Abstract:Silicosis is a chronic lung disease induced by the inhalation of crystalline silica. Exposure of cultured macrophages to crystalline silica leads to cell death; however, the mechanism of cell-particle interaction, the fate of particles, and the cause of death are unknown. Time-lapse imaging shows that mouse macrophages avidly bind particles that settle onto the cell surface and that cells also extend protrusions to capture distant particles. Using confocal optical sectioning, silica particles were shown to be … Show more
“…Within AM, the phagosome containing particle(s) fuses with lysosomes in order to attempt to degrade the particle. Consistent with this notion, others and our group have observed silica and ENM, including Multi-walled Carbon Nanotubes (MWCNT) and Titanium Nanobelts (TNB), within phagolysosomal compartments in AM following exposure (Gilberti et al , 2008; Hamilton et al , 2009; Hamilton et al , 2013; Hamilton et al , 2014). Silica, MWCNT, TNB and numerous other nanomaterials are resistant to lysosomal degradation, and consequently, downstream consequences are not fully understood.…”
NLRP3 inflammasome activation occurs in response to hazardous particle exposures and is critical for the development of particle-induced lung disease. Mechanisms of Lysosome Membrane Permeabilization (LMP), a central pathway for activation of the NLRP3 inflammasome by inhaled particles, are not fully understood. We demonstrate that the lysosomal vATPases inhibitor Bafilomycin A1 blocked LMP in vitro and ex vivo in primary murine macrophages following exposure to silica, multi-walled carbon nanotubes, and titanium nanobelts. Bafilomycin A1 treatment of particle-exposed macrophages also resulted in decreased active cathepsin L in the cytosol, a surrogate measure for leaked cathepsin B, which was associated with less NLRP3 inflammasome activity. Silica-induced LMP was partially dependent upon lysosomal cathepsins B and L, whereas nanoparticle-induced LMP occurred independent of cathepsin activity. Furthermore, inhibition of lysosomal cathepsin activity with CA-074-Me decreased the release of High Mobility Group Box 1. Together, these data support the notion that lysosome acidification is a prerequisite for particle-induced LMP, and the resultant leak of lysosome cathepsins is a primary regulator of ongoing NLRP3 inflammasome activity and release of HMGB1.
“…Within AM, the phagosome containing particle(s) fuses with lysosomes in order to attempt to degrade the particle. Consistent with this notion, others and our group have observed silica and ENM, including Multi-walled Carbon Nanotubes (MWCNT) and Titanium Nanobelts (TNB), within phagolysosomal compartments in AM following exposure (Gilberti et al , 2008; Hamilton et al , 2009; Hamilton et al , 2013; Hamilton et al , 2014). Silica, MWCNT, TNB and numerous other nanomaterials are resistant to lysosomal degradation, and consequently, downstream consequences are not fully understood.…”
NLRP3 inflammasome activation occurs in response to hazardous particle exposures and is critical for the development of particle-induced lung disease. Mechanisms of Lysosome Membrane Permeabilization (LMP), a central pathway for activation of the NLRP3 inflammasome by inhaled particles, are not fully understood. We demonstrate that the lysosomal vATPases inhibitor Bafilomycin A1 blocked LMP in vitro and ex vivo in primary murine macrophages following exposure to silica, multi-walled carbon nanotubes, and titanium nanobelts. Bafilomycin A1 treatment of particle-exposed macrophages also resulted in decreased active cathepsin L in the cytosol, a surrogate measure for leaked cathepsin B, which was associated with less NLRP3 inflammasome activity. Silica-induced LMP was partially dependent upon lysosomal cathepsins B and L, whereas nanoparticle-induced LMP occurred independent of cathepsin activity. Furthermore, inhibition of lysosomal cathepsin activity with CA-074-Me decreased the release of High Mobility Group Box 1. Together, these data support the notion that lysosome acidification is a prerequisite for particle-induced LMP, and the resultant leak of lysosome cathepsins is a primary regulator of ongoing NLRP3 inflammasome activity and release of HMGB1.
“…Among such nanosystems, synthetic amorphous silica (SiO 2 )based nanosystems are the most interesting for two reasons: they are emerging as candidates for nanomedical-biotechnological applications (including the use of SiO 2 as a coat ing agent to protect biofluids and cells from the very toxic action of other NPs, such as quantum dots); and they are widely used in industry as clarifying agents for beverages or additives for paper, rubber and plastics. Although crystalline SiO 2 microparticles are well known to be toxic to cells and strongly proinflammatory in vitro, in animal models and in humans [4,5], a grow ing amount of evidence suggests that amorphous SiO 2 NPs also exert a significant degree of cell damage and toxicological effects [6,7]. Xie et al demonstrated that SiO 2 NPs (20 and 80nm diameter) injected in murine models are preva lently found in lungs, liver and spleen macro phages, but are rarely found in other nonphago cytic tissue cells [8].…”
The physiological specialization of monocytes/macrophages to effectively capture NPs may expose them to the risk of catastrophic inflammatory death upon saturation of their maximal storage capacity.
“…Eighty percent of these macrophages die within 12 hours. 9 It may be that the phospholipidosis in the lung of silica exposed animals is the result of an interaction between stimulated AMs and fibroblasts to induce phospholipid production by type II cells in an attempt to coat particles and lessen toxicity. 10 In vitro studies show that coating of quartz particles with polyvinylpyridine-N-oxide (PVNO) or aluminum lactate (AL) impairs the ability of the particle to elicit inflammation or generate ROS by neutrophils or AMs.…”
Section: Silica Structure Particle Size and Surface Chemistrymentioning
Over the last half century, there has been a sustained decline in the prevalence of silicosis in developed countries. This success has primarily been the result of an emphasis on engineering controls, with the capture of generated silica dust. This has allowed for adherence to exposure limits and the protection of the respiratory health of the worker. Yet sporadic cases continue to occur in developed countries and epidemics are still recognized in underdeveloped countries.In this review, we address data describing the pathogenesis of silicosis. Although untried, much of this research suggests that pathways associated with the development and progression of silicosis may be altered by currently available interventions.
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