生物谷报道:最近美国爱荷华大学的一项研究揭示了一种新的存在于正常气管中的免疫防御机制,这项研究能更好地解释为什么囊性纤维化患者更易于罹患肺部细菌性感染。这项研究结果也为寻求这种疾病的新疗法指明了道路。
爱荷华大学的研究揭示了气管宿主防御系统是抵御细菌侵袭最有效的防御系统之一,正常气管中能产生两种酶并利用反应性氧分子(ROS)杀伤细菌。同时他们发现在囊性纤维化基因突变的气管组织和细胞中此过程缺陷,囊性纤维化患者先天性免疫能力弱的一个可能原因是缺乏这种天然的宿主氧化防御机制。
他们取材大鼠、奶牛和人类的气管细胞及组织,发现了两种酶,一种是气管酶(Duox),能产生过氧化氢,第二种酶是乳酸过氧化物酶 (lactoperoxidase),可利用过氧化氢将一种称为硫氰酸的小分子转变为可以杀死细菌的hypothiocyanite。他们同时发现,CF基因发生突变的患者无法将关键分子硫氰酸运输穿越气管细胞,因此不能生成具有杀伤作用的hypothiocyanite。换言之,硫氰酸分子的缺乏打破了氧化抗菌系统。
硫氰酸一般存在于体液中,如血液和唾液。除名称和化学结构上和氰化物有相似之处外,硫化氢是无毒的。Hypothiocyanite对人体细胞和组织同样是无害的,但它能非常有效地杀伤细菌,包括那些与囊性纤维化患者肺部致命感染密切普遍相关的菌种—金黄色葡萄菌和绿脓杆菌。如果能使硫氰酸在气管表面粘液层中维持一定的浓度,或许可以尝试使用喷雾的方法,辅助增强囊性纤维化患者的宿主防御系统,避免致命性肺部细菌感染。”
此项研究是由囊性纤维化基金会部分资助。研究结果发表在11月2日美国呼吸和急症医学杂志的网络版中。
原文出处:
University of Iowa News Release
Nov. 30, 2006
Newly Discovered Immune Defense May Be Impaired In CF Airways
A recent University of Iowa study reveals a new immune defense mechanism in normal airways and may help explain why people with cystic fibrosis (CF) are particularly susceptible to bacterial lung infections. The findings also may point the way to new approaches for treating the disease.
The UI study shows how two enzymes generate and use reactive oxygen species (ROS) to destroy bacteria in normal airways. The team also found that this process is defective in airway tissue and cells containing the CF gene mutation. The study is published in the Nov. 2 online issue of the American Journal of Respiratory and Critical Care Medicine.
"Among the host defense systems that we know of in the airway, at least in cell culture and tissue explants, this is one of the most efficient antibacterial system we have identified," said Botond Banfi, M.D., Ph.D., UI assistant professor of anatomy and cell biology and senior study author. "The findings suggest that one reason for CF patients' weakened innate immunity might be the absence of this natural oxidative host defense mechanism."
Banfi added that correcting the problem by reconstituting the oxidative system might represent a totally new approach for preventing the onset of bacterial lung infections that often become chronic and eventually fatal in CF patients.
Working with airway cells and tissues from rats, cows and humans, the UI team uncovered the oxidative system, which produces hypothiocyanite -- a highly effective antibacterial compound. Banfi and his colleagues, including Patryk Moskwa, M.D., Ph.D., a UI postdoctoral fellow and first author of the study, showed that one airway enzyme (Duox) makes hydrogen peroxide and a second enzyme (lactoperoxidase) uses the hydrogen peroxide to convert a small molecule called thiocyanate into the bacteria-killing hypothiocyanite.
The UI researchers also showed that the critical thiocyanate cannot be transported across airway cells with the CF mutation, which means that hypothiocyanite is not produced. In other words, without thiocyanate the oxidative antibacterial system breaks down.
These results suggest that thiocyanate may not be present in the airway surface liquid of individuals with CF. Banfi and his colleagues intend to test that hypothesis by comparing thiocyanate levels in airway surface liquid from CF patients and from healthy individuals.
Thiocyanate is naturally present in body fluids like blood and saliva. Despite its name and its chemical relationship to cyanide, thiocyanate is not toxic. Hypothiocyanite is also harmless to human cells and tissues, but the UI team found that it is extremely efficient at killing bacteria including those most commonly associated with fatal lung infections in CF patients - Staphylococcus aureus and Pseudomonas aeruginosa.
"If we could reconstitute thiocyanate concentrations in the airway surface liquid, perhaps using a nebulizer, it might boost host defenses in CF patients and help prevent bacterial lung infections," Banfi said.
In addition to Banfi and Moskwa, the UI team included graduate student, Daniel Lorentzen; Katherine Excoffon, Ph.D., associate research scientist; Joseph Zabner, M.D., professor of internal medicine; Paul McCray, M.D., the Roy J. Carver Chair in Pulmonary Research and professor of pediatrics; and William Nauseef, M.D., professor of internal medicine. Corinne Dupuy at INSERM in Paris, France also was part of the research team.
The study was funded in part by the Cystic Fibrosis Foundation.
STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178
PHOTO: A photo of Dr. Banfi is available online at http://www.anatomy.uiowa.edu/pages/directory/faculty/bonfi.htm
CONTACT: Jennifer Brown, 319-335-9917 jennifer-l-brown@uiowa.edu
http://news-releases.uiowa.edu/2006/november/113006immune-defense.html