Zanubrutinib ameliorates experimental idiopathic inflammatory myopathy-associated interstitial lung disease by BTK/NF-κB signaling pathway

Abstract

Abstract Idiopathic inflammatory myopathy, abbreviated as myositis, is a heterogeneous disease characterized by proximal muscle involvement and chronic inflammation, primarily affecting the lungs. The aim of this study was to establish a stable Idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD) mouse model and evaluate the effects of zanubrutinib on IIM-ILD. We induced an IIM lung involvement model in balb/c mice through intramuscular injection of skeletal muscle homogenate and intraperitoneal injection of pertussis toxin. We observed that the combination of skeletal muscle protein and pertussis toxin in balb/c mice could establish a stable IIM lung involvement model, characterized by muscle inflammation and pulmonary interstitial changes similar to clinical pathology. Zanubrutinib alleviated IIM and ILD, and its anti-inflammatory properties were demonstrated by a reduction in inflammatory cells and inflammatory factors in bronchoalveolar lavage fluid and bronchial inflammation. Its anti-inflammatory and anti-fibrotic effects were mainly achieved through the inhibition of BTK and NF-κB phosphorylation. This study established a stable IIM-ILD animal model and demonstrated for the first time that the BTK inhibitor Zanubrutinib effectively attenuates experimental IIM-ILD in this model.