Nakashima Shota, Kakugawa Tomoyuki, Yura Hirokazu, Tomonaga Masaomi, Harada Tatsuhiko, Hara Atsuko, Hara Shintaro, Nakano Masayuki, Yamasaki Eiki, Sakamoto Noriho, Ishimatsu Yuji, Isomoto Hajime, Gochuico Bernadette R, Suffredini Anthony F, Mukae Hiroshi, Kurazono Hisao, Hirayama Toshiya, Moss Joel, Kohno Shigeru
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan.
Biochem Biophys Res Commun. 2015 May 8;460(3):721-726. doi: 10.1016/j.bbrc.2015.03.096. Epub 2015 Mar 25.
Prior reports suggested that infection with Helicobacter pylori was associated with respiratory diseases; pathogenetic mechanisms however, were not defined. We tested the hypothesis that VacA, an exotoxin of H. pylori, a gastric pathogen, was aspirated into the lung and could stimulate secretion of inflammatory cytokines by lung epithelial cells.
The presence of VacA was determined by immunohistochemistry in surgical lung biopsy tissue samples from 72 patients with interstitial pneumonia. The effects of VacA on A549 human alveolar epithelial adenocarcinoma cells and normal human bronchial epithelial cells were determined. After incubation with VacA, the secretions of cytokines were measured by Multiplex Luminex(®) Assays.
VacA was detected with anti-VacA antibodies in bronchial epithelial cells and alveolar epithelial cells from 10 of 72 patients with interstitial pneumonia. VacA was more prevalent in lungs of patients with collagen vascular disease-associated interstitial pneumonia than in those of patients with idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia and cryptogenic organizing pneumonia. Incubation of A549 cells and normal human bronchial epithelial cells with VacA for 24 h was cytotoxic, and resulted in vacuolation. VacA induced interleukin-8 production by A549 cells and normal human bronchial epithelial cells and interleukin-6 production by A549 cells. Based on multiplex screening, interleukin-8 and interleukin-6 were the primary secretory products induced by VacA.
H. pylori VacA is present in human lung and can induce interleukin-8 and interleukin-6 production by human lung cells. VacA could have a role in the pathogenesis of respiratory diseases by its cytotoxic effects and by inducing the secretion of interleukin-8 and interleukin-6 by targeted airway epithelial cells.
先前的报告表明，幽门螺杆菌感染与呼吸道疾病有关；然而，其致病机制尚未明确。我们验证了这样一个假说，即幽门螺杆菌（一种胃部病原体）的外毒素VacA可被吸入肺部，并能刺激肺上皮细胞分泌炎性细胞因子。
通过免疫组织化学法检测72例间质性肺炎患者手术肺活检组织样本中VacA的存在情况。确定VacA对人肺泡上皮腺癌细胞A549和正常人支气管上皮细胞的影响。用VacA孵育后，通过多重Luminex（®）检测法测量细胞因子的分泌情况。
在72例间质性肺炎患者中的10例患者的支气管上皮细胞和肺泡上皮细胞中，用抗VacA抗体检测到了VacA。与特发性肺纤维化、非特异性间质性肺炎和隐源性机化性肺炎患者相比，VacA在胶原血管病相关间质性肺炎患者的肺部更为普遍。用VacA孵育人肺泡上皮腺癌细胞A549和正常人支气管上皮细胞24小时具有细胞毒性，并导致空泡形成。VacA诱导人肺泡上皮腺癌细胞A549和正常人支气管上皮细胞产生白细胞介素-8，并诱导人肺泡上皮腺癌细胞A549产生白细胞介素-6。基于多重筛选，白细胞介素-8和白细胞介素-6是VacA诱导的主要分泌产物。
幽门螺杆菌VacA存在于人类肺部，可诱导人肺细胞产生白细胞介素-8和白细胞介素-6。VacA可能因其细胞毒性作用以及诱导气道靶上皮细胞分泌白细胞介素-8和白细胞介素-6，而在呼吸道疾病的发病机制中发挥作用。
