Andreas H. Wagner

Fatal pulmonary edema after nitric acid inhalation.

We report a case of acute inhalation injury of nitric acid in a 56-year old white male. The patient presented conscious and dyspnoic at the emergency department after cleaning a copper chandelier with nitric acid. He had to be intubated 2 h after admission and mechanically ventilated because of fulminant respiratory insufficiency. As all sources of mechanical ventilation failed, extracorporeal membrane oxygenation had to be established 7 h after admission. With the additional use of surfactant and low dose inhalation therapy with nitric oxide (NO), the patient could be stabilised for 3 days and lung function improved temporarily. Despite all efforts the patient died at the fourth day from refactory respiratory failure. Pathologic examination revealed massive pulmonary edema without signs of inflammation. Thus, nitric acid inhalation induced pulmonary edema appears to be a most severe situation in which even most modern therapeutic interventions fail. As, in respect of recent literature and our case no promising therapy for nitric acid inhalation pulmonary edema is available, our efforts have to be directed towards prevention of nitric acid exposure.

Plasma endothelin in patients with acute aortic disease

PURPOSE AND BACKGROUNDnWe investigated the plasma levels of endothelin 1/2 in patients with acute symptoms relating to a known or newly diagnosed aortic aneurysm in order to investigate the possible role of peptides in the development of the disease.nnnMETHODSnEndothelin 1/2 plasma levels were determined in patients admitted to the emergency unit with suspected acute aortic disease. The history, type of aneurysm, outcome and laboratory findings were determined and compared to endothelin 1/2 levels collected on admission.nnnRESULTSnIn patients with ruptured aneurysm (n=27) or acute aortic dissection (n=18) the endothelin 1/2 median levels were higher 1.1 (25th and 75th quartile 0.7, 1.7) fmol/ml than in patients (n=20) with pre-existing aneurysm 0.7 (0.4, 1.1) fmol/ml (P=0.013). Patients who died had significantly higher endothelin levels 1.3 (0.8, 1.9) fmol/ml than the survivors 0.8 (0.5, 1.4) fmol/ml (P=0.04). In a logistic regression analysis, only a higher blood pressure on admission was an independent predictor of survival.nnnCONCLUSIONnEndothelin 1/2 levels are elevated in patients with acute dissection or ruptured aneurysm, but they are not an independent predictor of survival.

Mechanism and functional impact of CD40 ligand-induced von Willebrand factor release from endothelial cells

Co-stimulation via CD154 binding to CD40, pivotal for both innate and adaptive immunity, may also link haemostasis to vascular remodelling. Here we demonstrate that human platelet-bound or recombinant soluble CD154 (sCD154) elicit the release from and tethering of ultra-large (UL) von Willebrand factor (vWF) multimers to the surface of human cultured endothelial cells (ECs) exposed to shear stress. This CD40-mediated ULVWF multimer release from the Weibel-Palade bodies was triggered by consecutive activation of TRAF6, the tyrosine kinase c-Src and phospholipase Cγ1 followed by inositol-1,4,5 trisphosphate-mediated calcium mobilisation. Subsequent exposure to human washed platelets caused ULVWF multimer-platelet string formation on the EC surface in a shear stress-dependent manner. Platelets tethered to these ULVWF multimers exhibited P-selectin on their surface and captured labelled monocytes from the superfusate. When exposed to shear stress and sCD154, native ECs from wild-type but not CD40 or vWF-deficient mice revealed a comparable release of ULVWF multimers to which murine washed platelets rapidly adhered, turning P-selectin-positive and subsequently capturing monocytes from the perfusate. This novel CD154-provoked ULVWF multimer-platelet string formation at normal to fast flow may contribute to vascular remodelling processes requiring the perivascular or intravascular accumulation of pro-inflammatory macrophages such as arteriogenesis or atherosclerosis.

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Background/Aims: Reactive dicarbonyl compounds, such as methylglyoxal (MG), contribute to diabetic complications. MG-scavenging capacities of carnosine and anserine, which have been shown to mitigate diabetic nephropathy, were evaluated in vitro and in vivo. Methods: MG-induced cell toxicity was characterized by MTT and MG-H1-formation, scavenging abilities by Western Blot and NMR spectroscopies, cellular carnosine transport by qPCR and microplate luminescence and carnosine concentration by HPLC. Results: In vitro, carnosine and anserine dose-dependently reduced N-carboxyethyl lysine (CEL) and advanced glycation end products (AGEs) formation. NMR studies revealed the formation of oligo/polymeric products of MG catalyzed by carnosine or anserine. MG toxicity (0.3-1 mM) was dose-dependent for podocytes, tubular and mesangial cells whereas low MG levels (0.2 mM) resulted in increased cell viability in podocytes (143±13%, p<0.001) and tubular cells (129±3%, p<0.001). Incubation with carnosine/anserine did not reduce MG-induced toxicity, independent of incubation times and across large ranges of MG to carnosine/anserine ratios. Cellular carnosine uptake was low (<0.1% in 20 hours) and cellular carnosine concentrations remained unaffected. The putative carnosine transporter PHT1 along with the taurine transporter (TauT) was expressed in all cell types while PEPT1, PEPT2 and PHT2, also belonging to the proton-coupled oligopeptide transporter (POT) family, were only expressed in tubular cells. Conclusion: While carnosine and anserine catalyze the formation of MG oligo/polymers, the molar ratios required for protection from MG-induced cellular toxicity are not achievable in renal cells. The effect of carnosine in vivo, to mitigate diabetic nephropathy may therefore be independent upon its ability to scavenge MG and/or carnosine is mainly acting extracellularly.

Pre-Transplant Therapy in Experimental Heart Transplantation

Heart transplantation is a life-saving procedure for patients with end-stage cardiac dysfunction. Currently one-year graft survival ranges between 77-88%, three-year survival between 77-79% and five-year survival between 67-73% (http://www.americanheart.org/presenter.jhtml?identifier=4588). Despite these encouraging results, primary graft failure accounts for about 23% of deaths in the first 90 days post transplantation. Pretransplant variables associated with primary graft failure include: ischemia time, donor gender, donor age, multiorgan donation, center volume, extracorporeal membrane oxygenation, mechanical circulatory support, etiology of heart failure, and reoperative heart transplantation (Russo et al., 2010). To target rejection of allografts, a variety of immunosuppressive protocols are used solely in the recipient who is the main focus of the therapy (The International Society of Heart and Lung Transplantation Guidelines for the Care of Heart Transplant Recipients Task Force 2: Immunosuppression and Rejection (Nov. 8, 2010)). Typically, neither donor nor grafts are specifically treated before or during organ harvesting except for the maintenance of circulatory and respiratory functions of the donor and irrigation of grafts with preservation solutions.

Chapter 7:Decoy Oligodeoxynucleotides to Treat Inflammatory Diseases

Apart from epigenetic causes an increased genetic risk for diseases typically stems from mutations or polymorphisms in one or several genes (monogenetic and/or polygenetic diseases) that result either in erroneous transcription of these genes into the corresponding messenger RNA (mRNA) or translatio...