Mechanisms associated with human alveolar macrophage stimulation by particulates.

Abstract

Asbestos and silica are well-known fibrogenic dusts. However, there is no comprehensive understanding of the molecular and cellular events that lead to fibrosis as a consequence of asbestos or silica inhalation. Previous studies have shown that asbestos stimulates superoxide anion production in alveolar macrophages through the phospholipase C/protein kinase C pathway. In contrast, silica does not appear to activate this pathway nor stimulate superoxide anion production, but silica does stimulate cytokine release by some undetermined pathway. Therefore, using human alveolar macrophages isolated from normal healthy volunteers, we evaluated the potential involvement of intracellular calcium and tyrosine kinases as potential signal transduction pathways. In the absence of serum, crystalline silica, and to a lesser extent amorphous silica, caused a rapid and dose-dependent elevation of intracellular calcium coming from the extracellular space. However, in the presence of serum, which is required for silica-stimulated cytokine release, neither form of silica caused noticeable elevation of intracellular calcium. Silica, however, did increase the extent of tyrosine phosphorylation, most notably of proteins at approximately 46 and 50 kDa, suggesting activation of a tyrosine kinase pathway. Preincubation of alveolar macrophages for 24 hr with silica-primed human alveolar macrophages for enhanced interleukin-1 0 (IL-1 3) release stimulated by endotoxin (LPS) that was dose dependent. The enhanced LPS-stimulated release of IL-1i correlated with enhanced mitogen-activated protein kinase activity. Taken together, these results indicate that a tyrosine kinase pathway is activated during silica stimulation of human alveolar macrophages. -Environ Health Perspect 102(Suppl 10): 69-74 (1994)

Functional expression of system xc−is upregulated by asbestos but not crystalline silica in murine macrophages

“…While crystalline silica has been shown to signal through scavenger receptors such as MARCO (Hamilton et al, 2006), amphibole asbestos may signal through TLR4 (Pfau, unpublished data). Interestingly, others have reported effects that are similar for amphibole asbestos and LPS, but different for silica, such as induction of iNOS and of superoxide anion production through protein kinase C by asbestos and/or LPS but not silica (Lim et al, 1997; Quinlan et al, 1998), and induction of tyrosine phosphorylation by silica (Holian et al, 1994). These differences remain to be confirmed and clarified, and the current study provides a new pathway where differences in the effects of silica and asbestos may lead to a much better understanding of the molecular mechanisms that govern the ultimate outcomes of exposure.…”

Update of in vitro, in vivo and ex vivo fluoro‑edenite effects on malignant mesothelioma: A systematic review (Review)

“…Alveolar macrophages have an important role in the fibrotic process involved in silicosis and in other lung diseases ( 79 ). They are mediators in the interaction between inhaled particulates and different types of cells, by the release of a variety of inflammatory and growth-mediating factors ( 80 ). Cyclooxygenase-2 (COX-2) catalyses the conversion of arachinodic acid to prostaglandins (PGs) and it is mainly induced in response to proinflammatory stimuli, cytokines, growth factors and mitogens.…”

Biological Responses to Asbestos Inhalation and Pathogenesis of Asbestos-Related Benign and Malignant Disease

“…Silica, an important component of asbestos fibers, has also been shown to increase tyrosine kinase activity in human lung macrophages. 39 Similarly, asbestos exposure is associated with activation of oncogenes and loss of tumor suppressor genes. Oncogenes play a central role in cell proliferation and cell transformation.…”

“…Asbestos has also been shown to activate tyrosine kinases, which promote cell proliferation, growth factor signal transduction, and alterations in cell–cell adherence. Silica, an important component of asbestos fibers, has also been shown to increase tyrosine kinase activity in human lung macrophages 39…”