In vivo models of Drug Induced ILD; tools to study and improve drug safety

Background: A number of systemically administered drugs may cause Drug Induce Interstitial Lung Disease (DIILD). We aim to investigate the underlying mechanisms of cell and matrix interactions and develop imaging biomarkers for detection and quantification of DIILD. Methods: SD rats received a single i.t. administration of bleomycin and were longitudinally imaged at d. 0, 3, 7, 14, 21 and 28 post dosing using MRI. BAL fluid (BALF) was analysed for total protein and inflammatory cells, and lungs taken for histology and stained for inflammation and collagen deposition. Results: Bleomycin induced a significant increase vs. control in total protein concentration assessed in BALF at d.3 (p>0.001), d.7 (p>0.001), and d.14 (p>0.01) and a significant reduction at d.14 (p>0.05) and forward. The total cell count in BALF was significantly increased vs. control from d.3 (p>0.01) peaking at d.7 (p>0.001) containing mainly neutrophils. At d.14-21 cell counts were back to baseline, and increased again at d.28 (p>0.01) showing mainly macrophages present. Lung volume assessed by imaging was reduced due to oedema at early time points while fibrotic tissue contributed to volume reduction at later time points. Fibrosis found on MRI was confirmed by histological Trichrome-Masson staining with significant score increase (p Conclusion: Total protein and cells increased at various time points post-Bleomycin, and different immune cells dominated the different stages of lung injury. Histology and MRI findings related to bleomycin dose, exposure time and disease severity correlated very well. This study takes the search of DIILD imaging-biomarkers as well as the development of our translational in vivo model forward.