Name: design of cecal ligation and puncture and intranasal infection dual model of sepsis-induced immunosuppression
Uploaded: 2019-06-15T15:00:00
Description: Watch this Scientific Journal Video about Design of Cecal Ligation and Puncture and Intranasal Infection Dual Model of Sepsis-Induced Immunosuppression at JoVE.com

这项工作得到了国家卫生研究院支持 R01 AI138203-01、AI109317-04、AI101973-01 和 AI097532-01A1 到 M. W.北达科他大学核心设施由NIH赠款(INBRE P20GM103442和COBRE P20GM113123)提供支持。这项工作还得到了国家自然科学基金(81530063)国家重点项目(81530063)对江建新的支持。资助者在研究设计、数据收集和分析、决定出版或编写手稿方面没有作用。我们感谢马文·莱尔(北达科他大学农村卫生中心)制作了这段视频。

此处描述的所有方法均按照国家卫生指南实验室动物护理和使用研究所执行,并经北达科他大学机构动物护理和使用委员会 (IACUC) 批准。
1. 切卡结扎和穿刺
注:雌性C57BL/6小鼠(体重18-22克;年龄6-8周)随机分为六组:对照组(Ctrl)、感染组(SA为S.aureus)、两个假组和两个CLP组。Ctrl动物没有手术和继发感染伤害。SA 动物在未进行手术的情况下受到金黄色肺?...

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作为败血症研究的黄金标准模型,中电具有三种侮辱的组合,包括腹腔切除术造成的组织创伤、因结扎而导致的坏死,以及微生物泄漏导致腹腔炎和易位性腹腔炎引起的感染。细菌进入血液8。因此,CLP 比许多其他模型更能模仿人类败血症的复杂性。然而,目前CLP模式的一个主要限制是不能反映在ICU3、4、5患者中看到的脓毒症的更长期阶段。<sup class="xr...

败血症启动宿主亲炎和抗炎过程的复杂相互作用,其特点是高炎反应和随后的免疫功能障碍1,2。败血症是全球卫生优先事项,在重症监护病房(Ioc)中造成大量死亡。据估计,全世界每年脓毒症的发病率超过3000万例,尽管ICU管理取得了进步,但死亡率仍高达30%。2017年,世界卫生组织通过决议,改善这一致命疾病的预防、诊断和管理。然而,最近的研究表明,死亡不是由严重败血症患者的原发性感染引起的,而是由免疫抑制6,7引起的继发性感染(特别是肺炎).因此,迫切需要了解败血症患者为何发展为继发感染的机制,并发现更有效的治疗方法。本文描述了一种双模型,也称为双击模型,用于研究长期败血症患者的免疫抑制现象。
作为多微生物败血症、囊性结扎和穿刺(CLP)研究的黄金标准实验模型,是一种以囊性结扎和穿孔为特征的手术,有助于多微生物性囊炎8、9.病理生理学过程和细胞因子轮廓,以及动力学和量级,类似于临床败血症。结扎的位置、用于穿刺的针体尺寸以及尖刺次数是影响 CLP 后死亡率的主要因素。
肺炎是败血症危重病人死亡的主要原因。引起严重败血症的主要生物类型包括金黄色葡萄球菌(20.5%)、伪多米诺类(19.9%)、肠杆菌(主要是大肠杆菌,16.0%)和真菌(19%)。 同时,最近的研究表明,克阳性生物的发病率在增加,现在几乎和克阴性感染3一样常见。
该协议中描述的方法涉及CLP,作为"第一击"来诱导亚致死多微生物性包炎,表现为免疫抑制。该程序还涉及后续的鼻内灌输S.aureus作为"第二击",以提供一个临床相关的研究平台。

