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基因替换表面活性蛋白-C 可减轻呼吸道合胞病毒引起的肺损伤。

Genetic replacement of surfactant protein-C reduces respiratory syncytial virus induced lung injury.

机构信息

Cincinnati Children's Hospital Medical Center, Perinatal Institute, Division of Neonatology, Perinatal and Pulmonary Biology, MLC7029, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.

出版信息

Respir Res. 2013 Feb 12;14(1):19. doi: 10.1186/1465-9921-14-19.

DOI:10.1186/1465-9921-14-19
PMID:23399055
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3598668/
Abstract

BACKGROUND

Individuals with deficiencies of pulmonary surfactant protein C (SP-C) develop interstitial lung disease (ILD) that is exacerbated by viral infections including respiratory syncytial virus (RSV). SP-C gene targeted mice (Sftpc -/-) lack SP-C, develop an ILD-like disease and are susceptible to infection with RSV.

METHODS

In order to determine requirements for correction of RSV induced injury we have generated compound transgenic mice where SP-C expression can be induced on the Sftpc -/- background (SP-C/Sftpc -/-) by the administration of doxycycline (dox). The pattern of induced SP-C expression was determined by immunohistochemistry and processing by Western blot analysis. Tissue and cellular inflammation was measured following RSV infection and the RSV-induced cytokine response of isolated Sftpc +/+ and -/- type II cells determined.

RESULTS

After 5 days of dox administration transgene SP-C mRNA expression was detected by RT-PCR in the lungs of two independent lines of bitransgenic SP-C/Sftpc -/- mice (lines 55.3 and 54.2). ProSP-C was expressed in the lung, and mature SP-C was detected by Western blot analysis of the lavage fluid from both lines of SP-C/Sftpc -/- mice. Induced SP-C expression was localized to alveolar type II cells by immunostaining with an antibody to proSP-C. Line 55.3 SP-C/Sftpc -/- mice were maintained on or off dox for 7 days and infected with 2.6x107 RSV pfu. On day 3 post RSV infection total inflammatory cell counts were reduced in the lavage of dox treated 55.3 SP-C/Sftpc -/- mice (p = 0.004). The percentage of neutrophils was reduced (p = 0.05). The viral titers of lung homogenates from dox treated 55.3 SP-C/Sftpc -/- mice were decreased relative to 55.3 SP-C/Sftpc -/- mice without dox (p = 0.01). The cytokine response of Sftpc -/- type II cells to RSV was increased over that of Sftpc +/+ cells.

CONCLUSIONS

Transgenic restoration of SP-C reduced inflammation and improved viral clearance in the lungs of SP-C deficient mice. The loss of SP-C in alveolar type II cells compromises their response to infection. These findings show that the restoration of SP-C in Sftpc -/- mice in response to RSV infection is a useful model to determine parameters for therapeutic intervention.

摘要

背景

肺表面活性蛋白 C（SP-C）缺乏的个体患有间质性肺病（ILD），这种疾病会因呼吸道合胞病毒（RSV）等病毒感染而加重。SP-C 基因靶向小鼠（Sftpc -/-）缺乏 SP-C，会发展出类似 ILD 的疾病，并且容易感染 RSV。

方法

为了确定纠正 RSV 诱导损伤的要求，我们生成了复合转基因小鼠，在 Sftpc -/- 背景下（SP-C/Sftpc -/-）通过给予强力霉素（dox）可诱导 SP-C 表达。通过免疫组织化学和 Western blot 分析来确定诱导的 SP-C 表达模式。在 RSV 感染后测量组织和细胞炎症，并确定分离的 Sftpc +/+ 和 -/- 型 II 细胞的 RSV 诱导细胞因子反应。

结果

在 dox 给药后 5 天，通过 RT-PCR 在两条独立的 SP-C/Sftpc -/- 小鼠（品系 55.3 和 54.2）的双转基因肺中检测到转基因 SP-C mRNA 表达。ProSP-C 在肺中表达，并通过对来自两条 SP-C/Sftpc -/- 小鼠系的冲洗液进行 Western blot 分析检测到成熟的 SP-C。通过针对 proSP-C 的抗体进行免疫染色，将诱导的 SP-C 表达定位于肺泡型 II 细胞。55.3 SP-C/Sftpc -/- 小鼠在 dox 存在或不存在的情况下维持 7 天，并感染 2.6x107 RSV pfu。在 RSV 感染后第 3 天，dox 处理的 55.3 SP-C/Sftpc -/- 小鼠的灌洗液中总炎症细胞计数减少（p = 0.004）。中性粒细胞的百分比减少（p = 0.05）。与没有 dox 的 55.3 SP-C/Sftpc -/- 小鼠相比， dox 处理的 55.3 SP-C/Sftpc -/- 小鼠肺匀浆中的病毒滴度降低（p = 0.01）。Sftpc -/- 型 II 细胞对 RSV 的细胞因子反应高于 Sftpc +/+ 细胞。

结论

SP-C 的转基因恢复减轻了 SP-C 缺乏小鼠肺部的炎症并改善了病毒清除。肺泡型 II 细胞中 SP-C 的缺失损害了它们对感染的反应。这些发现表明，在 RSV 感染时，在 Sftpc -/- 小鼠中恢复 SP-C 是确定治疗干预参数的有用模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b009/3598668/66d2d1f41202/1465-9921-14-19-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b009/3598668/04db640251a7/1465-9921-14-19-1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b009/3598668/2673be7e2741/1465-9921-14-19-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b009/3598668/66d2d1f41202/1465-9921-14-19-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b009/3598668/04db640251a7/1465-9921-14-19-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b009/3598668/74007fcf9393/1465-9921-14-19-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b009/3598668/2d5e350b1044/1465-9921-14-19-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b009/3598668/3bc53c2de739/1465-9921-14-19-4.jpg
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