Intermedin stabilized endothelial barrier function and attenuated ventilator-induced lung injury in mice

• Published in: PloS one 2012-05, Vol.7 (5), p.e35832
• Main Authors: Müller-Redetzky, Holger Christian, Kummer, Wolfgang, Pfeil, Uwe, Hellwig, Katharina, Will, Daniel, Paddenberg, Renate, Tabeling, Christoph, Hippenstiel, Stefan, Suttorp, Norbert, Witzenrath, Martin
• Format: Article
• Language: English
• Subjects: Adrenomedullin; Animals; Attenuation; Biology; Calcitonin; Calcitonin Receptor-Like Protein - genetics; Calcitonin Receptor-Like Protein - metabolism; Catheters; Cells, Cultured; Edema; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Female; Fluorescent Antibody Technique; Gene Expression - drug effects; Humans; Hypoxia; Immunofluorescence; In Vitro Techniques; In vivo methods and tests; Infectious diseases; Inflammation; Intensive care; Ischemia; Leukocytes; Localization; Lung - blood supply; Lung - drug effects; Lung - metabolism; Lung Injury - etiology; Lung Injury - genetics; Lung Injury - prevention & control; Lungs; Mechanical properties; Mechanical ventilation; Medical research; Medicine; Mice; Mice, Inbred C57BL; Microvasculature; Microvessels - cytology; Microvessels - drug effects; Microvessels - physiopathology; Monomolecular films; Oxygenation; Peptide Hormones - genetics; Peptide Hormones - metabolism; Peptide Hormones - pharmacology; Permeability; Pharmacology; Pneumonia; Proteins; Pulmonary arteries; Ramps; Receptor activity modifying proteins; Receptor Activity-Modifying Protein 1 - genetics; Receptor Activity-Modifying Protein 1 - metabolism; Receptor Activity-Modifying Protein 2 - genetics; Receptor Activity-Modifying Protein 2 - metabolism; Receptor Activity-Modifying Protein 3 - genetics; Receptor Activity-Modifying Protein 3 - metabolism; Recruitment; Respiration, Artificial - adverse effects; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Sepsis; Staphylococcus aureus; Vasoconstriction; Vasoconstriction - drug effects; Ventilation; Ventilators; White blood cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035832

Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1-3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxic vasoconstriction due to IMD treatment. IMD had minor impact on pulmonary leukocyte recruitment and did not reduce cytokine levels in VILI. IMD may possibly provide a new approach to attenuate VILI.