Background/Purpose: Cardiopulmonary disease is a severe comorbidity in many connective tissue diseases (CTD). Rheumatoid arthritis, systemic sclerosis, and systemic lupus patients are all at increased risk of pulmonary complications and mortality secondary to these complications. Specifically, pulmonary arteriole vasculopathy can lead to right ventricle hypertrophy and eventually, right heart failure. Recently, TNF transgenic (TNF-Tg) mice with inflammatory erosive arthritis was described to have inflammatory interstitial lung disease with significant arteriole thickening, concomitant with right ventricle hypertrophy. However, the source of the pathogenic TNF in this model remains unknown.  Thus, we performed adoptive transfer experiments to test the hypothesis that non-hematopoietic derived TNF mediates pulmonary vasculopathy in the setting of inflammatory arthritis.

Methods: Female TNF-Tg and WT littermates were treated with a 10 Gy split dose at 6 weeks of age, and syngeneic TNF-Tg or WT bone marrow was transferred back into the irradiated mice. Following bone marrow reconstitution, the mice were euthanized at 4-5 months of age for histology of the hearts and lungs. Histomorphometry was performed to assess, right ventricular (RV) area, lung cellular area, and pulmonary arteriole thickness.

Results: Representative images (Figure 1A-E) of the hearts show an increase in RV area (Arrows) in the TNF-Tg and the TNF-Tg donor into TNF-Tg recipients (TNF-Tg → TNF-Tg) compared to the WT mice (5.4±1.2 and 3.7±0.6 vs 2.0±0.6 mm², p<0.05). However, the WT recipient of TNF-Tg bone marrow (TNF-Tg → WT) showed no signs of ventricular hypertrophy. In contrast, the TNF-Tg recipient of WT bone marrow (WT → TNF-Tg) displayed increased RV area compared to the TNF-Tg → WT mice (4.8±1.1 vs 1.3±0.1 mm³, p<0.05). The lung cellular infiltrate is also reduced in the TNF-Tg → WT compared to the WT → TNF-Tg (Arrows, Figure 2 A-C, 6.8±0.2 vs 12.5±1.3%, p<0.05), as well as the pulmonary arteriole thickness (Arrows, Figure 2 D-E, 29.5±8.4 vs 38.3±14.2 μm, p<0.05).

Conclusion: We have previously described significant cardiopulmonary disease in the TNF-Tg mouse. Here, we interrogated the role of the non-hematopoietic derived TNF to drive cardiopulmonary pathology associated with connective tissue disorders. These data suggest a critical role of tissue resident cells and their inflammatory profile in the development of vasculopathy and pulmonary hypertension.