• Christian S Bruells, Karen Maes, Rolf Rossaint, Debby Thomas, Nele Cielen, Christian Bleilevens, Ingmar Bergs, Ursina Loetscher, Agnes Dreier, Ghislaine Gayan-Ramirez, Brad J Behnke, and Joachim Weis.
• Department of Anesthesiology, University Hospital of the RWTH Aachen, Aachen, Germany. cbruells@ukaachen.de
• Plos One. 2013 Jan 1; 8 (8): e70524.

ObjectiveMechanical ventilation (MV) is a life saving intervention for patients with respiratory failure. Even after 6 hours of MV, diaphragm atrophy and dysfunction (collectively referred to as ventilator-induced diaphragmatic dysfunction, VIDD) occurs in concert with a blunted blood flow and oxygen delivery. The regulation of hypoxia sensitive factors (i.e. hypoxia inducible factor 1α, 2α (HIF-1α,-2α), vascular endothelial growth factor (VEGF)) and angio-neogenetic factors (angiopoietin 1-3, Ang) might contribute to reactive and compensatory alterations in diaphragm muscle.MethodsMale Wistar rats (n = 8) were ventilated for 24 hours or directly sacrificed (n = 8), diaphragm and mixed gastrocnemius muscle tissue was removed. Quantitative real time PCR and western blot analyses were performed to detect changes in angio-neogenetic factors and inflammatory markers. Tissues were stained using Isolectin (IB 4) to determine capillarity and calculate the capillary/fiber ratio.ResultsMV resulted in up-regulation of Ang 2 and HIF-1α mRNA in both diaphragm and gastrocnemius, while VEGF mRNA was down-regulated in both tissues. HIF-2α mRNA was reduced in both tissues, while GLUT 4 mRNA was increased in gastrocnemius and reduced in diaphragm samples. Protein levels of VEGF, HIF-1α, -2α and 4 did not change significantly. Additionally, inflammatory cytokine mRNA (Interleukin (IL)-6, IL-1β and TNF α) were elevated in diaphragm tissue.ConclusionThe results demonstrate that 24 hrs of MV and the associated limb disuse induce an up-regulation of angio-neogenetic factors that are connected to HIF-1α. Changes in HIF-1α expression may be due to several interactions occurring during MV.

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