Children's Foundation Research Center at Le Bonheur Children's Medical Center, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
J Immunol. 2010 Mar 15;184(6):3145-56. doi: 10.4049/jimmunol.0903718. Epub 2010 Feb 8.
Hypersensitivity pneumonitis is an interstitial lung disease that results from repeated pulmonary exposure to various organic Ags, including Saccharopolyspora rectivirgula, the causative agent of farmer's lung disease. Although the contributions of proinflammatory mediators to the disease pathogenesis are relatively well documented, the mechanism(s) involved in the initiation of proinflammatory responses against the causative microorganisms and the contribution of signaling molecules involved in the host immune defense have not been fully elucidated. In the current study, we found that S. rectivirgula induces the activation of protein kinase D (PKD)1 in lung cells in vitro and in vivo. Activation of PKD1 by S. rectivirgula was dependent on MyD88. Inhibition of PKD by pharmacological PKD inhibitor Gö6976 and silencing of PKD1 expression by small interfering RNA revealed that PKD1 is indispensable for S. rectivirgula-mediated activation of MAPKs and NF-kappaB and the expression of various proinflammatory cytokines and chemokines. In addition, compared with controls, mice pretreated with Gö6976 showed significantly suppressed alveolitis and neutrophil influx in bronchial alveolar lavage fluid and interstitial lung tissue, as well as substantially decreased myeloperoxidase activity in the lung after pulmonary exposure to S. rectivirgula. These results demonstrate that PKD1 is essential for S. rectivirgula-mediated proinflammatory immune responses and neutrophil influx in the lung. Our findings also imply the possibility that PKD1 is one of the critical factors that play a regulatory role in the development of hypersensitivity pneumonitis caused by microbial Ags and that inhibition of PKD1 activation could be an effective way to control microbial Ag-induced hypersensitivity pneumonitis.
过敏性肺炎是一种间质性肺疾病，由反复肺部暴露于各种有机抗原引起，包括农民肺疾病的病原体嗜热放线菌。虽然促炎介质对疾病发病机制的贡献相对较好地记录在案，但参与启动针对致病微生物的促炎反应的机制以及参与宿主免疫防御的信号分子的贡献尚未完全阐明。在本研究中，我们发现嗜热放线菌在体外和体内诱导肺细胞中蛋白激酶 D（PKD）1 的激活。嗜热放线菌激活 PKD1 依赖于 MyD88。通过药理学 PKD 抑制剂 Gö6976 抑制 PKD 和小干扰 RNA 沉默 PKD1 表达表明，PKD1 对于嗜热放线菌介导的 MAPKs 和 NF-κB 的激活以及各种促炎细胞因子和趋化因子的表达是必不可少的。此外，与对照组相比，用 Gö6976 预处理的小鼠在暴露于嗜热放线菌后，支气管肺泡灌洗液和肺间质组织中的肺泡炎和中性粒细胞浸润明显受到抑制，肺组织中的髓过氧化物酶活性也明显降低。这些结果表明，PKD1 对于嗜热放线菌介导的促炎免疫反应和肺内中性粒细胞浸润是必不可少的。我们的研究结果还表明，PKD1 可能是在微生物抗原引起的过敏性肺炎发展中起调节作用的关键因素之一，抑制 PKD1 激活可能是控制微生物抗原诱导的过敏性肺炎的有效方法。
