Progress toward a systems biology approach to acute lung injury.
Progress toward a systems biology approach to acute lung injury.
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急性肺损伤系统生物学方法的进展。
DOI：
10.1152/ajplung.00220.2007
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Erle,DavidJ
中科院分区：
文献类型：
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作者：
Frank,JamesA;Erle,DavidJ
现代肺水肿和急性肺损伤机制研究的先驱 Norman Staub 在 2002 年新奥尔良实验生物学会议上发表 COMROE 讲座时，谴责了临床医学与分子生物学之间的脱节 (12)。他将这种脱节部分归因于对“生物科学之女王和母亲”的生理学的时尚忽视。小鼠模型系统为剖析疾病的遗传和基因组方法提供了巨大的机会，但小鼠体型较小，通常使得对多个相关生理终点的详细测量变得不切实际。较大的动物通常更适合生理分析，但可用的遗传和基因组工具较少。 2001 年，出现了一项令人兴奋的进展，有望将生理学和分子生物学重新结合起来：威斯康星医学院和查尔斯河在国家心肺血液研究所的资助下共同努力，培育出第一组商业化的健康大鼠 (4)。当然，大鼠模型在生理学方面有着悠久而杰出的记录。康体大鼠是使用育种和遗传筛选策略产生的，该策略用来自不同品系的相同染色体替换来自一个近交品系的单个染色体。与用于复杂性状图谱的传统隔离杂交策略相比，Consomic 大鼠具有一定的优势 (3)。体型大鼠组可用于剖析特定染色体上的基因对各种性状的贡献，就像现在对与心血管和肺部疾病相关的数百个基线生理测量所做的那样（http://pga.mcw.edu）。在 Nonas 及其同事最近发表的文章 (9) 中，他们向我们提供了一份指导性进展报告，介绍了他们针对临床相关的复杂疾病表型：呼吸机引起的肺损伤 (VILI) 的联合体和基因组方法。对两种大鼠品系进行了筛选，以确定其对 VILI 的易感性，该 VILI 是由于无呼气末正压的高潮气量通气引起的。比较机械通气前后布朗挪威 (BN) 大鼠和达尔盐敏感 (SS) 大鼠的支气管肺泡灌洗 (BAL) 液蛋白浓度和细胞计数。与 SS 大鼠相比，BN 大鼠相对容易受到这些措施的伤害。 DNA微阵列被用来识别数百个基因，这些基因在基线或受伤后在这两种菌株的肺部中存在差异表达。其中一些基因之前已使用传统的基因表达谱 (8, 11) 或蛋白质组 (7) 方法进行了鉴定，而其他基因则是新的候选基因。尽管全基因组表达谱是生成长候选基因列表的绝佳方法，但事实证明，开发后续方法来选择关键基因更加困难。在这项 VILI 研究中，研究人员尝试使用健康大鼠来达到此目的。他们推断，差异表达基因密度较高的染色体可能更有可能包含 VILI 中重要的基因。利用这种方法，他们发现 2、13、16 和 17 号染色体的差异表达基因最为丰富。他们使用 consomic 品系测试了 SS 背景下 BN 大鼠的 2、13 和 16 号染色体对 VILI 的潜在贡献。尚无 17 号染色体的大鼠。 20 号染色体的同体大鼠被用作某种对照，因为来自阵列研究的差异表达探针相对较少位于该染色体上。对体鼠的检查显示出一系列表型。例如，SS：BN16...
PRESENTING THE COMROE LECTURE at the Experimental Biology 2002 conference in New Orleans, Norman Staub, a pioneer of modern research into the mechanisms of pulmonary edema and acute lung injury, decried the disconnection between clinical medicine and molecular biology (12). He attributed this disconnection in part to a fashionable neglect of physiology, the “queen and mother of biological sciences.” Mouse model systems offer tremendous opportunities for genetic and genomic approaches to dissecting disease, but the small size of mice often makes detailed measurements of multiple relevant physiological endpoints impractical. Larger animals are typically better suited for physiological analysis, but fewer genetic and genomic tools are available. In 2001, an exciting development with the promise of reuniting physiology and molecular biology was introduced: a collaborative effort between Medical College of Wisconsin and Charles River with funding from the National Heart, Lung, and Blood Institute yielded the first commercially available set of consomic rats (4). Rat models, of course, have a long and distinguished record in physiology. Consomic rats are produced using a breeding and genetic screening strategy that substitutes a single chromosome from one inbred strain with the same chromosome from a different strain. Consomic rats offer certain advantages over traditional segregating crossbreeding strategies used for complex trait mapping (3). Panels of consomic rats can be used to dissect the contribution of genes on specific chromosomes to various traits, as is now being done with hundreds of baseline physiological measurements relevant to cardiovascular and lung disease (http://pga. mcw. edu). In the recent article by Nonas and colleagues (9), they give us an instructive progress report on their combined consomic and genomic approach to a clinically relevant complex disease phenotype: ventilator-induced lung injury (VILI). Two rat strains were screened for susceptibility to VILI resulting from high tidal volume ventilation without positive end-expiratory pressure. Bronchoalveolar lavage (BAL) fluid protein concentration and cell count were compared in Brown Norway (BN) rats and Dahl salt-sensitive (SS) rats before and after mechanical ventilation. BN rats were relatively susceptible to injury by these measures compared with SS rats. DNA microarrays were used to identify hundreds of genes that were differentially expressed in lungs of these two strains at baseline or following injury. Some of these genes have been previously identified using conventional, gene expression profiling (8, 11), or proteomic (7) approaches, whereas others are novel candidates. Although genome-wide expression profiling is an excellent method for generating long lists of candidates, it is proving to be more difficult to develop follow-on approaches to select critical genes. In this VILI study, the investigators attempt to use consomic rats for this purpose. They reasoned that chromosomes with a higher density of differentially expressed genes may be more likely to contain genes important in VILI. Using this approach, they found chromosomes 2, 13, 16, and 17 to be most enriched for differentially expressed genes. Using consomic strains, they tested the potential contribution of chromosomes 2, 13, and 16 from BN rats to VILI in the SS background. A consomic chromosome 17 rat was not available. Chromosome 20 consomic rats were used as a control, of sorts, in that relatively few differentially expressed probes from the array study reside on this chromosome. Examination of the consomic rats showed a range of phenotypes. For example, SS: BN16 …