title: 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 beta (IL-1 beta) release stimulated by endotoxin (LPS) that was dose dependent. The enhanced LPS-stimulated release of IL-1 beta 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.
authors.affiliation: Department of Internal Medicine, University of Texas Medical School at Houston 77225.
authors.forename: A
authors.initials: A
authors.lastname: Holian
authors.forename: K
authors.initials: K
authors.lastname: Kelley
authors.forename: R F
authors.initials: RF
authors.lastname: Hamilton
mesh_terms: D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012822:Silicon Dioxide / Q000494:pharmacology*
chemical_list: D012822:Silicon Dioxide; D011505:Protein-Tyrosine Kinases; D002118:Calcium