Robriquet Laurent, Collet François, Tournoys Antoine, Prangère Thierry, Nevière Rémi, Fourrier François, Guery Benoît P
EA 2689, Faculté de Médecine, Université de Lille 2, 1 place de Verdun, 59045 Lille Cedex, France.
Respir Res. 2006 Mar 22;7(1):41. doi: 10.1186/1465-9921-7-41.
Acute lung injury (ALI) induces a coagulation/fibrinolysis imbalance and leads to fibrin deposition. The protein C pathway is an important regulator of the coagulation system and reduces the inflammatory response. The aim of the study was to examine the effects of recombinant human activated protein C (rhAPC) in the early phase of Pseudomonas aeruginosa (Pa)-induced lung injury.
The study was conducted in vivo on a rat model of Pa-induced ALI. Continuous intravenous (IV) rhAPC was administrated simultaneously with intratracheal (IT) Pa. We instilled into the airspaces a 5% bovine albumin solution with 1 mu(Ci of (125)I-albumin and injected IV 1 mu(Ci of (111)In-albumin to measure lung liquid clearance (LLC) and endothelial injury. Cytokines levels (TNFalpha and IL-6) and thrombin-antithrombin (TAT) complexes were measured in blood and bronchoalveolar lavage fluid (BALF) at 4 hours. Four groups were compared: control (CTR), pneumonia (PNP) receiving IT Pa (0.5 ml/kg of 1 x 10(9) cfu), APC: IV rhAPC (300 microg/kg/h), A-PNP: IT Pa /IV rhAPC.
Alveolar-capillary permeability was increased in the PNP versus the CTR group (0.28 +/- 0.08 vs. 0.03 +/- 0.01, p < 0.05). IV rhAPC in Pa-induced ALI led to further injury (0.47 +/- 0.17 vs. 0.28 +/- 0.08, p = 0.2). The LLC was significantly decreased in the A-PNP group compared to PNP group (9.1 +/- (4.3% vs. 33.4 +/- 2.6%, p < 0.05). The lung wet to dry weight ratio was significantly increased in the PNP group (4.62 +/- 0.31) compared to the CTR group (3.87 +/- 0.22, p < 0.05). IV rhAPC administration tends to increase this parameter in Pa-induced ALI (5.80 +/- 0.66, p = 0.07). These findings were associated with a loss of inflammatory response compartmentalization measured by TNFalpha and IL-6 systemic levels. TAT complexes in BALF were increased in the A-PNP group (23.17 +/- 2.89 ng/ml) compared to the CTR group (0.92 +/- 0.17 ng/ml, p < 0.05) and the PNP group (11.06 +/- 2.76 ng/ml, p < 0.05).
rhAPC reduces LLC following Pa-induced ALI and may influence pulmonary edema formation. The early massive fibrin formation is probably beneficial in ALI limiting both the extent of injury and permeability disorders.
急性肺损伤（ALI）可导致凝血/纤溶失衡并引发纤维蛋白沉积。蛋白C途径是凝血系统的重要调节因子，可减轻炎症反应。本研究旨在探讨重组人活化蛋白C（rhAPC）在铜绿假单胞菌（Pa）诱导的肺损伤早期阶段的作用。
本研究在Pa诱导的ALI大鼠模型上进行体内实验。在气管内注入Pa的同时持续静脉注射rhAPC。我们向肺泡腔内注入含1μCi（125）I-白蛋白的5%牛白蛋白溶液，并静脉注射1μCi（111）In-白蛋白以测量肺液清除率（LLC）和内皮损伤。在4小时时检测血液和支气管肺泡灌洗液（BALF）中的细胞因子水平（TNFα和IL-6）以及凝血酶-抗凝血酶（TAT）复合物。比较四组：对照组（CTR）、接受气管内注入Pa（0.5ml/kg，1×10⁹cfu）的肺炎组（PNP）、APC组：静脉注射rhAPC（300μg/kg/h）、A-PNP组：气管内注入Pa/静脉注射rhAPC。
与CTR组相比，PNP组的肺泡-毛细血管通透性增加（0.28±0.08对0.03±0.01，p<0.05）。在Pa诱导的ALI中静脉注射rhAPC导致进一步损伤（0.47±0.17对0.28±0.08，p = 0.2）。与PNP组相比，A-PNP组的LLC显著降低（9.1±4.3%对33.4±2.6%，p<0.05）。与CTR组（3.87±0.22）相比，PNP组的肺湿重与干重之比显著增加（4.62±0.31，p<0.05）。在Pa诱导的ALI中静脉注射rhAPC倾向于增加该参数（5.80±0.66，p = 0.07）。这些发现与通过TNFα和IL-6全身水平测量的炎症反应分区丧失有关。与CTR组（0.92±0.17ng/ml，p<0.05）和PNP组（11.06±2.76ng/ml，p<0.
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