Cigarette smoke-induced lung pathology in SMP30 knockout mice

衰老标记蛋白-30 （smp30）最初是在大鼠肝脏中发现的一种新的蛋白，它的表达与雄激素无关，随着年龄的增长而降低，并具有保护细胞凋亡的功能。通过逆转录聚合酶链反应（RT-PCR）分析，在小鼠肺、肝、肾、睾丸和大脑中均发现SMP30 mRNA转录物。我们检测了衰老过程中C57/BL6小鼠肺、肾和肝脏中SMP30的表达，在每个组织中都发现了SMP30表达的不同时间谱。肺组织中SMP30 mRNA水平在出生后逐渐升高，在12月龄时达到峰值，随后逐渐下降。为了研究SMP30在肺中的生理作用，我们对野生型（SMP30Y/+）小鼠进行了免疫组织化学研究，并对SMP30敲除型（SMP30Y/-）小鼠进行了组织病理学检查。抗smp30抗体的免疫反应性主要在支气管上皮细胞中检测到，在6 ~ 12月龄强烈检测到。肺Clara细胞、肺泡巨噬细胞和浆细胞免疫染色均呈阳性。形态学分析测量了平均线性截距（MLI）和破坏指数（DI），发现SMP30Y/-小鼠在1、3和6月龄时与SMP30Y/+小鼠相比，周围空域扩大，但肺泡破坏。当野生型（SMP30Y/+）和SMP30Y/-小鼠在3月龄时暴露于1%香烟烟雾（iRi研究香烟）1个月时，SMP30Y/-小鼠的MLI与对照相比显著增加，而野生型（SMP30Y/+）小鼠则没有。我们的研究结果强烈提示SMP30Y/-小鼠可能成为老年性肺的新模型，并成为暴露于香烟烟雾时肺气肿的模型。对SMP30Y/-小鼠的进一步检查可能为阐明老年人肺部疾病的发生机制提供线索。

Senescence marker protein-30 (SMP3O) was originally identified as a novel protein of which expression decreases androgen-independent manner with aging in the rat liver and functions to protect cells from apoptosis. By reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, SMP30 mRNA transcripts were found in the mouse lung, liver, kidney, testis and cerebrum. We examined SMP30 expression in the C57/BL6 mouse lung, kidney, and liver during aging and a distinct temporal profile of SMP30 expression was found in each tissues. In the lungs, SMP30 mRNA level gradually increased after birth, peaked at 12 month old, and decreased thereafter. To investigate physiological role of SMP30 in the lung, immunohistochemical studies of wild-type (SMP30Y/+) mice and histopathological examinations of SMP30 knockout (SMP30Y/-) mice were performed. Immunoreactivity against anti-SMP30 antibody was mainly detected in bronchial epithelial cells and strongly detected at 6 to 12 months old. Positive immunostaining was also demonstrated in Clara cells, alveolar macrophages, and plasma cells in the lung. The morphometric analysis was performed to measure mean linear intercept (MLI) and destructive index (DI) and found peripheral airspace enlargement without alveolar destruction in SMP30Y/-mice at 1, 3 and 6 months old compared with that in SMP30Y/+ mice. When wild-type (SMP30Y/+) and SMP30Y/-mice at 3 months of age were exposed to 1% cigarette smoke (iRi research cigarette) for 1 month, MLI significantly increased as compared with vehicle control in SMP30Y/-mice, but not in wild-type (SMP30Y/+) mice. Our results strongly suggest that SMP30Y/-mouse could be a novel model for a senile lung and become a model for emphysema when exposed to cigarette smoke. Further examinations of SMP30Y/-mice may offer clues to elucidate the mechanisms of the development of pulmonary diseases in the elderly.