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The Role of the Spleen in the Febrile Reponse

脾在退热中的作用

基本信息

批准号：
7451528
负责人：
Carlos Feleder
金额：
$ 23.1万
依托单位：
ALBANY COLLEGE OF PHARMACY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7451528
关键词：
Acute-Phase Reaction Anesthesia procedures Animals Antilymphocyte Globulin Appearance Attenuated Bacteria Biological Assay Blood Blood Circulation Body Temperature Cavia Cell Wall Cells Cessation of life Chemicals Conscious Convulsions Data Dehydration Delirium Development Dichloromethylene Diphosphonate Dinoprostone Disease Dose Estradiol Exhibits Fever Gas Chromatography Health Host Defense Immune Infection Infection prevention Injection of therapeutic agent Intravenous Knowledge Kupffer Cells Laboratories Laboratory Animals Lead Ligation Link Lipids Lipopolysaccharides Liposomes Liver Mass Chromatography Methods Molecular Weight Morbidity - disease rate Normal Range Organ Patients Pharmaceutical Preparations Phase Portal vein structure Production Prostaglandin D2 Prostaglandins Proteins Public Health Purpose Pyrogens Range Reaction Reporting Research Risk Role Route Saline Series Solid Source Spectrum Analysis Spleen Splenectomy Splenic Tissue Standards of Weights and Measures Steroids Structure of splenic vein T-Lymphocyte Temperature Testing Thin Layer Chromatography Thinking Thromboxane B2 Tissue Extracts Travel Veins Virus automobile accident day in vivo insight intraperitoneal macrophage pathogen prevent prostaglandin F1 research study response tool uptake

项目摘要

DESCRIPTION (provided by applicant): The role of the spleen in the febrile response has not been systematically investigated in spite of its fundamental participation in the host defenses against infections. We reported recently that the onset of lipopolysaccharide (LPS)-induced fever, irrespective of its route of administration, is temporally correlated with the appearance of LPS in the liver, and that splenectomy significantly increases both the febrile response to LPS and the uptake of LPS by the liver (Kupffer cells [KC]). To further evaluate the association between the spleen and the liver in LPS fever production, we ligated the connection between them, the splenic vein of guinea pigs and, 7 and 30 days later, challenged the conscious animals with LPS intraperitoneally (ip). Both the febrile response and the uptake of LPS by KC were augmented until new collateral veins developed, suggesting that the spleen may normally contribute a factor that limits the KC uptake of LPS and, thus, modulates the febrile response. To further verify the presence of a splenic inhibitory factor, we prepared an extract of spleens from guinea pigs pretreated ip with LPS or pyrogen-free saline, homogenized and ultrafiltered it, and injected it intravenously (iv) into splenectomized guinea pigs pre-treated with LPS ip. The results confirmed our presumption, viz., the splenic extract from LPS treated guinea pigs inhibited the exaggerated febrile response observed in the Splex guinea pigs, supporting the putative presence of a splenic inhibitory factor. Preliminary data indicates that the factor/s most likely is a lipid. The identity of the splenic factor(s) that may thus be released into the splenic vein, however, is (are) still uncertain, but the fact that the active principle passes through a microporous filter having a nominal molecular weight cutoff of 10,000 d suggests it could be a prostanoid, e.g., PGD2, PGE2, PGF11, thromboxane B2, or a steroid, such as estradiol. These factors occur in the spleen and influence KC activity. The purpose of the present study, therefore, is to substantiate the involvement of the spleen in LPS-induced fever by isolating this factor, and verifying that splenic macrophages are its source. This study will be important for better understanding how the febrile response may be regulated by the spleen to defend health and mitigate the potentially harmful effects of high fevers in infected hosts. PUBLIC HEALTH RELEVANCE The spleen is an important organ of the body. One of its most critical functions is to help prevent infection by bacteria and virus. If the spleen becomes damaged or destroyed (in an automobile accident, for example), the risk of a serious infection becomes much greater, as does the possibility of illness, disease, and even death. Our laboratory has been studying how the spleen protects us from infection by investigating the role of the spleen in the production of fever, one of the first responses to a serious infection. Mild fever can be produced in laboratory animals by treating them with lipopolysaccharide (LPS) a chemical extracted from the cell wall of bacteria. In earlier experiments we found that if we surgically removed the spleen of guinea pigs, LPS caused a much higher fever than it does in animals that still have a spleen. Why does removing the spleen potentiate LPS fever? We think that it involves the liver. Normally, LPS causes fever, at least in part, by stimulating a type of immune cell, the Kupffer cell, which is found in the liver. LPS stimulates Kupffer cells from the inside; that is, LPS must first be taken up into the Kupffer cell before it can cause fever. Our data indicate that the spleen normally protects us against fever by making a chemical that travels through the blood to the liver and tells the Kupffer cells NOT to take up LPS. When we remove the spleen, this splenic factor, as we call it, it not available and Kupffer cells are able to take up a lot more LPS and produce a much higher fever. The objective of our research is to discover the identity of the substance released from the spleen, confirm that Kupffer cells are the target of the splenic factor, and to identify its cell source. To accomplish this, we will treat guinea pigs with LPS to cause the spleen to make the splenic factor, remove the spleen under anesthesia, and then make extracts of the spleen. We will then treat splenectomized guinea pigs with the spleen extracts and see if the extract protects them against the excess of LPS and the exaggerated febrile response of splenectomized animals. With this approach, we should be able to isolate the splenic factor from the extracts that protect guinea pigs against the effects of LPS. In the longer term, if we can identify this splenic factor, we might be able to discover a drug that will reduce fever and protect patients from the dangerous effects of infection.

