Restrictive lung disease in TNF-transgenic mice: correlation of pulmonary function testing and micro-CT imaging

Abstract

Purpose: Micro-computed tomography (µCT) is increasingly being used on animal models as a minimally-invasive longitudinal outcome measure of pulmonary disease progression. However, while imaging can elucidate macroscopic structural changes over the whole lung, µCT is unable to describe the mechanical changes and functional impairments imposed by progressive disease, which can only be measured via pulmonary function tests (PFTs). The tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA) develops pulmonary pathology that mimics many aspects of the inflammatory interstitial lung disease (ILD) seen in a subset of patients with RA. Prior studies using µCT imaging of these mice found increased pulmonary density, characteristic of restrictive disease; however, there have been conflicting reports in the literature regarding the obstructive versus restrictive phenotype of this model. Our study looks to 1) define the functional impairments and 2) characterize the restrictive/obstructive nature of the disease found in this model. Materials and Methods: In this study, we performed PFTs at end-stage ILD, and paired these findings with µCT results, correlating radiology to functional parameters. TNF-Tg and WT littermates of both sexes underwent µCT imaging and PFT testing at 5.5 months-old. Spearman’s correlation analyses were performed comparing lung tissue volume (LTV) to PFT parameters of gas exchange and tissue stiffness. Results: Compared to WT, TNF-Tg mice had impaired gas exchange capacity, increased respiratory resistance, and reduced lung compliance, elastance, and inspiratory capacity, indicating increased tissue stiffness and compromised pulmonary function. LTV was also consistently higher in TNF-Tg lungs. Conclusions: These findings demonstrate that: 1) TNF-Tg mice display a restrictive pathology, and 2) in vivo µCT is a valid outcome measure to infer changes in pulmonary mechanical and functional parameters.

Keywords:

• micro-CT
• pulmonary function testing
• rheumatoid arthritis-associated interstitial lung disease
• TNF-transgenic

Acknowledgments

The authors would like to thank Michael Thullen for help with the µCT imaging and analysis.

Declaration of interest

The authors declare that they have no competing interests.

Additional information

Funding

This work was funded by grants from NIH MSTP T32 GM007356, NIH/NIAMS T32 AR053459, NIH/NIAMS P30 AR069655, NIH/NIAMS K08 AR067885, NIH/NIAMS R01 AR56702, and NIH/NHLBI R01 HL122424.