MECHANISMS OF PARTICLE-INDUCED LUNG DISEASE

各种人造颗粒物是环境纤维增生性肺部疾病的来源。这些疾病的一个主要特征是成纤维细胞增生。我们已经通过一种致纤维化的金属五氧化二钒来研究导致肺纤维化的机制。我们最近的实验证明，钒对大鼠的损伤导致了与细支气管周纤维化、粘液细胞化生和平滑肌细胞增厚相关的气道重塑，这与哮喘的病理机制是一致的。在大鼠体内的实验表明，钒可诱导血小板衍生生长因子受体(PDGF-Ra)的产生。体外实验已经阐明了介导PDGF-Ra诱导的机制。一种必需的信号中间产物是p38 MAP激酶，它稳定PDGF-Ra mRNA，从而上调该受体的表达。我们还观察到，在钒诱导的肺损伤后，丝裂原活化蛋白(MAP)激酶在体内被激活。在体外，我们研究了钒诱导MAP激酶激活的机制，发现钒通过氧化剂介导的机制引起表皮生长因子受体(EGF-R)的磷酸化，进而触发Raf-1、MEK-1和MAP激酶等分子的下游激活。免疫组织化学观察到钒暴露后体内肺细胞中硝基酪氨酸的形成，这是一个潜在的重要观察。这表明过氧亚硝酸盐在钒诱导的肺纤维化中起作用。在体外，硝基酪氨酸的形成与MAP激酶的激活和受体酪氨酸激酶的激活有关，包括PDGF-R和EGF-R。钒等金属和过氧亚硝酸盐等氧化剂激活MAP激酶和磷酸化生长因子受体酪氨酸激酶的结果尚不清楚，但推测这些环境因素导致了参与增殖信号转导的蛋白质的失调。最后，我们已经证明了体内应用酪氨酸激酶抑制剂可以阻断五氧化二钒诱导的肺纤维化的进展。预计这些研究将导致环境引起的炎症性肺部疾病的治疗干预。

A variety of man-made particles are sources of environmental fibroproliferative lung diseases. A key feature of these diseases is fibroblast hyperplasia. We have investigated the mechanisms through with a fibrogenic metal, vanadium pentoxide, causes lung fibrosis. Our recent experiments have demonstrated that vanadium injury in rats causes airway remodeling associated with peribronchiolar fibrosis, mucous cell metaplasia and smooth muscle cell thickening, which is consistent with the pathology of asthma. In vivo experiments in rats have shown that vanadium causes induction of the platelet-derived growth factor receptor (PDGF-Ra). In vitro experiments have elucidated the mechanisms that mediate PDGF-Ra induction. A required signaling intermediate is p38 MAP kinase, which stabilizes the PDGF-Ra mRNA and thereby up-regulates the expression of this receptor. We have also observed that mitogen-activated protein (MAP) kinases are activated in vivo following vanadium-induced lung injury. In vitro, we have investigated the mechanism of vanadium-induced MAP kinase activation and discovered that vanadium acts via an oxidant-mediated mechanism to cause phosphorylation of the epidermal growth factor receptor (EGF-R), which then triggers downstream activation of molecules such as Raf-1, MEK-1 and MAP kinase. A potentially important observation regards the formation of nitrotyrosine in lung cells in vivo following vanadium exposure as observed by immunohistochemistry. This suggests a role for peroxynitrite in vanadium-induced lung fibrosis. In vitro, nitrotyrosine formation is associated with MAP kinase activation and activation of receptor tyrosine kinases, including PDGF-R and EGF-R. The consequence of MAP kinase activation and phosphorylation of growth factor receptor tyrosine kinases by metals such as vanadium and oxidants such as peroxynitrite remains to be elucidated, but it is postulated that these environmental agents cause dysregulation of proteins involved in proliferative signaling. Finally, we have shown that tyrosine kinase inhibitors administered in vivo block the progression of lung fibrosis induced by vanadium pentoxide. It is anticipated that these studies will lead to therapeutic intervention of environmentally-induced, inflammatory lung diseases.