Abstract
BackgroundEven 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.Methodology/Principal FindingsHuman 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/SignificanceIMD may possibly provide a new approach to attenuate VILI.
Highlights
Mechanical ventilation (MV) is a life saving treatment without alternatives in acute respiratory failure, and MV is employed following surgery or trauma
ventilator-induced lung injury (VILI) caused down regulation of pulmonary RAMP3 mRNA levels while the mRNA levels of IMD, calcitonin receptor-like receptor (CRLR), calcitonin gene-related peptide (CGRP) and RAMP1-2 were not affected by MV
Preinjured lungs are susceptible to VILI, and VILI may contribute to lung injury in acute respiratory distress syndrome (ARDS) patients despite lung protective ventilation strategies [4,5]
Summary
Mechanical ventilation (MV) is a life saving treatment without alternatives in acute respiratory failure, and MV is employed following surgery or trauma. Minimization of MV-induced physical stress by reduction of tidal volumes to 6 ml/kg significantly improved clinical outcome of mechanically ventilated patients [3]. Preinjured lungs are sensitive for the development of VILI even in the setting of lung-protective ventilation [4,5]. As the necessity to guarantee sufficient gas exchange frequently limits a further substantial reduction of tidal volumes and oxygen supply, new adjuvant pharmacological therapies enhancing pulmonary vascular barrier function in VILI/acute respiratory distress syndrome (ARDS) in addition to lung-protective ventilation are needed to prevent or ameliorate VILI. Even protective ventilation may aggravate or induce lung failure, in preinjured lungs. New adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). We hypothesized that IMD may attenuate VILIassociated lung permeability in vivo
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