Silica binding and toxicity in alveolar macrophages

Abstract

Inhalation of the crystalline form of silica is associated with a variety of pathologies, from acute lung inflammation to silicosis, in addition to autoimmune disorders and cancer. Basic science investigators looking at the mechanisms involved with the earliest initiators of disease are focused on how the alveolar macrophage interacts with the inhaled silica particle and the consequences of silica-induced toxicity on the cellular level. Based on experimental results, several rationales have been developed for exactly how crystalline silica particles are toxic to the macrophage cell that is functionally responsible for clearance of the foreign particle. For example, silica is capable of producing reactive oxygen species (ROS) either directly (on the particle surface) or indirectly (produced by the cell as a response to silica), triggering cell-signaling pathways initiating cytokine release and apoptosis. With murine macrophages, reactive nitrogen species are produced in the initial respiratory burst in addition to ROS. An alternative explanation for silica toxicity includes lysosomal permeability, by which silica disrupts the normal internalization process leading to cytokine release and cell death. Still other research has focused on the cell surface receptors (collectively known as scavenger receptors) involved in silica binding and internalization. The silica-induced cytokine release and apoptosis are described as the function of receptor-mediated signaling rather than free radical damage. Current research ideas on silica toxicity and binding in the alveolar macrophage are reviewed and discussed.

Figure 1

Schematic of bronchio-alveolar internal spaceillustrating the source and location of epithelial cells responsible for phospholipid (PL) and surfactant protein (SP) production. Also indicated in this figure: the alveoli as a respiratory endpoint for inhaled silica (SiO₂) particles, where phagocytic alveolar macrophages (AM) will internalize the particles for removal from the lung while signaling to the epithelial cells for surfactant overproduction.

Figure 2. Schematic of A class scavenger receptors involved with silica (SiO₂) binding

The extracellular functional domains and proposed silica binding locations are indicated for SR-AI, SR-AII, and MARCO membrane receptors.

Figure 3. Diagram of the free radical hypothesis of silica toxicity in the alveolar macrophage

An overview of the effect of silica (SiO₂ indicated with surface oxygen radical) endocytosis; the consequential respiratory burst, the signal transduction resulting in inflammatory cytokine release, and the antioxidant compensatory mechanisms are illustrated in this figure.

Figure 4. Diagram of the lysosomal permeability hypothesis of silica toxicity in the alveolar macrophage (AM)

The leakage of active cathepsin D from the lysosomal membrane leads to acidic sphingomylinase activity, ceramide generation, mitochondrial depolarization, caspase activation and ultimately cell apoptosis.

Figure 5. Schematic of the potential sources of autoimmune dysfunction with regard to silica (SiO₂) processing and the alveolar macrophage (AM)

Excessive cell death and apoptosis can lead to a source of autoantigens (apoptotic bodies, self-protein, DNA). The AM/T cell interaction following silica exposure in vitro has been characterized by enhanced T cell activity determined by excessive IL-4 (human only), IFN-γ, and IL-13 release. The free silica particle is indicative of the fact that SiO₂ can be internalized more than once by different AM due to its capacity to kill the engulfing cell.