CXCR2 is critical for dsRNA-induced lung injury: relevance to viral lung infection.
CXCR2 is critical for dsRNA-induced lung injury: relevance to viral lung infection.
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DOI：
10.1186/1476-9255-2-4
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发表时间：
2005-05-28
期刊：
影响因子：
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通讯作者：
Strieter, Robert M
中科院分区：
文献类型：
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作者：
Londhe, Vedang A;Belperio, John A;Strieter, Robert M
背景：呼吸道病毒感染的特征是白细胞的浸润，包括活化的中性粒细胞进入肺部，可导致持续的肺损伤，并可能导致慢性肺部疾病。在病毒诱导的肺部炎症和损伤期间，中性粒细胞向肺部募集的具体机制尚未完全阐明。由于CXCL1和CXCL2/3通过CXCR2起作用，是有效的中性粒细胞趋化剂，我们研究了它们在dsRNA诱导的肺损伤中的作用，其中dsRNA （Poly IC）是一种很好的模拟急性病毒感染的合成剂。方法：选用6-8周龄雌性BALB/c小鼠，气管内注射单链RNA （ssRNA）或双链RNA （dsRNA）。然后在指定的时间点采集肺，以表征dsRNA暴露后引发的趋化因子反应和由此导致的肺损伤，通过组织病理学分析定性证明，并通过流式细胞仪、蛋白质和mRNA分析定量证明BAL液体和组织样本。然后我们重复实验，首先用抗pmn或相应的对照抗体预处理小鼠，然后在dsRNA暴露之前用抗cxcr2或相应的对照抗体预处理另一组小鼠。结果：气管内dsRNA导致BALB/c小鼠在dsRNA后72小时中性粒细胞浸润和肺损伤显著增加，但对ssRNA （Poly c；对照）处理没有反应。CXCR2配体和CXCR2的表达与肺中性粒细胞募集有关。中性粒细胞耗竭研究表明，用抗pmn单克隆抗体预处理小鼠，可显著减少dsRNA对中性粒细胞浸润和肺损伤的反应。此外，用抗CXCR2中和抗体预处理dsRNA暴露小鼠，抑制CXCR2配体/CXCR2相互作用也可显著减轻中性粒细胞隔离和肺损伤。结论：CXC趋化因子配体/CXCR2生物轴在dsrna诱导的急性病毒感染相关肺损伤发病过程中起关键作用。
BACKGROUND: Respiratory viral infections are characterized by the infiltration of leukocytes, including activated neutrophils into the lung that can lead to sustained lung injury and potentially contribute to chronic lung disease. Specific mechanisms recruiting neutrophils to the lung during virus-induced lung inflammation and injury have not been fully elucidated. Since CXCL1 and CXCL2/3, acting through CXCR2, are potent neutrophil chemoattractants, we investigated their role in dsRNA-induced lung injury, where dsRNA (Poly IC) is a well-described synthetic agent mimicking acute viral infection. METHODS: We used 6-8 week old female BALB/c mice to intratracheally inject either single-stranded (ssRNA) or double-stranded RNA (dsRNA) into the airways. The lungs were then harvested at designated timepoints to characterize the elicited chemokine response and resultant lung injury following dsRNA exposure as demonstrated qualititatively by histopathologic analysis, and quantitatively by FACS, protein, and mRNA analysis of BAL fluid and tissue samples. We then repeated the experiments by first pretreating mice with an anti-PMN or corresponding control antibody, and then subsequently pretreating a separate cohort of mice with an anti-CXCR2 or corresponding control antibody prior to dsRNA exposure. RESULTS: Intratracheal dsRNA led to significant increases in neutrophil infiltration and lung injury in BALB/c mice at 72 h following dsRNA, but not in response to ssRNA (Poly C; control) treatment. Expression of CXCR2 ligands and CXCR2 paralleled neutrophil recruitment to the lung. Neutrophil depletion studies significantly reduced neutrophil infiltration and lung injury in response to dsRNA when mice were pretreated with an anti-PMN monoclonal Ab. Furthermore, inhibition of CXCR2 ligands/CXCR2 interaction by pretreating dsRNA-exposed mice with an anti-CXCR2 neutralizing Ab also significantly attenuated neutrophil sequestration and lung injury. CONCLUSION: These findings demonstrate that CXC chemokine ligand/CXCR2 biological axis is critical during the pathogenesis of dsRNA-induced lung injury relevant to acute viral infections.