Background/Purpose: A better knowledge of the mechanisms and biomarkers of skin and lung damage in systemic sclerosis (SSc) related fibrosis remain a challenge. Our aim was to characterize serological and vascular manifestations, functional and histopathological features of skin and lung in the purpose of establishing a novel SSc murine model induced by Collagen V immunization.

Methods: Female C57BL/6 mice (n=19, IMU-COLV) were subcutaneously immunized with two doses of Col V (150μg) emulsified in complete Freund adjuvant, followed by two intramuscular boosters. The control group (n=19) did not receive Col V. After 120 days, respiratory mechanics, serum autoantibodies and vascular manifestations were examined. The skin and lung inflammatory process and the collagen gene/protein expression were analyzed.

Results: After immunization, the skin of the animals presented increased thickness (28.59±1.79 vs. 22.84±0.82; p=0.0132), epidermal rectification, decreased papillary dermis, and appendages atrophy, also showing increased deposition of collagen III (20.05±2.20 vs. 11.65±1.29; p=0.0147) and collagen V (3.65±0.47 vs. 1.05±0.18; p=0.011) fibers, and increased gene expression of COL5A1 (3,15±0,80 vs. 0,90±0,32; p=0,0316) and COL5A2 (2,10±0,24 vs. 0,56±0,24; p=0,0401). Vascular changes included endothelial cell activity and apoptosis by increased expression of VEGF (21.1±1.55 vs. 6.88±0.19; p< 0,004), endothelin-1 (10.20±0.81 vs. 2.35±0.44, p< 0,0022) and caspase-3 (21.21±1.34 vs. 8.26±0.29, p=0,0007), coinciding with increased gene expression of endothelin-1 (2,02±0,32 vs. 0,78±0,07; p=0,0351), VEGF (2.26±0.37 vs. 0.97±0.11; p=0.0019) and caspase-3 (1.99±0.17 vs. 0.92±0.10; p< 001). Immunized animals presented lung dysfunction characterized by increased tissue elastance and remodeling of parenchyma by non-specific interstitial pneumonia and vascular sclerosis. Compared to controls, immunization promoted increase of total collagen (6.95±0.42 vs. 5.33±0.31, p=0,0071), collagen I (25.90±3.31 vs. 5.57±0.59; p=0.003) and V (18.53±1.05 vs. 7.53±0.41; p< 0.0001) fibers in lung parenchyma, coinciding with COL1A1 (2.34±0.40 vs. 0.85±0.12; p=0.0070), COL1A2 (2.39±0.23 vs. 1.30±0.06; p=0.0016), COL5A1 (1.80±0.32 vs. 0.97±0.13; p=0.0379) and COL5A2 (1.56±0.18 vs. 0.93±0.10; p=0.014) gene expression. Anti-collagen III (0,15±0,006 vs. 0,09±0,005; p=0,0001) and IV (1,369±0,005 vs. 0,15±0,044; p< 0,0001) and antinuclear antibodies (ANA) (p=0,001) were detected in sera from IMU-COLV.

Conclusion: We demonstrated that cutaneous, vascular and pulmonary remodeling are mimicked by type V collagen-induced SSc mice model, thus representing a suitable preclinical model to study the mechanisms and therapeutic approaches in SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/proposition-of-a-novel-animal-model-of-systemic-sclerosis-induced-by-type-v-collagen-in-c57bl-6-mice-reproducing-fibrosis-vasculopathy-and-autoimmunity/