生物谷報(bào)道：在12月在線出版的《自然—醫(yī)學(xué)》期刊上,，一篇論文指出：囊性纖維病變患者肺部高水平的蛋白酶導(dǎo)致免疫細(xì)胞功能的喪失，從而解釋了為何這種疾病患者不能清除自身肺部感染的原因,。新發(fā)現(xiàn)提供了一種恢復(fù)這類疾病患者殺菌能力的治療戰(zhàn)略,。
囊性纖維病變患者的肺部含有高水平的IL-8蛋白質(zhì)。通常情況下,，IL-8蛋白質(zhì)通過一種名為嗜中粒細(xì)胞的免疫細(xì)胞來觸發(fā)細(xì)菌的滅亡,，然而，盡管有大量的肺部嗜中性粒細(xì)胞的存在,，囊性纖維病變患者的肺部依然被細(xì)胞“殖民”,。不知何故，這種患者體內(nèi)的嗜中性粒細(xì)胞不能正常工作,。
Dominik Hartl和同事報(bào)告說,，IL-8蛋白質(zhì)通過與細(xì)胞因子受體IL-8的結(jié)合，激活了嗜中性粒細(xì)胞,。囊性纖維病變患者不正常地?fù)碛懈咚降姆蔚鞍酌负透咚降氖戎行粤＜?xì)胞激活細(xì)胞因子IL-8,。這種高水平的蛋白酶活性解釋了囊性纖維病變患者體內(nèi)嗜中性粒細(xì)胞功能的失效和肺部高水平的IL-8,。蛋白酶吸附在CXCR1受體上，讓細(xì)胞不能對(duì)IL-8的存在作出反應(yīng),，從而有效地抑制了嗜中性粒細(xì)胞的滅菌能力,。與此同時(shí)，黏附的受體片段進(jìn)一步刺激了肺部上皮細(xì)胞分泌IL-8,。
α1抗胰蛋白酶是一種蛋白酶抑制劑,。作者還發(fā)現(xiàn)，在接受了4周的吸入性α1抗胰蛋白酶抗治療后,，囊性纖維病變患者唾液中綠膿桿菌的數(shù)量減少了,，表明患者嗜中性粒細(xì)胞的殺菌能力提高，并恢復(fù)了嗜中性粒細(xì)胞表面的CXCR1,，同時(shí)也降低了肺部可溶性受體片段的數(shù)量,。
原始出處：
Nature Medicine 13, 1423 - 1430 (2007)
Published online: 2 December 2007 | doi:10.1038/nm1690
Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease
Dominik Hartl1,2, Philipp Latzin3, Peter Hordijk4, Veronica Marcos1, Carsten Rudolph1, Markus Woischnik1, Susanne Krauss-Etschmann1,5, Barbara Koller1, Dietrich Reinhardt1, Adelbert A Roscher1, Dirk Roos4 & Matthias Griese1
Interleukin-8 (IL-8) activates neutrophils via the chemokine receptors CXCR1 and CXCR2. However, the airways of individuals with cystic fibrosis are frequently colonized by bacterial pathogens, despite the presence of large numbers of neutrophils and IL-8. Here we show that IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2. Unopposed proteolytic activity in the airways of individuals with cystic fibrosis cleaved CXCR1 on neutrophils and disabled their bacterial-killing capacity. These effects were protease concentration–dependent and also occurred to a lesser extent in individuals with chronic obstructive pulmonary disease. Receptor cleavage induced the release of glycosylated CXCR1 fragments that were capable of stimulating IL-8 production in bronchial epithelial cells via Toll-like receptor 2. In vivo inhibition of proteases by inhalation of 1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis. The cleavage of CXCR1, the functional consequences of its cleavage, and the identification of soluble CXCR1 fragments that behave as bioactive components represent a new pathophysiologic mechanism in cystic fibrosis and other chronic lung diseases.
Children's Hospital Research Center, Ludwig-Maximilians University, Munich 80337, Germany.
Pulmonary and Critical Care Section, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Children's Hospital, University of Berne, Berne 3010, Switzerland.
Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam 1066, The Netherlands.
Gesellschaft für Strahlenforschung–National Research Center for Environment and Health, Munich 85764, Germany.
Correspondence to: Dominik Hartl1,2 e-mail: [email protected]
