Rectenwald John E, Deatrick K Barry, Sukheepod Pasu, Lynch Erin M, Moore Andrea J, Moaveni Daria M, Dewyer Nicholas A, Luke Catherine E, Upchurch Gilbert R, Wakefield Thomas W, Kunkel Steven L, Henke Peter K
Department of Surgery, Jobst Vascular Research Laboratory, Section of Vascular Surgery, University of Michigan, Ann Arbor, USA.
J Vasc Surg. 2006 Apr;43(4):800-8. doi: 10.1016/j.jvs.2005.12.010.
Pulmonary embolism (PE) is a life-threatening condition that is associated with the long-term sequelae of chronic pulmonary hypertension. Prior experimental work has suggested that post-PE inflammation is accompanied by pulmonary artery intimal hyperplasia. This study evaluated the effect of the thrombus and tested the hypothesis that thrombolytic, antiplatelet, and anticoagulant agents would decrease pulmonary injury.
Male Sprague-Dawley rats (n = 267) underwent laparotomy and temporary clip occlusion of the infrarenal inferior vena cava for the formation of endogenous thrombus or placement of an inert silicone "thrombus." Two days later, repeat laparotomy was performed, the clip removed, and the thrombus or silicone plug was embolized to the lungs. The endogenous thrombus group received normal saline, low-molecular-weight heparin (LMWH), tissue plasminogen activator (tPA), or a gIIB/IIIA antagonist (abciximab). Lung tissue was harvested at various times over 21 days and assayed for total collagen, monocyte chemoattractant protein-1 (MCP-1), interleukin-13 (IL-13), and transforming growth factor-beta (TGF-beta). Fixed sections were stained with trichrome for intimal hyperplasia determination and ED-1 monocytes and alpha-actin-positive staining.
The overall survival for rats undergoing PE was 90%, was not affected by treatment, and 84% of all PE localized to the right pulmonary artery. The PE significantly reduced Pa(O2) in all groups. Compared with controls, the silicone emboli group had an increased level of IL-13 on day 1, an increased level of MCP-1 on day 4, and an increase in the levels of all inflammatory mediators on day 14 (P < .05). Accompanying these differences were greater pulmonary artery intimal hyperplasia at days 4 and 21 in the silicone group compared with controls (P < .05). LMWH treatment in the thrombus of PE rats significantly decreased IL-13 levels at all time points, whereas treatment with abciximab or tPA significantly increased IL-13 levels compared with controls. TGF-beta levels were significantly increased by LMWH at day 4 and 14, and abciximab was associated with lower TGF-beta at day 14. Only LMWH was associated with less pulmonary artery intimal hyperplasia at day 14 compared with controls and the other treatment groups.
Persistent pulmonary artery distention by an inert material is sufficient to invoke significant inflammation and intimal hyperplasia independent of the thrombus itself. Compared with nontreated PE, LMWH is the only therapy associated with a significant reduction in late intimal hyperplasia and, with the exception of TGF-beta, lower profibrotic growth-factor production.
肺栓塞（PE）是一种危及生命的疾病，与慢性肺动脉高压的长期后遗症相关。先前的实验研究表明，PE后的炎症伴有肺动脉内膜增生。本研究评估了血栓的影响，并验证了溶栓、抗血小板和抗凝药物可减轻肺损伤的假说。
雄性Sprague-Dawley大鼠（n = 267）接受剖腹手术，并暂时夹闭肾下腔静脉以形成内源性血栓或放置惰性硅胶“血栓”。两天后，再次进行剖腹手术，移除夹子，并将血栓或硅胶栓子栓塞至肺部。内源性血栓组接受生理盐水、低分子量肝素（LMWH）、组织型纤溶酶原激活剂（tPA）或糖蛋白IIb/IIIa拮抗剂（阿昔单抗）。在21天内的不同时间点采集肺组织，检测总胶原蛋白、单核细胞趋化蛋白-1（MCP-1）、白细胞介素-13（IL-13）和转化生长因子-β（TGF-β）。固定切片用三色染色法测定内膜增生，并检测ED-1单核细胞和α-肌动蛋白阳性染色。
接受PE的大鼠总体存活率为90%，不受治疗影响，且所有PE的84%位于右肺动脉。PE显著降低了所有组的动脉血氧分压（Pa[O₂]）。与对照组相比，硅胶栓塞组在第1天IL-13水平升高，第4天MCP-1水平升高，第14天所有炎症介质水平均升高（P < 0.05）。与这些差异相伴的是，与对照组相比，硅胶组在第4天和第21天肺动脉内膜增生更明显（P < 0.05）。PE大鼠血栓中LMWH治疗在所有时间点均显著降低IL-13水平，而与对照组相比，阿昔单抗或tPA治疗显著升高IL-13水平。LMWH在第4天和第14天显著升高TGF-β水平，阿昔单抗在第14天与较低的TGF-β相关。与对照组和其他治疗组相比，仅LMWH在第14天与较少的肺动脉内膜增生相关。
惰性材料持续导致肺动脉扩张足以引发显著的炎症和内膜增生，而与血栓本身无关。与未治疗的PE相比，LMWH是唯一与晚期内膜增生显著减少相关的治疗方法，并且除TGF-β外，可降低促纤维化生长因子的产生。
