ABSTRACT
Acyloxydiene-Fe(CO)3 complexes can act as enzyme-triggered CO-releasing molecules (ET-CORMs). Their biological activity strongly depends on the mother compound from which they are derived, i.e. cyclohexenone or cyclohexanedione, and on the position of the ester functionality they harbour. The present study addresses if the latter characteristic affects CO release, if cytotoxicity of ET-CORMs is mediated through iron release or inhibition of cell respiration and to what extent cyclohexenone and cyclohexanedione derived ET-CORMs differ in their ability to counteract TNF-α mediated inflammation. Irrespective of the formulation (DMSO or cyclodextrin), toxicity in HUVEC was significantly higher for ET-CORMs bearing the ester functionality at the outer (rac-4), as compared to the inner (rac-1) position of the cyclohexenone moiety. This was paralleled by an increased CO release from the former ET-CORM. Toxicity was not mediated via iron as EC50 values for rac-4 were significantly lower than for FeCl2 or FeCl3 and were not influenced by iron chelation. ATP depletion preceded toxicity suggesting impaired cell respiration as putative cause for cell death. In long-term HUVEC cultures inhibition of VCAM-1 expression by rac-1 waned in time, while for the cyclohexanedione derived rac-8 inhibition seems to increase. NFκB was inhibited by both rac-1 and rac-8 independent of IκBα degradation. Both ET-CORMs activated Nrf-2 and consequently induced the expression of HO-1. This study further provides a rational framework for designing acyloxydiene-Fe(CO)3 complexes as ET-CORMs with differential CO release and biological activities. We also provide a better understanding of how these complexes affect cell-biology in mechanistic terms.
Subject(s)
Apoptosis/drug effects , Carbon Monoxide/metabolism , Coordination Complexes/toxicity , Cyclohexanones/toxicity , Inflammation/metabolism , Iron Compounds/toxicity , Coordination Complexes/chemistry , Cyclohexanones/chemistry , Gene Expression Regulation/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Inflammation/pathology , Iron Compounds/chemistry , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Vascular Cell Adhesion Molecule-1/chemistry , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
PURPOSE: This study evaluated the impact and value of bedside chest X-ray in intensive care units. MATERIALS AND METHODS: This observational study considered the bedside chest X-rays performed on 258 consecutive patients (160 men, 98 women; mean age, 58 years) admitted to intensive care units. Stratification of patients according to the reason for hospitalisation and analysis of the reasons for chest X-ray examinations were performed to assess the diagnostic efficacy (DE). RESULTS: DE for chest X-rays was 84.5%, with 15.5% of tests remaining unchanged over time. Patient stratification by disease indicated that the DE was 85.27% in transplant, 90.79% in postoperative care after general surgery, 83.89% in respiratory failure, 82.42% in polytrauma, 90.54% in postoperative care after neurosurgery, 86.6% in postoperative care after vascular surgery, 83.3% in neurological conditions and 93.4% in other diseases. CONCLUSIONS: Chest X-rays performed at the bedside are the most widely used imaging method in the follow-up of critically ill patients. DE is approximately 84.5%. Radiologists should maintain familiarity with the interpretation of this examination.
