DIFFERENTIAL SUSCEPTIBILITY OF HUMAN SP-B GENETIC VARIANTS ON LUNG INJURY CAUSED BY BACTERIAL PNEUMONIA AND THE EFFECT OF A CHEMICALLY MODIFIED CURCUMIN.
DIFFERENTIAL SUSCEPTIBILITY OF HUMAN SP-B GENETIC VARIANTS ON LUNG INJURY CAUSED BY BACTERIAL PNEUMONIA AND THE EFFECT OF A CHEMICALLY MODIFIED CURCUMIN.
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人类 SP-B 基因变异体对细菌性肺炎引起的肺损伤的不同易感性以及化学修饰姜黄素的作用
DOI：
10.1097/shk.0000000000000535
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Wang G
中科院分区：
文献类型：
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作者：
Xu Y;Ge L;Abdel-Razek O;Jain S;Liu Z;Hong Y;Nieman G;Johnson F;Golub LM;Cooney RN;Wang G
摘要金黄色葡萄球菌是医院内肺炎的常见病原菌，常导致急性呼吸窘迫综合征(ARDS)。表面活性蛋白B(SP-B)基因表达两种与降低表面张力和宿主防御有关的蛋白质。基因分型研究表明，人类SP-B基因变异与ARDS之间存在显著关联。在许多脓毒症模型中，姜黄素已被证明可以减轻宿主炎症。我们的假设是，SP-B突变体的功能差异和姜黄素(CMC2.24)治疗调节了细菌性肺炎的肺损伤。采用人源化转基因小鼠，表达不含SP-B基因的T等位基因或C等位基因。用生物荧光标记的金黄色葡萄球菌Xen 36(50 &MGR；L)气管内注射致肺炎。感染小鼠每日灌胃CMC2.24(40 mg/kg)或单独口服赋形剂。用活体成像系统监测细菌的动态变化。感染后48 h观察肺损伤的组织学、细胞学和分子生物学指标。体内成像分析显示，感染SP-B-C小鼠的肺总通量(细菌数量)高于感染SP-B-T小鼠(P <； 0.05)。与感染SP-B-T的小鼠相比，感染SP-B-C的小鼠的死亡率、肺损伤、细胞凋亡和NF-&KGR；B的表达增加。与对照组相比，CMC2.24治疗组的死亡率、总细菌流量、肺组织细胞凋亡率、炎症细胞数、核因子-2、KGR；B的表达(P <； )和基质金属蛋白酶-2、-9、-12的活性(P <； )均显著降低(P<0.05)。我们的结论是，携带SP-B-C等位基因的小鼠比携带SP-B-T等位基因的小鼠更容易感染金黄色葡萄球菌肺炎，CMC2.24可减轻肺损伤，从而降低死亡率。
ABSTRACT Staphylococcus aureus is a common cause of nosocomial pneumonia frequently resulting in acute respiratory distress syndrome (ARDS). Surfactant protein B (SP-B) gene expresses two proteins involved in lowering surface tension and host defense. Genotyping studies demonstrate a significant association between human SP-B genetic variants and ARDS. Curcumins have been shown to attenuate host inflammation in many sepsis models. Our hypothesis is that functional differences of SP-B variants and treatment with curcumin (CMC2.24) modulate lung injury in bacterial pneumonia. Humanized transgenic mice, expressing either SP-B T or C allele without mouse SP-B gene, were used. Bioluminescent labeled S. aureus Xen 36 (50 &mgr;L) was injected intratracheally to cause pneumonia. Infected mice received daily CMC2.24 (40 mg/kg) or vehicle alone by oral gavage. Dynamic changes of bacteria were monitored using in vivo imaging system. Histological, cellular, and molecular indices of lung injury were studied in infected mice 48 h after infection. In vivo imaging analysis revealed total flux (bacterial number) was higher in the lung of infected SP-B-C mice compared with infected SP-B-T mice (P < 0.05). Infected SP-B-C mice demonstrated increased mortality, lung injury, apoptosis, and NF-&kgr;B expression compared with infected SP-B-T mice. Compared with controls, CMC2.24 treatment significantly reduced the following: mortality, total bacterial flux and lung tissue apoptosis, inflammatory cells, NF-&kgr;B expression (P < 0.05), and MMPs-2, -9, -12 activities (P < 0.05). We conclude that mice with SP-B-C allele are more susceptible to S. aureus pneumonia than mice with SP-B-T allele, and that CMC2.24 attenuates lung injury thus reducing mortality.