描述（由申请方提供）：尽管脾脏基本上参与了宿主对感染的防御，但其在发热反应中的作用尚未得到系统研究。我们最近报道，脂多糖（LPS）诱导的发热的发作，无论其给药途径如何，都与肝脏中LPS的出现存在时间相关性，并且脾切除术显著增加了对LPS的发热反应和肝脏（枯否细胞[KC]）对LPS的摄取。为了进一步评估脾和肝在LPS发热产生中的关联，我们结扎了它们之间的连接，豚鼠的脾静脉，并在7天和30天后，用LPS腹腔内（ip）攻击清醒的动物。发热反应和KC对LPS的摄取均增加，直到新的侧支静脉形成，这表明脾脏通常可能是限制KC摄取LPS的因素，从而调节发热反应。为了进一步验证脾抑制因子的存在，我们制备了用LPS或无热原盐水预处理的豚鼠的脾提取物，将其均质化并超滤，并将其静脉内（iv）注射到用LPS预处理的脾切除豚鼠中。结果证实了我们的假设，即，来自LPS处理的豚鼠的脾提取物抑制了在Splex豚鼠中观察到的过度发热反应，这支持了脾抑制因子的假定存在。初步数据表明，该因素最有可能是脂质。然而，可能因此释放到脾静脉中的脾因子的身份仍然是不确定的，但是活性成分通过具有10，000 d的标称分子量截留的微孔过滤器的事实表明它可能是前列腺素类，例如，PGD 2、PGE 2、PGF 11、血栓素B2或类固醇，如雌二醇。这些因素发生在脾脏中，影响KC活性。因此，本研究的目的是通过分离这种因子，并验证脾巨噬细胞是其来源，来证实脾参与LPS诱导的发热。这项研究将是重要的，更好地了解如何发热反应可能是由脾脏调节，以捍卫健康和减轻潜在的有害影响，高热感染的主机。脾是人体的重要器官。它最重要的功能之一是帮助预防细菌和病毒感染。如果脾脏受到损伤或破坏（例如在车祸中），严重感染的风险就会变得更大，生病，疾病甚至死亡的可能性也会增加。我们的实验室一直在研究脾脏如何保护我们免受感染，通过调查脾脏在发热中的作用，发热是对严重感染的第一反应之一。用脂多糖（LPS）（一种从细菌细胞壁中提取的化学物质）治疗实验室动物，可以使它们产生轻度发热。在早期的实验中，我们发现，如果我们通过手术切除豚鼠的脾脏，LPS会引起比仍有脾脏的动物更高的发烧。为什么切除脾脏会增强LPS发热？我们认为这和肝脏有关。通常情况下，LPS引起发烧，至少部分是通过刺激一种免疫细胞，即肝脏中的库普弗细胞。LPS从内部刺激枯否细胞;也就是说，LPS必须首先被枯否细胞吸收，然后才能引起发热。我们的数据表明，脾脏通常通过制造一种化学物质来保护我们免受发烧的影响，这种化学物质通过血液到达肝脏，并告诉枯否细胞不要吸收LPS。当我们切除脾脏时，我们称之为脾因子，它就不能被利用了枯否细胞就能吸收更多的脂多糖从而产生更高的体温.我们的研究目的是发现从脾脏释放的物质的身份，确认库普弗细胞是脾因子的靶点，并确定其细胞来源。为了实现这一点，我们将用LPS处理豚鼠，使脾脏产生脾因子，在麻醉下取出脾脏，然后制备脾脏提取物。然后，我们将用脾提取物处理脾切除的豚鼠，并观察提取物是否保护它们免受过量LPS和脾切除动物的过度发热反应。通过这种方法，我们应该能够从保护豚鼠免受LPS影响的提取物中分离出脾因子。从长远来看，如果我们能够确定这种脾脏因子，我们可能能够发现一种药物，可以减少发烧，保护患者免受感染的危险影响。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The OVLT initiates the fall in arterial pressure evoked by high dose lipopolysaccharide: evidence that dichotomous, dose-related mechanisms mediate endotoxic hypotension.

OVLT 引发高剂量脂多糖引起的动脉压下降：证据表明二分法、剂量相关机制介导内毒素性低血压。

DOI：
10.1016/j.jneuroim.2015.05.023
发表时间：
2015
期刊：
Journal of neuroimmunology
影响因子：
3.3
作者：
Feleder,Carlos;SertacYilmaz,M;Peng,Jianya;Göktalay,Gökhan;Millington,WilliamR
通讯作者：
Millington,WilliamR

Determination of prostaglandin profiles in lipopolysaccharide-challenged guinea pig spleen.