Mortality of Tumor Necrosis Factor Transgenic Arthritic Mice with Interstitial Lung Disease Occurs with Pulmonary Arteriole Thickening and Right Ventricular Hypertrophy but Is Not Associated with Inducible Nitric Oxide Synthase Dependent Inflammatory Cell Infiltration

Richard Bell¹, Emily Wu^1,2, Homaira Rahimi³ and Edward Schwarz^1,4,5, ¹Center for Musculoskeletal Research, University of Rochester, Rochester, NY, ²Department of Immunology, Microbiology, and Virology, University of Rochester, Rochester, NY, ³Rheumatology, University of Rochester/Golisano Children's Hosp, Rochester, NY, ⁴University of Rochester, Rochester, NY, ⁵Univ of Rochester Med Ctr, University of Rochester School of Medicine and Dentistry, Rochester, NY

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Inflammation, inflammatory arthritis, interstitial lung disease, rheumatoid arthritis (RA) and treatment

Session Information

Date: Monday, November 6, 2017

Title: Rheumatoid Arthritis – Animal Models Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Rheumatoid arthritis associated interstitial lung disease (RA-ILD) occurs in up to 15% of RA patients, whose median survival expectancy after diagnosis is only 2.6 years. The tumor necrosis factor-transgenic (TNF-Tg) mouse model of RA develops cellular ILD with increased mortality, which is presumed to be from lung and cardiac failure secondary to ILD. In the context of arthritis, inducible nitic oxide synthase (iNOS) is detrimental to clearance of immune cells from the joint, and selective iNOS inhibitors restore lymphatic flow. Thus, we hypothesize that ILD pathology is decreased in iNOS^-/-x TNF-Tg mice.

Methods: To test this, female TNF- Tg, iNOS^-/-, iNOS^-/-x TNF-Tg and WT littermates were weighed and scanned with μCT to investigate differences in ILD at 2, 3 and 4 months (Mixed Model with Tukey’s Post-Hoc, ***p<0.001). The mice were euthanized at 4 months to perform histology on the hearts and lungs for histomorphometry (ANOVA, **p<0.01). In a separate cohort, iNOS^-/-x TNF-Tg, TNF-Tg and WT littermate were aged to investigate lifespan differences.

Results: There were no differences in weight or lifespan between the iNOS^-/-x TNF-Tg and TNF-Tg, both failing to gain weight from 2mo and dying at 5mo. However, μCT 3D reconstructions of 4 months old WT (A), iNOS^-/- (B), TNF-Tg (C) and iNOS x TNF-Tg (D) show preservation of air space and decrease in tissue volume in the iNOS^-/- x TNF-Tg (Fig 1, Air = Green, Tissue = Orange). Quantification reveals a significant increase in air volume at 3 and 4 months in iNOS^-/- x TNF-Tg compared to TNF-Tg (E, 3mo: 229±26μm³ vs 116±32μm³, p<0.001;4mo: 225±48μm³ vs 133±42μm³, p<0.001), similar to WT and iNOS^-/- (4mo: 219±51μm³and 227±28μm³). Furthermore, tissue volume was significantly decreased at 4mo in iNOS^-/- x TNF-Tg compared to TNF-Tg (F, 438±55μm³vs 606±51μm³, p<0.001). Lung histomorphometry confirmed these μCT results finding more white area and less total cells in iNOS^-/- x TNF-Tg compared to TNF-Tg. Interestingly, iNOS^-/-x TNF-Tg and TNF-Tg had severe arteriole thickening (Green Arrows in Fig 2, B and C) in the lung (Fig 2 D, 0.01±0.01mm² and 0.007±0.005mm²) compared to WT (0.002±0.001mm², p<0.001). The right ventricle was also thicker in iNOS^-/-x TNF-Tg and TNF-Tg than WT (Fig 2 H, 726±108μm², 664±35μm² vs 359±85μm²,p<0.01).

Conclusion: This study demonstrates for the first time that the cellularity of ILD in this model of RA is iNOS dependent, and is not associated with decreased lifespan. Moreover, lung arteriole thickening and right ventricular hypertrophy are consistent with pulmonary hypertension, likely causing cardiac failure and increased mortality in TNF-Tg mice.

Disclosure: R. Bell, None; E. Wu, None; H. Rahimi, None; E. Schwarz, Janssen Pharmaceutica Product, L.P., 9,Lilly Inc., 9.

To cite this abstract in AMA style:

Bell R, Wu E, Rahimi H, Schwarz E. Mortality of Tumor Necrosis Factor Transgenic Arthritic Mice with Interstitial Lung Disease Occurs with Pulmonary Arteriole Thickening and Right Ventricular Hypertrophy but Is Not Associated with Inducible Nitric Oxide Synthase Dependent Inflammatory Cell Infiltration [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/mortality-of-tumor-necrosis-factor-transgenic-arthritic-mice-with-interstitial-lung-disease-occurs-with-pulmonary-arteriole-thickening-and-right-ventricular-hypertrophy-but-is-not-associated-with-indu/. Accessed .

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