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			<td height="21" style="height:21px;width:355px;">21 G 1 &#189; Needle</td>
			<td style="width:191px;">BD</td>
			<td style="width:201px;">BD305167</td>
			<td style="width:263px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">ACK lysing buffer</td>
			<td>Gibco</td>
			<td>A10492-01</td>
			<td></td>
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		<tr height="21">
			<td height="21" style="height:22px;width:355px;">Anti-mouse CD11b antibody</td>
			<td style="width:191px;">Biolegend</td>
			<td style="width:201px;">101201</td>
			<td></td>
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		<tr height="42">
			<td height="42" style="height:42px;width:355px;">Anti-mouse Ly-6G/Ly-6C (Gr-1) antibody</td>
			<td style="width:191px;">Biolegend</td>
			<td style="width:201px;">108401</td>
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			<td height="21" style="height:21px;width:355px;">C57BL/6 mice&#160;</td>
			<td style="width:191px;">Harlan (Indianapolis)</td>
			<td style="width:201px;">C57BL/6NHsd</td>
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			<td height="21" style="height:21px;width:355px;">Desk light</td>
			<td style="width:191px;">General Supply</td>
			<td style="width:201px;">General Supply</td>
			<td></td>
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		<tr height="21">
			<td height="21" style="height:21px;width:355px;">Disinfecting wipes</td>
			<td style="width:191px;">Clorox</td>
			<td style="width:201px;">B07NV5JMCS</td>
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		<tr height="21">
			<td height="21" style="height:22px;width:355px;">Electric razor</td>
			<td style="width:191px;">General Supply</td>
			<td style="width:201px;">General Supply</td>
			<td></td>
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		<tr height="21">
			<td height="21" style="height:22px;width:355px;">ELISA kits (mouse IL-1&#946;, IL-6 and TNF&#945;)</td>
			<td>Invitrogen</td>
			<td style="width:201px;">88-7013, 88-7064, and 88-7324</td>
			<td></td>
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			<td height="21" style="height:21px;width:355px;">Iodine</td>
			<td style="width:191px;">Dynarex</td>
			<td style="width:201px;">B003U463PY</td>
			<td>PVP Iodine Wipes</td>
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			<td height="21" style="height:21px;width:355px;">Ketamine</td>
			<td style="width:191px;">FORT DODGE</td>
			<td style="width:201px;">NDC 0856-2013-01</td>
			<td>Amine hydrochloride injection</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:355px;">Laboratory scale</td>
			<td style="width:191px;">General Supply</td>
			<td style="width:201px;">General Supply</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:355px;">LB Agar, Miller</td>
			<td style="width:191px;">Fisher Scientific</td>
			<td style="width:201px;">BP1425-500</td>
			<td>Molecular genetics, powder</td>
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			<td height="21" style="height:21px;width:355px;">Micropipette</td>
			<td style="width:191px;">ErgoOne</td>
			<td style="width:201px;">7100-1100</td>
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			<td height="21" style="height:21px;width:355px;">Normal saline</td>
			<td style="width:191px;">General Supply</td>
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			<td height="42" style="height:42px;">Polylined towel</td>
			<td>CardinalHealth, Convertors</td>
			<td>3520</td>
			<td style="width:263px;">Surgical drape, sterile, for single use only</td>
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		<tr height="21">
			<td height="21" style="height:22px;width:355px;">Silk suture, 4-0</td>
			<td style="width:191px;">DAVIS &#38; GECK</td>
			<td style="width:201px;">1123-31</td>
			<td></td>
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			<td height="21" style="height:21px;width:355px;">Small animal needle holder</td>
			<td style="width:191px;">General Supply</td>
			<td style="width:201px;">General Supply</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:355px;">Small animal surgery scissors</td>
			<td style="width:191px;">General Supply</td>
			<td style="width:201px;">General Supply</td>
			<td></td>
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		<tr height="21">
			<td height="21" style="height:21px;width:355px;">Small animal surgical forceps</td>
			<td style="width:191px;">General Supply</td>
			<td style="width:201px;">General Supply</td>
			<td></td>
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		<tr height="21">
			<td height="21" style="height:21px;">Staphylococcus aureus</td>
			<td>ATCC</td>
			<td style="width:201px;">13301</td>
			<td></td>
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			<td height="21" style="height:21px;width:355px;">Warm pad</td>
			<td style="width:191px;">General Supply</td>
			<td style="width:201px;">General Supply</td>
			<td></td>
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			<td height="21" style="height:21px;width:355px;">Xylazine</td>
			<td style="width:191px;">Alfa Aesar</td>
			<td style="width:201px;">7361-61-7</td>
			<td></td>
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design of cecal ligation and puncture and intranasal infection dual model of sepsis-induced immunosuppression

