated with terminal pathology measurements, such as normalized lung weights and histologic alveolar damage and edema. This study is a preliminary evaluation of the technology; our results demonstrate that continuously measured breathing rate and body motion served as physiologically relevant readouts to assess lung injury progression and drug response in a respiratory injury animal model.

Highlights

The ability to measure pulmonary response in preclinical studies is important in respiratory disease models and in safety pharmacology and toxicology studies (Murphy, 2002)
We investigated the utility of a continuous monitoring platform and its automated breathing rate and body motion readouts for assessing acute and chronic toxic injury progression in rats post-intra-tracheal PQ administration and compared these digital readouts with standard endpoint measurements
We investigated the utility of a continuous home cage monitoring platform and its automated breathing rate (BR) and body motion (BM) readouts to detect onset and track injury progression in a rodent model of PQiLI

Summary

Introduction

The ability to measure pulmonary response in preclinical studies is important in respiratory disease models and in safety pharmacology and toxicology studies (Murphy, 2002). Continuous Automated Monitoring of Lung Injury and pulmonary histopathology All these methods are discontinuous measures, highly limited in the frequency of study application, and with a significant degree of invasiveness and personnel resources. To overcome these time course and handling/interventional limitations, we evaluated a home cage monitoring system that incorporates continuous, automated readouts of breathing rate and whole-body motion (as a measure of activity) in individual animals. These features include time course changes from lung edema and interstitial inflammation to progressive fibrosis (Silva and Saldiva, 1998; Tomita et al, 2007; Sun and Chen, 2016). The PQiLI model has been used to evaluate safety and efficacy of therapies used to treat lung injury and fibrosis (Santos et al, 2011; Chen et al, 2013a,b, 2015; Liu et al, 2013; Qian et al, 2014; Shao et al, 2015)

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