Ma Li, Shaver Ciara M, Grove Brandon S, Mitchell Daphne B, Wickersham Nancy E, Carnahan Robert H, Cooper Tracy L, Brake Brittany E, Ware Lorraine B, Bastarache Julie A
Division of Emergency Intensive Care Unit, the Second Hospital of Lanzhou University, Lanzhou, China,
Clin Transl Med. 2015 Dec;4(1):63. doi: 10.1186/s40169-015-0063-4. Epub 2015 Jun 21.
Activation of coagulation by expression of tissue factor (TF) in the airspace is a hallmark of acute lung injury (ALI) but the timing of TF activation in relationship to increases in lung permeability and inflammation are unknown.
To test the hypothesis that TF is upregulated early in the course of acute bleomycin lung injury and precedes increased permeability and inflammation we studied the early course of bleomycin-induced ALI in mice. Mice were treated with 0.04U intratracheal bleomycin or vehicle control and bronchoalveolar lavage (BAL) and lung tissue were collected daily for 7 days. Whole lung TF mRNA was determined by QT-PCR. TF protein was assessed by ELISA and immunostaining. BAL procoagulant activity was measured by BAL clot time and thrombin-antithrombin complexes. Inflammation was assessed by BAL cell count, differentials and CXCL1/KC concentration. Lung permeability was assessed by BAL protein and lung wet to dry weight ratio.
Expression of CXCL1 occurred by day 1. BAL protein and lung wet-to-dry weight ratio increased significantly by day 3. TF mRNA and BAL procoagulant activity peaked on day 4 while whole lung TF protein peaked on day 6. Changes in permeability and procoagulant activity preceded inflammatory cell influx which was maximal at day 6 while whole lung TF protein peaked along with inflammation.
These data demonstrate that cytokine upregulation is the earliest response to bleomycin administration, followed by increased lung permeability, upregulation of TF, and recruitment of inflammatory cells.
肺泡腔中组织因子（TF）表达所激活的凝血过程是急性肺损伤（ALI）的一个标志，但TF激活与肺通透性增加和炎症反应之间的时间关系尚不清楚。
为了验证TF在急性博来霉素诱导的肺损伤早期上调且先于通透性增加和炎症反应这一假说，我们研究了博来霉素诱导的小鼠ALI的早期过程。给小鼠气管内注射0.04U博来霉素或赋形剂对照，连续7天每天收集支气管肺泡灌洗（BAL）液和肺组织。通过定量聚合酶链反应（QT-PCR）测定全肺TF mRNA。通过酶联免疫吸附测定（ELISA）和免疫染色评估TF蛋白。通过BAL凝块时间和凝血酶 - 抗凝血酶复合物测量BAL促凝活性。通过BAL细胞计数、分类和CXCL1 / KC浓度评估炎症反应。通过BAL蛋白和肺湿重与干重比评估肺通透性。
CXCL1在第1天开始表达。BAL蛋白和肺湿重与干重比在第3天显著增加。TF mRNA和BAL促凝活性在第4天达到峰值，而全肺TF蛋白在第6天达到峰值。通透性和促凝活性的变化先于炎症细胞流入，炎症细胞流入在第6天达到最大，而全肺TF蛋白与炎症反应同时达到峰值。
这些数据表明，细胞因子上调是对博来霉素给药的最早反应，随后是肺通透性增加、TF上调和炎症细胞募集。
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