败血症是一种严重而复杂的危及生命的感染,其特征是多个器官的亲炎和抗炎反应之间不平衡。随着疗法的发展,大多数患者在高炎阶段存活,但进展到免疫抑制阶段,这增加了继发性感染的出现。因此,更好地了解脓毒症期间免疫抑制阶段继发性医院获得性感染的发病机制非常重要。这里报道的模型是通过在小鼠中制造双重感染来测试传染性结果。标准外科手术用于通过结扎和穿刺(CLP)诱导多微生物性囊中膜炎,然后对金黄色葡萄球菌进行鼻内感染,以模拟在免疫抑制中发生的肺炎,这是常见的在败血症患者。这种双重模型可以反映长期败血症患者的免疫抑制状态,以及对非典型肺炎继发性感染的易感性。因此,该模型为研究败血症引起的继发性细菌性肺炎的病理生理学提供了一种简单的实验方法,可用于发现脓毒症及其并发症的新疗法。

根据实验设计和程序,C57BL/6小鼠接受中电,3天后,它们被施用细菌(图1)。如图2所示,小鼠在诱发性月炎后,在+12小时后开始死亡。CLP+SA组的两只小鼠和中电组三只小鼠在鼻内S.金尿体灌输前死亡。未感染非感染或假手术小鼠未发现死亡。因此,当小鼠在肺炎前有中电,死亡率要高得多(p < 0.05)。在鼻内细菌挑战(1 x 107<...

Watch this Scientific Journal Video about Design of Cecal Ligation and Puncture and Intranasal Infection Dual Model of Sepsis-Induced Immunosuppression at JoVE.com

Design of Cecal Ligation and Puncture and Intranasal Infection Dual Model of Sepsis-Induced Immunosuppression

该协议描述了在免疫抑制条件下测量继发医院感染的传染性结果的技术,首先通过建立结扎/穿刺小鼠,然后挑战他们与鼻内感染创建一个临床相关的免疫抑制败血症模型。

脓毒症诱导免疫抑制的切卡结扎和穿刺和鼻内感染双重模型的设计

Sepsis, a severe and complicated life-threatening infection, is characterized by an imbalance between pro- and anti-inflammatory responses in multiple ...

准备鼠标做手术。用剃须刀剃掉腹部的下部象限，用碘对该区域进行消毒。将鼠标放在其背面清洁的工作表面上，头部指向远离操作员的位置。在左下腹部做一个长约半厘米的纵向皮肤切口。小心不要穿透腹腔。用小剪刀将切口延长约一到两厘米。做一个肌肉切口，以获得进入腹腔。在大多数情况下，cecum 位于腹部左侧。隔离 cecum 。使用钝的解剖钳子，通过切口轻轻地和仔细地暴露 cecum。第四步是结扎。结扎在 cecum 上的位置决定了败血症的严重程度级别。连接约75%的塞库姆诱发严重的败血症。50%的塞库姆诱发中级败血症。而连接 25% 或更少的 cecum 将导致轻微的败血症。在指定位置将 cecum 拉起。确保不要将气量阀除垢。第五步是刺穿塞库姆。使用针头，在结扎和切库姆尖端之间的中间穿刺，用单通和穿刺打穿。确保不要刺穿任何血管。为确保完全穿刺，从两个针孔中挤出一小滴粪便。小心地将 cecum 更换到腹腔中。通过应用简单的运行缝合线关闭腹部肌肉并关闭皮肤。用碘清洁皮肤。将鼠标注入预热盐水溶液以复苏。将鼠标放回笼子，无限制地获得食物和水。在从切卡结扎和穿刺或CLP程序约三天后，我们让小鼠受到第二次鼻内感染，以刺激肺炎，经常发生在败血症。从后面接近鼠标的脖子，平稳而轻柔。左手的拇指和食指形成一个U形位置。将脖子放在耳朵后面，使鼠标头完全克制。引入鼻内感染。使用100微升移液器，在鼻内注入金黄色葡萄球菌菌株。将鼠标直立放置，缓慢地将两到三微升的细菌溶液滴入小鼠的两个鼻孔中。向上和向下抬起鼠标，其头部向上和尾部向下，以帮助细菌溶液进入气管。快速抬起鼠标，同时轻轻缓慢地降低鼠标。重复灌输15次，或直到所有细菌溶液被灌输。最后一步是完成该过程。将鼠标以大约 35 度角将鼠标放在倾斜的床上用品上以恢复。确保鼠标的背面是头部。观察鼠标，以确保它完全从麻醉和手术恢复。将床上用品压平后，将鼠标放回笼子，无限量获得食物和水。小鼠在进入周膜炎后大约12小时后开始死亡。肺炎前患有CLP的小鼠的死亡率要高得多。手术后三天，CLP小鼠的死亡率较高，而金黄色葡萄球菌的鼻内给法则较高。与单独使用CLP的小鼠或第二次击中的Sham手术小鼠相比，在败血症小鼠细菌注入后24小时内血清亲炎细胞因子的含量显著增加。然而，与SA和Sham手术加上SA小鼠相比，双击小鼠的BAL液体细胞因子水平显著降低。因此，CLP 会损害主机防御，增加感染的易感性。这种双命中模型是了解宿主-病原体相互作用的分子机制的宝贵工具，它可能为开发新的、有效的药物和其他治疗超级细菌感染的药物开辟途径。

