Lactoferrin for Immunomodulation of Systemic Inflammatory Response Syndrome

描述（由申请人提供）：该项目的总体目标是开发一种生物疗法，使用一种含有“人源化”糖基化模式的新型人重组乳铁蛋白来治疗全身炎症反应综合征（SIRS）。SIRS是复杂的急性期内在介质作用的临床表现，在败血症和随后的组织损伤导致多器官衰竭之前发生。全身性炎症反应综合征（SIRS）是败血症的前兆，被认为是重症监护病房死亡的主要原因，死亡率从30%到90%不等。在SIRS发展为败血症之前，非常需要开发治疗方法来对抗SIRS。在败血症期间，免疫稳态丢失导致破坏性免疫病理。本研究将研究乳铁蛋白在小鼠细菌诱导的全身性炎症发展过程中介导细胞反应的作用。重点将放在rhLF的效用上，并将剂量范围与市售的人乳和中性粒细胞衍生的乳铁蛋白进行比较。将采用一系列测试，包括测量促炎介质和特定细菌损伤后的基因表达谱。与乳铁蛋白介导相关的系统性事件也将通过耐甲氧西林金黄色葡萄球菌（MRSA）感染进行调查，这在医院相关（院内）感染中是很麻烦的。有明确的需要解决治疗和警戒程序的发展问题，以确保在一般人群中得到控制。事实上，对于开发一种新的策略（加强抗生素治疗）来控制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，目前还没有得到满足。

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.