Lactoferrin for Immunomodulation of Systemic Inflammatory Response Syndrome

描述(申请人提供)：该项目的总体目标是开发一种生物疗法来治疗全身炎症反应综合征(SIRS)，使用一种新型的人重组乳铁蛋白，该蛋白含有人源化的糖基化模式。SIRS是脓毒症和随后的组织损伤导致多器官衰竭之前复杂的急性期内在介质作用的临床表现。全身炎症反应综合征(SIRS)是脓毒症的先兆，已被认为是重症监护病房的主要死亡原因，死亡率从30%到90%不等。在SIRS发展为脓毒症之前，非常需要开发治疗方法来对抗SIRS。在脓毒症期间，免疫动态平衡丧失，导致破坏性的免疫病理。这项建议将研究乳铁蛋白在细菌诱导的小鼠全身炎症发展过程中介导细胞反应的作用。重点将放在重组人乳铁蛋白的用途上，并与商业上可获得的人乳和中性粒细胞来源的乳铁蛋白进行剂量范围的比较。将采用一系列测试，包括测量促炎介质和特定细菌侮辱后的基因表达谱。与乳铁蛋白调节相关的系统性事件也将使用甲氧西林耐药金黄色葡萄球菌(MRSA)感染进行调查，这在医院相关(医院)感染中是麻烦的。有一种明确的需要解决治疗和警示程序的发展，以确保在普通人群中遏制。事实上，开发一种新的策略(加强抗生素治疗)来控制由革兰氏阴性菌和革兰氏阳性菌(如金黄色葡萄球菌)引起的SIRS，还有一个尚未满足的要求。 公共卫生相关性：全身炎症反应综合征(SIRS)是败血症的先兆，已被认为是重症监护病房的主要死亡原因，死亡率从30%到90%不等。SIRS描述败血症前急性非特异性疾病的临床表现，而感染病因学是准确诊断败血症所必需的。迫切需要开发治疗方法来解决侮辱引起的炎症的早期阶段，并防止其发展。特别是，这对革兰氏阴性和革兰氏阳性细菌来说都是一个重要的问题，包括耐甲氧西林金黄色葡萄球菌(MRSA)，这在医院相关的(医院感染)中是麻烦的。事实上，对于开发一种新的策略(加强抗生素治疗)来控制由革兰氏阳性细菌(如金黄色葡萄球菌)以及来自革兰氏阴性实体的SIRS，还有一个尚未满足的要求。该建议的目的是研究一种新型的人重组乳铁蛋白在对抗SIRS方面的效用，并限制SIRS的进展。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a biologic therapeutic to treat systemic inflammatory response syndrome (SIRS) using a novel human recombinant lactoferrin that contains "humanized" glycosylation patterns. SIRS is a clinical expression of the action of complex acute-phase intrinsic mediators that precedes sepsis and subsequent tissue damage leading to Multiple Organ Failure. The systemic inflammatory response syndrome (SIRS) is a precursor to sepsis, and has been implicated as the leading cause of death in the intensive care unit, with mortality rates ranging from 30% to 90%. There is a great need for development of therapeutics to combat SIRS before its progression to sepsis. During sepsis, immune homeostasis is lost leading to destructive immunopathology. This proposal will examine lactoferrin's effects to mediate cellular responses during the development of bacterial-induced systemic inflammation in mice. Focus will be made on utility of rhLF, with dose range comparisons made to commercially available human milk- and neutrophil-derived lactoferrins. A battery of tests will be employed to include measurement of pro-inflammatory mediators and gene expression profiles following specific bacterial insult. The systemic events associated with lactoferrin mediation will also be investigated using methicillin-resistant Staphylococcus aureus bacteria (MRSA) infection, which is troublesome in hospital-associated (nosocomial) infections. There is a defined need to address development of therapeutics and cautionary procedures to ensure containment within the general population. Indeed, there is an unmet requirement for developing a new strategy (to augment antibiotic therapy) to control SIRS occurring from both Gram-negative bacteria, as well as Gram-positive bacteria such as Staphylococcus aureus. PUBLIC HEALTH RELEVANCE: The systemic inflammatory response syndrome (SIRS) is a precursor to sepsis, and has been implicated as the leading cause of death in the intensive care unit, with mortality rates ranging from 30% to 90%. SIRS describes the clinical manifestations derived from an acute nonspecific illness preceding septicemia, whereas an infectious etiology is required for the exact diagnosis of sepsis. There is a great need for development of therapeutics to address the early stages of insult-induced inflammation and to prevent its progression. In particular, this become an important issue with both Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which is troublesome in hospital-associated (nosocomial) infections. Indeed, there is an unmet requirement for developing a new strategy (to augment antibiotic therapy) to control SIRS occurring from Gram-positive bacteria, such as Staphylococcus aureus, as well as from Gram-negative entities. The goal of this proposal is to examine the utility of a novel human recombinant Lactoferrin to combat SIRS, and limit progression of SIRS.