Abstract
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.
Highlights
Inhalation of dust containing silica particles is associated with severe pulmonary inflammation and lung injury leading to chronic silicosis including fibrotic remodeling of the lung
The results were consistent with tetracycline reducing silica-induced pulmonary inflammation and chronic silicosis in terms of lung injury and fibrosis
Dependent on the time being exposed to silica particles, silicosis can be subdivided into an acute, inflammatory form marked by silicoproteinosis and a chronic form characterized by pulmonic collagen deposition and fibrotic remodeling of the lung [2, 5, 6]
Summary
Inhalation 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 is a pulmonary disease caused by inhalation of silica particles in occupational or environmental settings. With more than 45.000 deaths per year globally, silicosis represents one of the major occupational diseases worldwide [1, 2]. Ingestion of silica particles by alveolar macrophages leads to acute pulmonary inflammation hallmarked by excessive production of inflammatory mediators and cell death [4]. Dependent on the time being exposed to silica particles, silicosis can be subdivided into an acute, inflammatory form marked by silicoproteinosis and a chronic form characterized by pulmonic collagen deposition and fibrotic remodeling of the lung [2, 5, 6]. To embank morbidity and mortality associated with irreversible progressive and incurable silicosis, there is an urgent need for new therapies preventing prolonged inflammation and collagen deposition in silicosis [2]
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