Lactoferrin for Immunomodulation of Systemic Inflammatory Response Syndrome

描述（由申请人提供）：本项目的总体目标是开发一种生物治疗剂，使用含有“人源化”糖基化模式的新型人重组乳铁蛋白治疗全身炎症反应综合征（SIRS）。SIRS是脓毒症和随后导致多器官衰竭的组织损伤之前的复杂急性期内在介质作用的临床表现。全身炎症反应综合征（SIRS）是脓毒症的前兆，是重症监护室死亡的主要原因，死亡率为30%至90%。非常需要开发治疗剂以在SIRS进展为脓毒症之前对抗SIRS。在脓毒症期间，免疫稳态丧失，导致破坏性免疫病理学。该提案将研究乳铁蛋白在小鼠细菌诱导的全身炎症发展过程中介导细胞反应的作用。将重点放在rhLF的效用，与市售人乳和嗜酸乳杆菌衍生的乳铁蛋白进行剂量范围比较。将采用一系列试验，包括特定细菌损伤后促炎介质和基因表达谱的测量。还将使用耐甲氧西林金黄色葡萄球菌（MRSA）感染研究与乳铁蛋白介导相关的全身事件，这在医院相关（医院内）感染中是麻烦的。有明确的需要，以解决治疗和警戒程序的发展，以确保遏制在一般人群。实际上，对于开发新策略（以增强抗生素治疗）来控制由革兰氏阴性细菌以及革兰氏阳性细菌如金黄色葡萄球菌两者发生的SIRS存在未满足的需求。 公共卫生相关性：全身炎症反应综合征（SIRS）是脓毒症的前兆，是重症监护室死亡的主要原因，死亡率为30%至90%。SIRS描述了败血症前的急性非特异性疾病的临床表现，而败血症的确切诊断需要感染性病因。非常需要开发治疗剂来解决胰岛素诱导的炎症的早期阶段并防止其进展。特别地，这成为革兰氏阴性和革兰氏阳性细菌的重要问题，包括耐甲氧西林金黄色葡萄球菌（MRSA），其在医院相关（医院内）感染中是麻烦的。实际上，对于开发新策略（以增强抗生素治疗）来控制由革兰氏阳性细菌（如金黄色葡萄球菌）以及革兰氏阴性实体发生的SIRS存在未满足的需求。该提案的目的是检查新型人重组乳铁蛋白对抗SIRS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.