Research

JoVE Journal

Immunology and Infection

Characterization of Inflammatory Responses During Intranasal Colonization with Streptococcus pneumoniae

Characterization of Inflammatory Responses During Intranasal Colonization with Streptococcus pneumoniae

肺炎链球菌在鼻内殖民期间炎症反应的特征

Nasopharyngeal colonization by Streptococcus pneumoniae is a prerequisite to invasion to the lungs or bloodstream1. This organism is capable of colonizing ...

科研

免疫与感染

Use of Galleria mellonella as a Model Organism to Study Legionella pneumophila Infection

Use of Galleria mellonella as a Model Organism to Study Legionella pneumophila Infection

使用<em&gt;大蜡螟</em&gt;作为模式生物来研究<em&gt;嗜肺军团菌</em&gt;感染

Legionella pneumophila, the causative agent of a severe pneumonia named Legionnaires&#39; disease, is an important human pathogen that infects and ...

Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice

盲肠结扎穿孔致脓毒症作为模型小鼠中自噬研究

Experimental sepsis can be induced in mice using the cecal ligation and puncture (CLP) method, which causes polymicrobial sepsis. Here, a protocol is ...

Methods to Evaluate Cytotoxicity and Immunosuppression of Combustible Tobacco Product Preparations

方法评估细胞毒性的可燃烟草产品的准备和免疫抑制

Among other pathophysiological changes, chronic exposure to cigarette smoke causes inflammation and immune suppression, which have been linked to ...

Intranasal Administration of Recombinant Influenza Vaccines in Chimeric Mouse Models to Study Mucosal Immunity

重组流感疫苗的嵌合体小鼠模型鼻腔给药研究黏膜免疫

Vaccines are one of the greatest achievements of mankind, and have saved millions of lives over the last century. Paradoxically, little is known about the ...

Protective Efficacy and Pulmonary Immune Response Following Subcutaneous and Intranasal BCG Administration in Mice

保护疗效及肺部免疫反应皮下和鼻内BCG管理在小鼠

Despite global coverage of intradermal BCG vaccination, tuberculosis remains one of the most prevalent infectious diseases in the world. Preclinical data ...

A Platform of Anti-biofilm Assays Suited to the Exploration of Natural Compound Libraries

适合与天然化合物库的探索抗生物试验的平台

Biofilms are regarded as one of the most challenging topics of modern biomedicine, and they are potentially responsible for over 80% of ...

Establishment of the Dual Humanized TK-NOG Mouse Model for HIV-associated Liver Pathogenesis

建立与艾滋病毒相关的肝脏发病机制的双人性化TK-NOG小鼠模型

Despite the increased life expectancy of patients infected with human immunodeficiency virus-1 (HIV-1), liver disease has emerged as a common cause of ...

A Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System

在鼻内siRNA输送到中枢神经系统期间放置小鼠的定位装置

Intranasal (IN) drug delivery to the brain has emerged as a promising method to bypass the blood-brain barrier (BBB) for the delivery of drugs into the ...

Intranasal Immunization and Milk Collection in Studies of Maternal Immunization in New Zealand White Rabbits (Oryctolagus cuniculus)

Intranasal Immunization and Milk Collection in Studies of Maternal Immunization in New Zealand White Rabbits Oryctolagus cuniculus

新西兰白兔产妇免疫研究中的内在免疫和牛奶收集

Due to similarities in placentation and antibody transfer with humans, rabbits are an excellent model of maternal immunization. Additional advantages of ...