A genetic mouse model to investigate hyperoxic acute lung injury survival.
A genetic mouse model to investigate hyperoxic acute lung injury survival.
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DOI：
10.1152/physiolgenomics.00232.2006
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发表时间：
2007-08
影响因子：
4.6
通讯作者：
D. Prows;Amanda P Hafertepen;W. Gibbons;Abby V. Winterberg;T. Nick
中科院分区：
文献类型：
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作者：
D. Prows;Amanda P Hafertepen;W. Gibbons;Abby V. Winterberg;T. Nick
急性肺损伤（ALI）是一种毁灭性的疾病，尽管经过数十年的研究，死亡率仍然很高。高氧是治疗急性肺损伤和其他危重患者的通用疗法，但其本身会引起肺部损伤，从而极大地限制了其治疗潜力。我们规定，能够长时间使用更高水平的补充氧气将提高恢复率。为了实现这一目标，我们寻找小鼠模型来鉴定导致高氧性急性肺损伤 (HALI) 死亡率的基因。在连续 >95% O2 中筛选了 18 个近交系小鼠品系。敏感 C57BL/6J 菌株和耐药 129X1/SvJ 菌株之间存在显着的生存差异。尽管具有耐药性，但只有四分之一的 129X1/SvJ 小鼠比任何 C57BL/6J 小鼠的存活时间更长，这表明耐药性外显率降低。 F1 小鼠之间的生存时间差异暗示了亲本（印记）效应。为了进一步评估印记并开始描述 HALI 存活的遗传成分，我们从所有四种可能的杂交中产生了后代并进行了表型分析。分离分析支持一种或多种基因的母系遗传，但一种或多种贡献基因的父系遗传。证明了显着的性别效应，对于所有 F2 杂交，雄性比雌性更具抵抗力。不同F2杂交的存活时间范围和敏感/抗性比率也支持印记，并预测存活率的增加是由于抗性和敏感亲本菌株共同贡献的显性抗性等位基因。 HALI 存活是多基因的，具有复杂的遗传模式，应该适合用该小鼠模型进行遗传解剖。
Acute lung injury (ALI) is a devastating disease that maintains a high mortality rate, despite decades of research. Hyperoxia, a universal treatment for ALI and other critically ill patients, can itself cause pulmonary damage, which drastically restricts its therapeutic potential. We stipulate that having the ability to use higher levels of supplemental O2 for longer periods would improve recovery rates. Toward this goal, a mouse model was sought to identify genes contributing to hyperoxic ALI (HALI) mortality. Eighteen inbred mouse strains were screened in continuous >95% O2. A significant survival difference was identified between sensitive C57BL/6J and resistant 129X1/SvJ strains. Although resistant, only one-fourth of 129X1/SvJ mice survived longer than any C57BL/6J mouse, demonstrating decreased penetrance of resistance. A survival time difference between reciprocal F1 mice implicated a parent-of-origin (imprinting) effect. To further evaluate imprinting and begin to delineate the genetic components of HALI survival, we generated and phenotyped offspring from all four possible intercrosses. Segregation analysis supported maternal inheritance of one or more genes but paternal inheritance of one or more contributor genes. A significant sex effect was demonstrated, with males more resistant than females for all F2 crosses. Survival time ranges and sensitive-to-resistant ratios of the different F2 crosses also supported imprinting and predicted that increased survival is due to dominant resistance alleles contributed by both the resistant and sensitive parental strains. HALI survival is multigenic with a complex mode of inheritance, which should be amenable to genetic dissection with this mouse model.