Donaubauer Bernd, Busch Thilo, Lachmann Robert, Deja Maria, Petersen Bodil, Francis Roland, Träger Annette, Ebsen Michael, Boemke Willehad, Kaisers Udo
Department of Anesthesiology and Intensive Care Medicine, Charite, Campus Virchow-Klinikum, University Medical Center, Berlin, Germany.
Exp Biol Med (Maywood). 2006 Jun;231(6):960-6.
Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET(A) receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO2) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO2, 319 +/- 44 mm Hg vs. 57 +/- 3 mm Hg; MPAP, 32 +/- 2 mm Hg vs. 41 +/- 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 +/- 0.06 fmol/ml after induction of ALI to a maximum of 1.17 +/- 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 +/- 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET(A) receptor antagonist.
吸入内皮素（ET）-A受体拮抗剂已被证明可改善实验性急性肺损伤（ALI）中的气体交换，但可能会因循环中ET-1水平升高而引发副作用。我们研究了低剂量吸入性ET（A）受体拮抗剂LU-135252在不影响ET-1血浆浓度及ALI动物模型肺损伤的情况下，是否能改善气体交换。在一项前瞻性、随机、对照研究中对22头仔猪进行了检查。在麻醉动物中，通过表面活性剂耗竭诱导ALI。动物要么在20分钟内接受0.3mg/kg剂量的LU-135252（LU组；n = 11），要么雾化生理盐水缓冲液（对照组；n = 11）。采用曼-惠特尼U检验比较组间差异（P < 0.05）。在LU组中，与对照组相比，动脉血氧分压（PaO2）和平均肺动脉压（MPAP）有所改善（ALI诱导后6小时时的PaO2：319±44mmHg对57±3mmHg；MPAP：32±2mmHg对41±2mmHg；P < 0.05）。组间平均动脉压和心输出量无差异。LU组中，ET-1血浆浓度从ALI诱导后0.96±0.06fmol/ml在ALI发作后3小时最高升至1.17±0.09fmol/ml，与对照组（1.21±0.08fmol/ml，无显著差异）无显著差异。组织学检查发现，组间总肺损伤评分无差异。然而，LU组间质性炎症和出血明显减轻（与对照组相比，P < 0.05）。在这个ALI动物模型中，吸入0.3mg/kg剂量的LU-135252可显著且持续地改善气体交换，而ET-1血浆浓度无变化。此外，我们的数据表明接受吸入性ET（A）受体拮抗剂的组肺部炎症有减轻趋势。
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