Abstract
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.
Highlights
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)
The main purpose of this study was to examine the antifibrotic activity of nintedanib (NINT), a tyrosine-kinase inhibitor used to treat idiopathic pulmonary fibrosis and recently approved as a therapy for SSc associated with I LD18,19, in the aforementioned SSc-ILD mouse model
We have investigated the effect of NINT on the M2-like macrophages cell population in Bronchoalveolar lavage fluid (BALF), using a flow cytometry technique with CD206 as a surface marker
Summary
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. Systemic sclerosis (or scleroderma) (SSc) is an autoimmune disease of unknown aetiology, characterized by vasculopathy, excessive fibrous tissue generation and aberrant immune activation resulting in damage to various organs including the skin, esophagus, heart, lungs, and k idneys[1,2]. The main purpose of this study was to examine the antifibrotic activity of nintedanib (NINT), a tyrosine-kinase inhibitor used to treat idiopathic pulmonary fibrosis and recently approved as a therapy for SSc associated with I LD18,19, in the aforementioned SSc-ILD mouse model
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