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

Abstract

Background 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 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. Methods To 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. Results Tetracycline 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. Conclusions These 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.

Pyroptosis in inflammation-related respiratory disease

“…Recently, it is shown that GSDMD-dependent pyroptosis is triggered in silica-treated AMs by activating the TLR4/NLRP3/caspase-1/GSDMD pathway, which results in aggravated pulmonary inflammation and diffuses silicon nodules [ 66 , 83 ]. Blocking pyroptosis of macrophages by inhibiting the NLRP3 inflammasome or caspase-1 reduces silica-mediated pulmonary inflammation and fibrosis [ 50 , 83 ]. Meanwhile, silica induces the generation of ROS, which is important in the activation of the NLRP3/caspase-1 signaling pathway to accelerate pyroptosis in AMs [ 83 ].…”

Integrated analysis reveals crosstalk between pyroptosis and immune regulation in renal fibrosis

“…Caspase-1 (CASP1) is a major effector protease of pyroptosis. Experimental studies have reported that the inflammasome-caspase-1 pathway contributes to the development of inflammation and fibrosis in the liver and lungs via bioactive IL-1b and IL-18 production (38,39). NOD2 (nucleotide oligomerization domain 2) plays an important role in the host response to bacterial infection.…”

Lung decellularized matrix-derived 3D spheroids: Exploring silicosis through the impact of the Nrf2/Bax pathway on myofibroblast dynamics

“…These cytokines play a crucial role in the activation and proliferation of fibroblasts involved in the fibrotic processes seen in silicotic tissues. Research shows that silica exposure increases proliferative responses and cytokine secretion in peripheral blood mononuclear cells (PBMCs) from silicosis patients, indicating a specific modulation of the immune response compared to healthy controls [ 34 ]. This heightened response can lead to increased fibroblast activity and fibrosis, illustrating a direct link between immune cell stimulation by silica and fibroblast-mediated tissue remodeling.…”