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In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (V D /V T ) correlating with mortality. High V D /V T results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live-cell imaging of cultured AEC type 2 we could show that in terms of CO 2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (ΔΨ) rose causing a Ca 2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia-induced mitochondrial Ca 2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca 2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS.

Aims: The aim of the study was to evaluate the feasibility, safety and efficacy of renal sympathetic denervation with CT-guided periarterial injection of potentially neurolytic agents in pigs., Methods and Results: Unilateral injection of formulations containing either 5M hyperosmolar saline, vincristine, paclitaxel or guanethidine around the renal artery was performed in 24 normotensive pigs with six animals per group. Needle placement and injections were performed under CT fluoroscopy guidance. Blood pressure measurements and CT scans were performed immediately before and after the intervention and four weeks after treatment. After euthanasia, norepinephrine (NE) concentrations of both kidneys were determined. The renal arteries and surrounding tissue were examined histologically to evaluate nerve fibre degeneration. Procedures were technically successful with good periarterial distribution of the injectant in all but one pig in the guanethidine group. No major adverse events or post-interventional complications occurred. In the vincristine group, NE concentrations of the renal parenchyma were lower on the treated side in all pigs with a mean decrease of 53% (38%-62%, p<0.01) compared to the contralateral control. Correspondingly, histological examination revealed neural degeneration in all animals treated with vincristine. In the other groups, no significant drop of NE values, or histological signs of nerve fibre degeneration were found., Conclusions: CT-guided periarterial injection of the different substances was feasible and safe. Renal sympathetic denervation was achieved with vincristine. In contrast, hyperosmolar saline, paclitaxel and guanethidine do not seem to be appropriate for renal denervation in a pig model at the dosage used.

Background: Accumulation and infiltration of microglia/brain macrophages around and into glioma tissue promote tumor invasion and expansion. One tumor-promoting mechanism of microglia/brain macrophages is upregulation of membrane type 1 matrix metalloprotease (MT1-MMP), which promotes the degradation of extracellular matrix. MT1-MMP upregulation is induced by soluble factors released by glioma cells activating microglial Toll-like receptor 2 (TLR2)., Methods: Versican identified by proteomics was silenced in glioma cells by short interference RNA and short hairpin RNA approaches and studied in vitro and after injection into mouse brains or organotypic brain slices., Results: The splice variants V0/V1 of the endogenous TLR2 ligand versican are highly expressed in mouse and human glioma tissue. Versican-silenced gliomas induced less MT1-MMP expression in microglia both in vitro and in vivo, which resulted in smaller tumors and longer survival rates as compared with controls. Recombinant versican V1 induced significantly higher levels of MT1-MMP in wild-type microglia compared with untreated and treated TLR2 knockout microglial cells. Using glioma-injected organotypic brain slices, we found that the impact of versican signaling on glioma growth depended on the presence of microglia. Moreover, we found that TLR2 expression is upregulated in glioma-associated microglia but not in astrocytes. Additionally, an established TLR2 neutralizing antibody reduced glioma-induced microglial MT1-MMP expression as well as glioma growth ex vivo., Conclusions: Our results show that versican released from glioma promotes tumor expansion through glioma-associated microglial/macrophage TLR2 signaling and subsequent expression of MT1-MMP. This signaling cascade might be a novel target for glioma therapies., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)