title: Intermedin stabilized endothelial barrier function and attenuated ventilator-induced lung injury in mice.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  IMD may possibly provide a new approach to attenuate VILI.
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Holger Christian
authors.initials: HC
authors.lastname: Müller-Redetzky
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
authors.forename: Uwe
authors.initials: U
authors.lastname: Pfeil
authors.forename: Katharina
authors.initials: K
authors.lastname: Hellwig
authors.forename: Daniel
authors.initials: D
authors.lastname: Will
authors.forename: Renate
authors.initials: R
authors.lastname: Paddenberg
authors.forename: Christoph
authors.initials: C
authors.lastname: Tabeling
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
mesh_terms: D000818:Animals; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000860:Hypoxia; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D055370:Lung Injury / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics / Q000378:metabolism; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D058286:Calcitonin Receptor-Like Protein; D036361:Peptide Hormones; C545502:RAMP1 protein, human; C545503:RAMP2 protein, human; C545504:RAMP3 protein, human; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; C561869:intermedin (17-47)