内皮素-1和血栓素A2在粒细胞介导的肺损伤中增加肺血管阻力。

Schmeck J, Janzen R, Münter K, Neuhof H, Koch T, Janzen R

Department of Anesthesiology and Operative Intensive Care, University of Heidelberg, Mannheim, Germany.

Crit Care Med. 1998 Nov;26(11):1868-74. doi: 10.1097/00003246-199811000-00031.

OBJECTIVE

To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature.

DESIGN

Prospective experimental study in rabbits.

SETTING

Experimental laboratory in a university teaching hospital.

SUBJECTS

Thirty adult rabbits.

INTERVENTIONS

The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution.

MEASUREMENTS AND MAIN RESULTS

The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p< .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduced (p < .05) the delayed pressure increase. Using diclofenac (10 microg/mL) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injection significantly reduced the early and the delayed pressure increase.

CONCLUSIONS

Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A2. The endothelin-1 effects are probably mediated via endothelin-A receptors since the endothelin-A receptor antagonist LU135252 was able to suppress the early pressure reaction after FMLP injection, whereas the cyclooxygenase inhibitor diclofenac was able to reduce the second pressure increase.

目的

研究血管活性类二十烷酸和内皮素 -1 在粒细胞介导的肺血管效应中的病理生理作用。

设计

对家兔进行的前瞻性实验研究。

地点

大学教学医院的实验实验室。

对象

30 只成年家兔。

干预措施

实验在 30 个离体且通气的家兔肺上进行，这些肺用无细胞和无血浆的缓冲溶液灌注。

测量指标及主要结果

持续记录肺动脉压和肺重量增加情况。间歇性采集灌注样本以测定内皮素 -1 和血栓素 A2 的浓度。6 个未干预的实验作为假手术组。用 N - 甲酰 -L - 亮氨酰 -L - 甲硫氨酰 -L - 苯丙氨酸（FMLP；10⁻⁶ M；对照组，n = 6）刺激肺循环中的粒细胞。为研究活化的粒细胞是否通过内皮素 -1 影响肺血管，在注射 FMLP 前将内皮素 A 受体拮抗剂 LU135252（10⁻⁶ M）加入灌注液中（n = 6）。通过用环氧合酶抑制剂双氯芬酸（10 μg/mL；n = 6）预处理来研究血栓素 A2 在粒细胞 - 内皮细胞相互作用中的潜在作用。粒细胞活化导致肺动脉压急性升高（>9 mmHg），随后在 60 分钟后出现第二次延迟性压力升高（>14 mmHg），同时伴随大量血栓素 A2 的生成（>250 pg/mL）。FMLP 注射 15 分钟后，在灌注液中可检测到内皮素 -1。用选择性内皮素 A 拮抗剂 LU135252 预处理显著（p <.01）降低了 FMLP 刺激后的初始压力反应，而双氯芬酸显著降低（p <.05）了延迟性压力升高。在注射 FMLP 前联合使用双氯芬酸（10 μg/mL）和 LU135252（10⁻⁶ M；n = 6）显著降低了早期和延迟性压力升高。