Genetic susceptibility to ozone-induced lung hyperpermeability - Role of toll-like receptor 4
Genetic susceptibility to ozone-induced lung hyperpermeability - Role of toll-like receptor 4
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DOI：
10.1165/ajrcmb.22.5.3912
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发表时间：
2000-05-01
影响因子：
6.4
通讯作者：
Jedlicka, AE
中科院分区：
文献类型：
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作者：
Kleeberger, SR;Reddy, S;Jedlicka, AE
污染物臭氧（O-3）在人和动物模型中引起肺高通透性和炎症。在近交系小鼠中，暴露于0.3 ppm O-3 72小时后，支气管肺泡灌洗液（BAL）中恢复的总蛋白（通透性标志物）有3倍的差异。为了确定易感基因的染色体位置，我们使用来自o -3敏感的C57BL/6J （B6）和os抗性的C3H/HeJ （HeJ）祖细胞的重组近交系（RI）进行了基因组筛选。每个RI菌株表型为o -3诱导的高渗透性，并使用Map Manager QTb27对558个标记进行连锁评估。在4号染色体上鉴定出一个显著的数量性状位点（QTL）。QTL峰值的似然比chi(2)统计量（16.6）大于置换检验经验确定的显著性阈值（16.3）。这个QTL包含一个候选基因，toll样受体4 (TIr4)，最近被认为与先天免疫和内毒素易感性有关。QTL在TIr4处解释的性状总方差量，在QTL中似然比统计最高的基因约为70%。为了测试TIr4在O-3诱导的高通透性中的作用，我们比较了C3H/HeOuJ （OuJ）和HeJ小鼠（仅在TIr4编码区存在多态性差异）对O-3的BAL蛋白反应。暴露于O-3后，OuJ小鼠的蛋白质浓度（430 +/- 35 μ g/ml）显著高于HeJ小鼠（258 +/- 18 μ g/ml）。此外，逆转录酶/聚合酶链反应分析显示，O-3暴露后，He]和OuJ小鼠之间的TIr4信息表达水平存在差异。总之，结果表明，小鼠4号染色体上的QTL解释了o -3诱导的高通透性遗传变异的重要部分，并支持TIr4作为一个强候选易感基因的作用。
The pollutant ozone (O-3) induces lung hyperpermeability and inflammation in humans and animal models. Among inbred strains of mice, there is a 3-fold difference in total protein (a marker of permeability) recovered in bronchoalveolar lavage (BAL) fluid after a 72-h exposure to 0.3 ppm O-3. To determine the chromosomal locations of susceptibility genes, we performed a genome screen using recombinant inbred (RI) strains of mice derived from O-3-susceptible C57BL/6J (B6) and Os-resistant C3H/HeJ (HeJ) progenitors. Each RI strain was phenotyped for O-3-induced hyperpermeability, and linkage was assessed for 558 markers using Map Manager QTb27. A significant quantitative trait locus (QTL) was identified on chromosome 4. The likelihood ratio chi(2) statistic (16.6) for the peak of the QTL was greater than the significance threshold (16.3) determined empirically by permutation test. This QTL contains a candidate gene, Toll-like receptor 4 (TIr4), that recently has been implicated in innate immunity and endotoxin susceptibility. The amount of the total trait variance explained by the QTL at TIr4, the gene with the highest likelihood ratio statistic in the QTL was approximately 70%. To test the role of TIr4 in O-3-induced hyperpermeability, BAL protein responses to O-3 were compared in C3H/HeOuJ (OuJ) and HeJ mice that differ only at a polymorphism in the coding region of TIr4. Significantly greater protein concentrations (430 +/- 35 mu g/ml) were found in OuJ mice compared with HeJ mice (258 +/- 18 mu g/ml) after exposure to O-3 Furthermore, reverse transcriptase/polymerase chain reaction analysis demonstrated differential expression of TIr4 message levels between He] and OuJ mice after O-3 exposure. Together, results indicate that a QTL on mouse chromosome 4 explains a significant portion of the genetic variance in O-3-induced hyperpermeability, and support a role for TIr4 as a strong candidate susceptibility gene.