Age and Sex of Mice Markedly Affect Survival Times Associated with Hyperoxic Acute Lung Injury.
Age and Sex of Mice Markedly Affect Survival Times Associated with Hyperoxic Acute Lung Injury.
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DOI：
10.1371/journal.pone.0130936
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Martin LJ
中科院分区：
文献类型：
--
作者：
Prows DR;Gibbons WJ Jr;Smith JJ;Pilipenko V;Martin LJ
与急性肺损伤（ALI）相关的死亡率仍然很高，最近的估计为35-45%，与几十年前的估计相似。尽管性别相关的ALI死亡率差异的证据仍不明确，但死亡率在年龄上有明显差异，老年患者的死亡率比年轻患者高3倍以上。不同品系的小鼠在ALI死亡率方面也有很大差异。为了梳理出影响死亡率的遗传因素，我们建立了一个小鼠模型的差异高氧ALI（HALI）的生存。对敏感的C57 BL/6 J（B）和抗性的129 X1/SvJ（X1）祖株产生的回交和F2群体的单独遗传分析鉴定了两个数量性状位点（QTL; Shali 1和Shali 2），其对存活具有强的、相等但相反的株内效应。同源系证实了这些相反的QTL效应，但也保留了在6-12周X1对照品系中观察到的低遗传率。将小鼠分为不同的年龄组显示，“暴露年龄”与生存时间呈负相关，并解释了抵抗力特征的减少。虽然B小鼠在6周龄时已经敏感，但X1小鼠在长达3-4周的时间内保持了显著的抵抗力。F2数据的再分析给出了类似的年龄相关的结果，也支持Shali 1和Shali 2的性别特异性连锁。重要的是，我们已经在同类小鼠中证明，这些年龄对存活率的影响与放置在X1背景上的Shali 1（6周龄小鼠更敏感）和Shali 2（10周龄小鼠更耐药）的B等位基因相对应。进一步的研究表明，这两个QTL在亚同源群体中存在显著的性别特异性存活差异。考虑年龄和性别显著提高了两个QTL的变异率，从而减少了性状变异，将Shali 1细化到<8.5Mb，并支持Shali 2区间内的几个子QTL。总之，这些同源基因将允许年龄和性别特异性研究来询问在ALI发展和进展期间受影响的无数亚表型，并确定可以预测结果的中间损伤生物标志物。
Mortality associated with acute lung injury (ALI) remains substantial, with recent estimates of 35–45% similar to those obtained decades ago. Although evidence for sex-related differences in ALI mortality remains equivocal, death rates differ markedly for age, with more than 3-fold increased mortality in older versus younger patients. Strains of mice also show large differences in ALI mortality. To tease out genetic factors affecting mortality, we established a mouse model of differential hyperoxic ALI (HALI) survival. Separate genetic analyses of backcross and F2 populations generated from sensitive C57BL/6J (B) and resistant 129X1/SvJ (X1) progenitor strains identified two quantitative trait loci (QTLs; Shali1 and Shali2) with strong, equal but opposite, within-strain effects on survival. Congenic lines confirmed these opposing QTL effects, but also retained the low penetrance seen in the 6–12 week X1 control strain. Sorting mice into distinct age groups revealed that ‘age at exposure’ inversely correlated with survival time and explained reduced penetrance of the resistance trait. While B mice were already sensitive by 6 weeks old, X1 mice maintained significant resistance up to 3–4 weeks longer. Reanalysis of F2 data gave analogous age-related findings, and also supported sex-specific linkage for Shali1 and Shali2. Importantly, we have demonstrated in congenic mice that these age effects on survival correspond with B alleles for Shali1 (6-week old mice more sensitive) and Shali2 (10-week old mice more resistant) placed on the X1 background. Further studies revealed significant sex-specific survival differences in subcongenics for both QTLs. Accounting for age and sex markedly improved penetrance of both QTLs, thereby reducing trait variability, refining Shali1 to <8.5Mb, and supporting several sub-QTLs within the Shali2 interval. Together, these congenics will allow age- and sex-specific studies to interrogate myriad subphenotypes affected during ALI development and progression and identify intermediary injury biomarkers that can predict outcome.
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DOI：
10.1164/rccm.200404-544oc
发表时间：
2005-05-01
影响因子：
24.7
作者：
Flori, HR;Glidden, DV;Matthay, MA
通讯作者：
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影响因子：
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发表时间：
2012-01-15
影响因子：
24.7
作者：
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DOI：
10.1164/rccm.201006-0912oc
发表时间：
2011-06-01
影响因子：
24.7
作者：
Leikauf, George D.;Concel, Vincent J.;Prows, Daniel R.
通讯作者：
Prows, Daniel R.