Shota Nakashima1, Tomoyuki Kakugawa2, Hirokazu Yura1, Masaomi Tomonaga1, Tatsuhiko Harada1, Atsuko Hara1, Shintaro Hara1, Masayuki Nakano3, Eiki Yamasaki4, Noriho Sakamoto1, Yuji Ishimatsu1, Hajime Isomoto5, Bernadette R Gochuico6, Anthony F Suffredini7, Hiroshi Mukae8, Hisao Kurazono4, Toshiya Hirayama3, Joel Moss9, Shigeru Kohno1. 1. Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan. 2. Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan. Electronic address: kakugawa@nagasaki-u.ac.jp. 3. Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan. 4. Department of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan. 5. Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki 852-8501, Japan. 6. Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. 7. Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. 8. Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan. 9. Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. METHODS: 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 A549humanalveolar 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. RESULTS: 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. CONCLUSIONS: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.
Authors: Thomas J Richards; Naftali Kaminski; Fred Baribaud; Susan Flavin; Carrie Brodmerkel; Daniel Horowitz; Katherine Li; Jiin Choi; Louis J Vuga; Kathleen O Lindell; Melinda Klesen; Yingze Zhang; Kevin F Gibson Journal: Am J Respir Crit Care Med Date: 2012-01-01 Impact factor: 21.405
Authors: A Gasbarrini; I Massari; M Serricchio; P Tondi; A De Luca; F Franceschi; V Ojetti; A Dal Lago; R Flore; A Santoliquido; G Gasbarrini; P Pola Journal: Dig Dis Sci Date: 1998-08 Impact factor: 3.199
Authors: Daniel S Smyk; Andreas L Koutsoumpas; Maria G Mytilinaiou; Eirini I Rigopoulou; Lazaros I Sakkas; Dimitrios P Bogdanos Journal: World J Gastroenterol Date: 2014-01-21 Impact factor: 5.742
Authors: Stephen Farrell; Cyril McMaster; David Gibson; Michael D Shields; William A McCallion Journal: J Pediatr Surg Date: 2006-02 Impact factor: 2.545
Authors: K W Tsang; S K Lam; W K Lam; J Karlberg; B C Wong; W H Hu; W W Yew; M S Ip Journal: Am J Respir Crit Care Med Date: 1998-10 Impact factor: 21.405
Authors: Darryl A Knight; Matthias Ernst; Gary P Anderson; Yuben P Moodley; Steven E Mutsaers Journal: Pharmacol Ther Date: 2003-09 Impact factor: 12.310
Authors: M Yoshida; J Sakuma; S Hayashi; K Abe; I Saito; S Harada; M Sakatani; S Yamamoto; N Matsumoto; Y Kaneda Journal: Proc Natl Acad Sci U S A Date: 1995-10-10 Impact factor: 11.205
Authors: Zhi Tong Zuo; Ya Ma; Yan Sun; Cui Qing Bai; Chun Hua Ling; Feng Lai Yuan Journal: Int Arch Allergy Immunol Date: 2020-10-20 Impact factor: 2.749