A Closer Radiological Look at Chronic Rejection after Murine Orthotopic Lung Transplantation

Abstract

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is the main culprit for low survival after human lung transplantation (LTx). Within the clinical identification of CLAD, the immunological enigma of <i>chronic rejection</i> was lost. This is difficult to study in the complex patient setting; but an appropriate experimental model may help. Our goal was to further elaborate our mouse model of chronic rejection by implementing <i>in vivo</i> microCT (µCT). <h3>Methods</h3> Using the orthotopic single left LTx model with cuffing method, isografts (n=9; C57BL/6N to C57BL/6N) and allografts (n=8; Balb/c to C57BL/6N) were transplanted. Mice received daily immunosuppression with 10 mg/kg cyclosporine A and 1.6 mg/kg methylprednisolone for 10 weeks. <i>In vivo</i> respiratory-gated time resolved µCT (SkyScan 1278, Bruker) was performed at postoperative week 1, 5 and 10, lung density and volume (at in and expiration) were quantified. <h3>Results</h3> In 1 isografts technical failure was observed (on both CT and histology), the other 8 demonstrated normal lung structure at week 10. 5 isografts had normal lung density at week 1, 5 and 10 (1.03±0.02; 1.04±0.01; 1.01±0.02), compared to 3 isografts which had significant increased lung density at week 1 (1.22±0.01; p<0.0001) (Figure) that decreased to normal at week 5 and week 10 vs week 1 (0.99±0.04; p=0.001; 1.00±0.01; p<0.0001). Within allografts, 2 failures were observed. Lung density of 6 allografts at week 1 was comparable to isografts at week 1 (1.01±0.01; p=0.92) but increased at week 5 and week 10 vs week 1 (1.09±0.02; p=0.002; 1.08±0.03; p=0.005). In allografts, 4 had a mild pattern and 2 had a severe pattern with density difference at week 10 (1.05±0.04 versus 1.14±0.01; p=0.002) (Figure). Same patterns were observed for lung volume, tidal volume and airway volume. <h3>Conclusion</h3> Longitudinal µCT is useful to investigate lung volume, lung density, lung ventilation/tidal volume of the transplanted lung and can identify and monitor the evolution/severity of both chronic rejection and primary graft dysfunction (PGD).