Intra-alveolar tissue factor pathway inhibitor is not sufficient to block tissue factor procoagulant activity
Intra-alveolar tissue factor pathway inhibitor is not sufficient to block tissue factor procoagulant activity
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DOI：
10.1152/ajplung.00372.2007
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发表时间：
2008-05-01
影响因子：
4.9
通讯作者：
Ware, Lorraine B.
中科院分区：
文献类型：
--
作者：
Bastarache, Julie A.;Wang, Ling;Ware, Lorraine B.
急性肺损伤的肺泡室含有高水平的组织因子（TF）促凝活性，有利于纤维蛋白沉积。我们以前报道过肺泡上皮细胞可以释放TF促凝活性，以响应促炎刺激。为了验证肺泡上皮细胞通过分泌TF的内源性抑制剂组织因子途径抑制剂（TFPI）进一步调节肺泡内纤维蛋白沉积的假设，我们测量了急性呼吸窘迫综合征患者水肿液（EF）中的TFPI水平。为了确定肺泡上皮是否可以释放TFPI，在来自急性呼吸窘迫综合征（ARDS）患者和对照组的流体静力性肺水肿（HYDRO）患者的肺水肿液中测量（ELISA）全长TFPI和截短的TFPI。在暴露于cytomix（TNF-α、IL-1 β、IFN-γ）后，还测量了来自人肺泡上皮细胞（A549）的条件培养基（CM）和细胞裂解物（CL）中的TFPI蛋白。与HYDRO相比，ARDS患者肺水肿液中的TFPI蛋白水平更高。TFPI蛋白在CM中增加，并且在Cytomix处理后在CL中没有变化; TFPI mRNA水平（RT-PCR）没有变化。尽管TFPI水平较高，但EF和CM均保留了显著的TF促凝活性，如通过血浆凝固时间测量的。大多数肺泡内的TFPI是在一个截断的，无活性的形式，而大多数的TFPI释放的细胞是全长，这表明不同的失活机制。总之，肺泡上皮细胞释放TFPI响应炎症刺激，但不增加TFPI基因转录或蛋白质产生。由于肺泡内TFPI的截短和失活，ARDS中肺泡内TFPI的水平不足以阻断肺泡内TF促凝活性。
The alveolar compartment in acute lung injury contains high levels of tissue factor (TF) procoagulant activity favoring fibrin deposition. We previously reported that the alveolar epithelium can release TF procoagulant activity in response to a proinflammatory stimulus. To test the hypothesis that the alveolar epithelium further modulates intra-alveolar fibrin deposition through secretion of an endogenous inhibitor to TF, tissue factor pathway inhibitor ( TFPI), we measured TFPI levels in edema fluid (EF) from patients with acute respiratory distress syndrome. To determine whether the alveolar epithelium can release TFPI, both full-length TFPI and truncated TFPI were measured ( ELISA) in pulmonary edema fluid from patients with acute respiratory distress syndrome ( ARDS) and a control group of patients with hydrostatic pulmonary edema ( HYDRO). TFPI protein was also measured in conditioned media ( CM) and cell lysates ( CL) from human alveolar epithelial cells (A549) after exposure to cytomix (TNF-alpha, IL-1 beta, IFN-gamma). TFPI protein levels were higher in pulmonary edema fluid from patients with ARDS vs. HYDRO. TFPI protein was increased in CM and did not change in CL after cytomix treatment; TFPI mRNA levels (RT-PCR) did not change. Despite the high levels of TFPI, both the EF and CM retained significant TF procoagulant activity as measured by plasma recalcification time. The majority of intra-alveolar TFPI was in a truncated, inactive form, whereas the majority of TFPI released from cells was full length, suggesting different mechanisms of inactivation. In summary, the alveolar epithelium releases TFPI in response to an inflammatory stimulus but does not increase TFPI gene transcription or protein production. Levels of intra-alveolar TFPI in ARDS are not sufficient to block intra-alveolar TF procoagulant activity due to truncation and inactivation of intra-alveolar TFPI.