Mechanical ventilation modulates Toll-like receptor-3-induced lung inflammation via a MyD88-dependent, TLR4-independent pathway: a controlled animal study.
Mechanical ventilation modulates Toll-like receptor-3-induced lung inflammation via a MyD88-dependent, TLR4-independent pathway: a controlled animal study.
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DOI：
10.1186/1471-2466-10-57
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发表时间：
2010-11-19
影响因子：
3.1
通讯作者：
Altemeier WA
中科院分区：
文献类型：
--
作者：
Chun CD;Liles WC;Frevert CW;Glenny RW;Altemeier WA
机械通气会加重因暴露于微生物产物而导致的肺部炎症。本研究的目的是检验呼吸机相关免疫调节需要MyD 88依赖性信号传导的假设。由于MyD 88是用于所有Toll样受体（TLR）（TLR 3除外）以及IL-1和IL-18受体的促炎信号传导的关键衔接蛋白，因此MyD 88依赖性将涉及在机械通气期间产生由这些受体中的一种或多种识别的内源性可溶性配体，并且将为潜在的未来治疗干预提供机会。我们比较了机械通气对有或无MyD 88表达的poly（I：C）暴露小鼠之间的肺部炎症和通透性的影响。Poly（I：C）是TLR 3的合成配体，TLR 3是唯一的MyD 88非依赖性TLR，允许分离MyD 88缺失对肺部炎症的呼吸机增强的影响。通过肺组织匀浆中细胞因子浓度和支气管肺泡灌洗液（BALF）中多形核细胞（PMN）数量来评估肺炎症。通过BALF中总蛋白、IgM和静脉注射的FITC-葡聚糖浓度评估肺通透性。我们发现MyD 88是机械通气增强TLR 3诱导的肺部炎症和渗透性所必需的。由于TLR 4是组织损伤过程中产生的内源性配体的最常报道的受体，我们进行了第二个实验，比较野生型和TLR 4-/-小鼠。我们发现，机械通气增加TLR 3介导的炎症和通透性独立于TLR 4。这些数据支持以下假设：中等潮气量的机械通气产生由MyD 88依赖性受体识别的内源性配体，而不是TLR 4，并且该机制可能有助于呼吸机相关肺部炎症和损伤的发展。这些配体和/或受体的鉴定可能导致新的药物治疗ARDS。
Mechanical ventilation augments lung inflammation resulting from exposure to microbial products. The objective of this study was to test the hypothesis that ventilator-associated immune modulation requires MyD88-dependent signaling. Because MyD88 is a critical adapter protein utilized for pro-inflammatory signaling by all Toll-like receptors (TLRs), with the exception of TLR3, as well as by the IL-1 and IL-18 receptors, MyD88 dependence would implicate generation of an endogenous soluble ligand recognized by one or more of these receptors during mechanical ventilation and would provide an opportunity for a potential future therapeutic intervention. We compared the effect of mechanical ventilation on lung inflammation and permeability between poly(I:C) exposed mice with or without expression of MyD88. Poly(I:C) is a synthetic ligand for TLR3, the only MyD88-independent TLR, allowing isolation of the effect of MyD88 deletion on ventilator-augmentation of lung inflammation. Lung inflammation was assessed by cytokine concentration in lung tissue homogenate and polymorphonuclear cell (PMN) number in bronchoalveolar lavage fluid (BALF). Lung permeability was assessed by total protein, IgM, and intravenously injected FITC-dextran concentrations in BALF. We found that MyD88 was required for mechanical ventilation augmentation of TLR3-induced lung inflammation and permeability. Because TLR4 is the most commonly reported receptor for endogenous ligands generated during tissue injury, we performed a second experiment comparing wildtype and TLR4-/- mice. We found that mechanical ventilation increased TLR3-mediated inflammation and permeability independent of TLR4. These data support the hypothesis that mechanical ventilation with moderate tidal volumes generates an endogenous ligand(s) recognized by MyD88-dependent receptor(s) other than TLR4, and that this mechanism can contribute to the development of ventilator-associated lung inflammation and injury. Identification of these ligands and/or receptors could lead to new pharmacological treatments for ARDS.
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DOI：
10.1186/cc5050
发表时间：
2006
期刊：
Critical care (London, England)
影响因子：
--
作者：
O'Mahony DS;Liles WC;Altemeier WA;Dhanireddy S;Frevert CW;Liggitt D;Martin TR;Matute-Bello G
通讯作者：
Matute-Bello G
影响因子：
158.5
作者：
Amato, MBP;Barbas, CSV;Carvalho, CRR
通讯作者：
Carvalho, CRR
DOI：
10.1164/ajrccm.163.3.2003001
发表时间：
2001-03-01
影响因子：
24.7
作者：
Held, HD;Boettcher, S;Uhlig, S
通讯作者：
Uhlig, S
影响因子：
5.5
作者：
Altemeier, William A.;Zhu, Xiaodong;Liles, W. Conrad
通讯作者：
Liles, W. Conrad
影响因子：
8.8
作者：
Gajic, O;Dara, SI;Hubmayr, RD
通讯作者：
Hubmayr, RD