Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia
Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia
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DOI：
10.1172/jci1684
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发表时间：
1998-03-01
影响因子：
15.9
通讯作者：
Hynes, RO
中科院分区：
文献类型：
--
作者：
Lawler, J;Sunday, M;Hynes, RO
凝血酶原蛋白是一类调节细胞表型的细胞外钙结合蛋白家族，凝血酶敏感蛋白-L(TSP-L)在体外调节细胞的黏附、增殖、迁移和分化。为了探讨其在体内的功能，wt：通过小鼠基因组中的同源重组扰乱了TSP-1基因，这些小鼠的血小板完全缺乏TSP-1蛋白；然而，凝血酶诱导的血小板聚集没有减少，TSP-L缺陷小鼠从出生起就表现出轻微而可变的脊柱前凸，这些小鼠还表现出循环中白细胞的增加，其中单核细胞和嗜酸性粒细胞增加的百分比最大，脑、心、肾、脾、胃、肠、主动脉和肝脏没有出现重大异常。然而，与TSP-1在肺中的高水平表达一致，我们观察到出生时正常但缺乏TSP-1蛋白的小鼠肺部出现异常，4周龄TSP-1缺陷小鼠的肺组织病理学分析显示广泛的急性和机化性肺炎，中性粒细胞和巨噬细胞对含铁血黄素的巨噬细胞进行染色，表明弥漫性肺泡出血正在发生，随后，中性粒细胞数量减少，含含铁血黄素的巨噬细胞数量显著增加，与多系上皮细胞增生和胶原和弹性蛋白沉积有关。TSP-1缺陷小鼠的呼吸道上皮增厚和褶皱是由于TSP-1缺陷小鼠细胞增殖增加所致，这些结果表明TSP-I参与了正常的肺内稳态。
The thrombospondins are a family of extracellular calcium-binding proteins that modulate cellular phenotype, Thrombospondin-l (TSP-L) reportedly regulates cellular attachment, proliferation, migration, and differentiation in vitro. To explore its function in vivo, wt: have disrupted the TSP-1 gene by homologous recombination in the mouse genome, Platelets from these mice are completely deficient in TSP-1 protein; however, thrombin-induced platelet aggregation is not diminished, TSP-l-deficient mice display a mild and variable lordotic curvature of the spine that is apparent from birth, These mice also display an increase in the number of circulating white blood cells, with monocytes and eosinophils having the largest percent increases, The brain, heart, kidney, spleen, stomach, intestines, aorta, and Liver of TSP-1-deficient mice showed no major abnormalities. However, consistent with high levels of expression of TSP-1 in lung, we observe abnormalities in the lungs of mice that lack the protein, Although normal at birth, histopathological analysis of lungs from 4-wk-old TSP-1-deficient mice reveals extensive acute and organizing pneumonia, with neutrophils and macrophages, The macrophages stain for hemosiderin, indicating that diffuse alveolar hemorrhage is occurring, At later times, the number of neutrophils decreases and a striking increase in the number of hemosiderin-containing macrophages is observed associated with multiple-lineage epithelial hyperplasia and the deposition of collagen and elastin, a thickening and ruffling of the epithelium of the airways results From increasing cell proliferation in TSP-1-deficient mice, These results indicate that TSP-I is involved in normal lung homeostasis.