Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

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.

Dexamethasone Attenuates VEGF Expression and Inflammation but Not Barrier Dysfunction in a Murine Model of Ventilator–Induced Lung Injury

“…In line, we previously described that the vessel protective factor angiopoietin (Ang)–1 only protects against ventilator–induced VEGF expression and pro–inflammation, not against alveolar–capillary barrier dysfunction [25]. The other way around, pharmacological agents that attenuate alveolar–capillary barrier dysfunction due to MV may not influence inflammation [42], [43]. The assumption that lung inflammation and injury are occurring sequentially in the pathogenesis of VILI may therefore be questioned.…”

Regulation of endothelial and epithelial barrier functions by peptide hormones of the adrenomedullin family

“…97 In human pulmonary microvascular endothelial cells (HPMVEC), IMD improved endothelial barrier stability as measured by transendothelial electrical resistance (TER). 98 In the same study, IMD also attenuated vascular hyperpermeability in a model of ventilator-induced lung injury (VILI) in C57BL/6 mice when compared to non-treated animals. However, the treatment was not capable of reducing pulmonary inflammation induced by VILI since the pulmonary and plasma levels of several proinflammatory cytokines including IL-1b, IL-6, KC, MCP-1 or IL-10 did not change.…”

Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases

“…In cerebral endothelial cells, ADM2 decreases basal and oxidative stress‐induced hyperpermeability and endothelial apoptosis in a cAMP/NO‐dependent manner (Chen et al , ). In pulmonary microvascular endothelial cells, ADM2/IMD 1–47 inhibits basal, pressure‐ and thrombin‐induced hyperpermeability through the CGRP/AM 1/2 receptor‐PKA pathway, improving ventilator‐induced pulmonary injury (Pfeil et al , ; Muller‐Redetzky et al , ).…”