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LUNG

Low-Dose Inhalation of an Endothelin-A Receptor Antagonist in Experimental Acute Lung Injury: ET-1 Plasma Concentration and Pulmonary Inflammation

Bernd Donaubauer^*,1, Thilo Busch^*,1, Robert Lachmann^*, Maria Deja^*, Bodil Petersen^*, Roland Francis^*, Annette Träger^*, Michael Ebsen, Willehad Boemke^* and Udo Kaisers^*,2

^* Department of Anesthesiology and Intensive Care Medicine, Charite, Campus Virchow-Klinikum, University Medical Center, D-13353 Berlin, Germany; and Department of Pathology, Ruhr University, D-44789 Bochum, Germany

To whom requests for reprints should be addressed at ² Klinik für Anaesthesiologie und operative Intensivmedizin, Charite, Campus Virchow Klinikum, Universitaetsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: udo.kaisers{at}charite.de

Abstract

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

Key Words: acute lung injury • endothelin-1 • endothelin-A receptor antagonist • inflammation