SSC-ILD mouse model induced by osmotic minipump delivered bleomycin: effect of Nintedanib

• Published in: Scientific reports Vol. 11; no. 1; pp. 18513 - 10
• Main Authors: Ravanetti, Francesca, Ferrini, Erica, Ragionieri, Luisa, Khalajzeyqami, Zahra, Nicastro, Maria, Ridwan, Yanto, Kleinjan, Alex, Villetti, Gino, Grandi, Andrea, Stellari, Franco Fabio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-09-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/1647/767/1424; 631/1647/767/2201; 631/1647/767/2202; Animal models; Animals; Autoimmune diseases; Bleomycin; Collagen; Computed tomography; Disease Models, Animal; Drug Delivery Systems; Drug development; Drug screening; Fibrosis; Histology; Humanities and Social Sciences; Hydroxyproline; Indoles - administration & dosage; Indoles - therapeutic use; Inflammation; Laboratory animals; Lipoatrophy; Lung - drug effects; Lung - pathology; Lung diseases; Lung Diseases, Interstitial - chemically induced; Lung Diseases, Interstitial - drug therapy; Lung Diseases, Interstitial - pathology; Lungs; Mice; Mimicry; multidisciplinary; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - therapeutic use; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - pathology; R&D; Research & development; Science; Science (multidisciplinary); Scleroderma; Scleroderma, Systemic - chemically induced; Scleroderma, Systemic - drug therapy; Scleroderma, Systemic - pathology; Skin; Systemic sclerosis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-97728-z

Systemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). Its pathogenetic mechanisms are unknown and the lack of animal models mimicking the features of the human disease is creating a gap between the selection of anti-fibrotic drug candidates and effective therapies. In this work, we intended to pharmacologically validate a SSc-ILD model based on 1 week infusion of bleomycin (BLM) by osmotic minipumps in C57/BL6 mice, since it will serve as a tool for secondary drug screening. Nintedanib (NINT) has been used as a reference compound to investigate antifibrotic activity either for lung or skin fibrosis. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, which was confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported here could reflect the clinical outcome, highlighting the reliability of this model to better profile potential clinical drug candidates. The integrative approach presented herein, which combines longitudinal assessments with endpoint analyses, could be harnessed in drug discovery to generate more reliable, reproducible and robust readouts.