Holian A, Kelley K, Hamilton R F
Department of Internal Medicine, University of Texas Medical School at Houston 77225.
Environ Health Perspect. 1994 Dec;102 Suppl 10(Suppl 10):69-74. doi: 10.1289/ehp.94102s1069.
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.
石棉和二氧化硅是众所周知的致纤维化粉尘。然而，对于因吸入石棉或二氧化硅而导致纤维化的分子和细胞事件，目前尚无全面的了解。先前的研究表明，石棉通过磷脂酶C/蛋白激酶C途径刺激肺泡巨噬细胞产生超氧阴离子。相比之下，二氧化硅似乎不会激活该途径，也不会刺激超氧阴离子的产生，但二氧化硅确实会通过某种未确定的途径刺激细胞因子的释放。因此，我们使用从正常健康志愿者中分离出的人肺泡巨噬细胞，评估了细胞内钙和酪氨酸激酶作为潜在信号转导途径的潜在参与情况。在无血清的情况下，结晶二氧化硅以及程度较轻的无定形二氧化硅会导致细胞内钙从细胞外空间迅速且呈剂量依赖性升高。然而，在二氧化硅刺激细胞因子释放所需的血清存在的情况下，两种形式的二氧化硅均未引起细胞内钙的明显升高。不过，二氧化硅确实增加了酪氨酸磷酸化的程度，最显著的是约46 kDa和50 kDa的蛋白质，这表明酪氨酸激酶途径被激活。用二氧化硅预处理肺泡巨噬细胞24小时后，可增强由内毒素（LPS）刺激的白细胞介素-1β（IL-1β）的释放，且这种增强呈剂量依赖性。LPS刺激的IL-1β释放增强与丝裂原活化蛋白激酶活性增强相关。综上所述，这些结果表明，在二氧化硅刺激人肺泡巨噬细胞的过程中，酪氨酸激酶途径被激活。
