Tetracycline ameliorates silica-induced pulmonary inflammation and fibrosis via inhibition of caspase-1

Respiratory Research

Christian Bode¹  Stilla Frede¹  Mario Fox¹  Susanne Schulz¹  Christian Putensen¹  Caroline Feuerborn¹  Konrad Peukert¹  Andrea Sauer¹  Folkert Steinhagen²  Matthias Schneider³  Patrick Schuss³  Benjamin Seeliger⁴  Christoph Wilhelm⁵  Eicke Latz⁶ 

[1] Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany;Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany;Department of Anesthesiology and Intensive Care Medicine, SHG Hospital Voelklingen, Richard-Str. 5-9, 66333, Voelklingen, Germany;Department of Neurosurgery, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany;Department of Respiratory Medicine and German Centre of Lung Research (DZL), Hannover Medical School, Carl-Neuberg-Str. 1, 30635, Hannover, Germany;Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany;Institute of Innate Immunity, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany;

关键词: Anti-bacterial agents;    Immunomodulation;    Inflammasomes;    Pyroptosis;    Silicosis;    Lung injury;    NLR Proteins;    Silicon dioxide;   

DOI  :  10.1186/s12931-022-01937-7

来源: Springer

【 摘 要 】

BackgroundInhalation of dust containing silica particles is associated with severe pulmonary inflammation and lung injury leading to chronic silicosis including fibrotic remodeling of the lung. Silicosis represents a major global health problem causing more than 45.000 deaths per year. The inflammasome-caspase-1 pathway contributes to the development of silica-induced inflammation and fibrosis via IL-1β and IL-18 production. Recent studies indicate that tetracycline can be used to treat inflammatory diseases mediated by IL-1β and IL-18. Therefore, we hypothesized that tetracycline reduces silica-induced lung injury and lung fibrosis resulting from chronic silicosis via limiting IL-1β and IL-18 driven inflammation.MethodsTo investigate whether tetracycline is a therapeutic option to block inflammasome-caspase-1 driven inflammation in silicosis, we incubated macrophages with silica alone or combined with tetracycline. The in vivo effect of tetracycline was determined after intratracheal administration of silica into the mouse lung.ResultsTetracycline selectively blocks IL-1β production and pyroptotic cell death via inhibition of caspase-1 in macrophages exposed to silica particles. Consistent, treatment of silica-instilled mice with tetracycline significantly reduced pulmonary caspase-1 activation as well as IL-1β and IL-18 production, thereby ameliorating pulmonary inflammation and lung injury. Furthermore, prolonged tetracycline administration in a model of chronic silicosis reduced lung damage and fibrotic remodeling.ConclusionsThese findings suggest that tetracycline inhibits caspase-1-dependent production of IL-1β in response to silica in vitro and in vivo. The results were consistent with tetracycline reducing silica-induced pulmonary inflammation and chronic silicosis in terms of lung injury and fibrosis. Thus, tetracycline could be effective in the treatment of patients with silicosis as well as other diseases involving silicotic inflammation.

【 授权许可】

CC BY