生物谷报道：在12月在线出版的《自然—医学》期刊上，一篇论文指出：囊性纤维病变患者肺部高水平的蛋白酶导致免疫细胞功能的丧失，从而解释了为何这种疾病患者不能清除自身肺部感染的原因。新发现提供了一种恢复这类疾病患者杀菌能力的治疗战略。
囊性纤维病变患者的肺部含有高水平的IL-8蛋白质。通常情况下，IL-8蛋白质通过一种名为嗜中粒细胞的免疫细胞来触发细菌的灭亡，然而，尽管有大量的肺部嗜中性粒细胞的存在，囊性纤维病变患者的肺部依然被细胞“殖民”。不知何故，这种患者体内的嗜中性粒细胞不能正常工作。
Dominik Hartl和同事报告说，IL-8蛋白质通过与细胞因子受体IL-8的结合，激活了嗜中性粒细胞。囊性纤维病变患者不正常地拥有高水平的肺蛋白酶和高水平的嗜中性粒细胞激活细胞因子IL-8。这种高水平的蛋白酶活性解释了囊性纤维病变患者体内嗜中性粒细胞功能的失效和肺部高水平的IL-8。蛋白酶吸附在CXCR1受体上，让细胞不能对IL-8的存在作出反应，从而有效地抑制了嗜中性粒细胞的灭菌能力。与此同时，黏附的受体片段进一步刺激了肺部上皮细胞分泌IL-8。
α1抗胰蛋白酶是一种蛋白酶抑制剂。作者还发现，在接受了4周的吸入性α1抗胰蛋白酶抗治疗后，囊性纤维病变患者唾液中绿脓杆菌的数量减少了，表明患者嗜中性粒细胞的杀菌能力提高，并恢复了嗜中性粒细胞表面的CXCR1，同时也降低了肺部可溶性受体片段的数量。
原始出处：
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: dhartl@med.uni-muenchen.de
