Monocytes and tissue factor promote thrombosis in a murine model of oxygen deprivation
Monocytes and tissue factor promote thrombosis in a murine model of oxygen deprivation
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DOI：
10.1172/jci119337
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发表时间：
1997-04-01
影响因子：
15.9
通讯作者：
Pinsky, DJ
中科院分区：
文献类型：
--
作者：
Lawson, CA;Yan, SD;Pinsky, DJ
与局部或全身充血相关的临床状况可导致促血栓形成素质。进行本研究是为了建立整个动物缺氧模型，其中缺氧本身足以引发组织血栓形成。此外，该模型用于检验以下假设：缺氧诱导的单核吞噬细胞（MP）募集和组织因子（TF）表达可能触发响应缺氧而发生的纤维蛋白局部沉积。使用吸入氧压降低至 6% 的环境室，8 小时后在小鼠肺脉管系统中证明了血栓形成的缺氧诱导：(a) 使用抗纤维蛋白抗体在缺氧肺组织中形成纤维蛋白的免疫组织学证据，通过电子显微镜 22.5 nm 链周期证实； (b) 免疫印迹显示缺氧但常氧小鼠或用水蛭素处理的缺氧小鼠的肺中存在纤维蛋白γ-γ链二聚体； (c)与含氧量正常的动物相比，缺氧的肺组织中I-125-纤维蛋白/纤维蛋白原和In-111标记的血小板加速沉积； (d) 在缺氧暴露前用水蛭素治疗或耗尽血小板的动物中，组织 I-125-纤维蛋白/纤维蛋白原积聚减少，因为缺氧肺组织的免疫组织化学分析显示 TF 的强 MP 染色，通过缺氧肺中 TF RNA 的增加证实，并且因为 In-111 标记的小鼠 MP 在缺氧肺组织中积累，我们评估了招募的 MP 是否可能负责启动缺氧诱导的血栓形成，这一假设得到了几条证据的支持：(a) 缺氧前 MP 消耗减少了血栓形成，通过免疫印迹通过减少 I-125-纤维蛋白/纤维蛋白原沉积和减少交联纤维蛋白积累来测量； (b) 分离的小鼠 MP 在暴露于缺氧时表现出 TF 免疫染色增加； (c)施用与鼠TF交叉反应的抗兔TF抗体可减少响应体内缺氧的I-125-纤维蛋白/纤维蛋白原积累和交联纤维蛋白积累。 总之，这些使用新的体内模型的研究表明MP积累和TF表达可能促进缺氧诱导的血栓形成。
Clinical conditions associated with local or systemic hyperemia can lead to prothrombotic diatheses, This study was undertaken to establish a model of whole-animal hypoxia wherein oxygen deprivation by itself would be sufficient to trigger tissue thrombosis. Furthermore, this model was used to test the hypothesis that hypoxia-induced mononuclear phagocyte (MP) recruitment and tissue factor (TF) expression may trigger the local deposition of fibrin which occurs in response to oxygen deprivation. Using an environmental chamber in which inhaled oxygen tension was lowered to 6%, hypoxic induction of thrombosis was demonstrated in murine pulmonary vasculature by 8 h based upon: (a) immunohistologic evidence of fibrin formation in hypoxic lung tissue using an antifibrin antibody, confirmed by 22.5-nm strand periodicity by electron microscopy; (b) immunoblots revealing fibrin gamma-gamma chain dimers in lungs from hypoxic but not normoxic mice or hypoxic mice treated with hirudin; (c) accelerated deposition of I-125-fibrin/fibrinogen and In-111-labeled platelets in the lung tissue of hypoxic compared with normoxic animals; (d) reduction of tissue I-125-fibrin/ fibrinogen accumulation in animals which had either been treated with hirudin or depleted of platelets before hypoxic exposure, Because immunohistochemical analysis of hypoxic pulmonary tissue revealed strong MP staining for TF, confirmed by increased TF RNA in hypoxic lungs, and because In-111-labeled murine MPs accumulated in hypoxic pulmonary tissue, we evaluated whether recruited MPs might be responsible for initiation of hypoxia-induced thrombosis, This hypothesis was supported by several lines of evidence: (a) MP depletion before hypoxia reduced thrombosis, as measured by reduced I-125-fibrin/fibrinogen deposition and reduced accumulation of cross-linked fibrin by immunoblot; (b) isolated murine MPs demonstrated increased TF immunostaining when exposed to hypoxia; and (c) administration of an anti-rabbit TF antibody that crossreacts with murine TF decreased I-125-fibrin/fibrinogen accumulation and cross-linked fibrin accumulation in response to hypoxia in vivo, In summary, these studies using a novel in vivo model suggest that MP accumulation and TF expression may promote hypoxia-induced thrombosis.