Low-dose adrenomedullin-2/intermedin(8-47) reduces pulmonary ischemia/reperfusion injury.

ABSTRACT

Adrenomedullin-2/intermedin stabilizes the pulmonary microvascular barrier challenged by application of thrombin ex vivo and by experimental ventilation in vivo. Here, we test the hypothesis that adrenomedullin-2/intermedin(8-47) protects mouse lungs from ischemia/reperfusion injury in vivo. C57BL/6 mice were anesthetized, intubated, ventilated, and heparinized. Blood vessels and the main bronchus of the left lung were clamped for 90min. Thereafter, lungs were reperfused for 120min. Five min before clamping and before reperfusion, mice obtained intravenous injections of adrenomedullin-2/intermedin(8-47). After reperfusion, mice were sacrificed and bronchoalveolar lavage of the left and the right lung was performed separately. The integrity of the blood-air barrier was investigated by electron microscopy using stereological methods. In response to ischemia/reperfusion injury, intraalveolar leukocytes accumulated in the ischemic lung. Two applications of 10ng/kg body weight adrenomedullin-2/intermedin(8-47) dramatically reduced leukocyte infiltration to about 15% (p≤0.001). Also the proportion of the subpopulation of neutrophil granulocytes decreased (12% vs 5%, p=0.013). Electron microscopy revealed a protection of the blood-air barrier by adrenomedullin-2/intermedin(8-47). Adrenomedullin-2/intermedin(8-47) ameliorates early ischemia/reperfusion injury in mouse lungs by protecting the integrity of the blood-air barrier and by potently reducing leukocyte influx into the alveolar space. Adrenomedullin-2/intermedin(8-47) might be of therapeutic interest in lung transplantation and cardiopulmonary bypass.