Indication and implementation of lipidapheresis, rheopheresis, or immunoadsorption (lessons learnt from Germany's largest apheresis center).

Efficient modes of extracorporeal blood purification are available today for apheresis treatment of progressive atherosclerosis, autoimmune disease, or for improving hemorheology. Advanced technology and sophisticated care render apheresis treatment selective, safe and tolerable. Our task is to constantly update indications for apheresis based on best evidence available and good clinical practice, as well as, to determine how apheresis therapy can be made available to those in need or with otherwise refractory disease. Presenting examples of lipid apheresis, rheopheresis, or immunoadsorption for treatment of hypercholesterolemia, hyperlipoproteinemia (a), acute hearing loss, refractory or exacerbating multiple sclerosis, we highlight real world obstacles for implementation of treatment, resulting in still too many patients with proven or recommended indication left untreated. Based on the experience of the largest apheresis center in Germany, with more than 3,300 treatments per year, we depict the necessary structure for identification of patients, defining indication, referral, implementation of therapy, and reimbursement. Apheresis is unfamiliar to most patients and many practitioners or consultants. Nephrologists, performing >90% of apheresis treatments in Germany, have to form a network for referral comprising all regional care-givers, general practitioners as well as the respective specialists (mainly, cardiologists, endocrinologists, diabetologists, ORL specialists, neurologists, ophthalmologists, or rheumatologists), and insurances or other cost-bearing parties for offering a scientifically approved therapeutic regimen and comprehensive care. We have realized this concept in a high volume apheresis center acting in a closely knit network characterized by an unrelenting effort at ongoing medical education. As a consequence, we include approximately 10 times more patients with appropriate diagnoses in our apheresis program as compared to the national average.

Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2.

A plethora of evidence supports a link between inflammation and atherogenesis. Both the vasoactive peptide angiotensin II (ANG II) as well as the CD40/CD154 signaling pathway exhibit proinflammatory properties with a direct influence on atherogenesis. We therefore tested the hypothesis that ANG II interacts with CD40/CD154 in human vascular smooth muscle cells (SMC). ANG II did not increase expression of CD40 in human SMC. However, when SMC were prestimulated with ANG II and thereafter stimulated with CD154, the ligand for CD40, the release of IL-6 as a marker of inflammatory activation was augmented compared to cells not primed with ANG II. TNF receptor-associated factor 2 (TRAF-2), an important adaptor protein involved in CD40 signaling, but not TRAF-5 or -6, was increased by ANG II via activation of the angiotensin II type 1 (AT1) receptor subtype. These results suggest that a signaling pathway downstream of CD40 may be altered by ANG II prestimulation. Thus, ANG II can also indirectly cause inflammatory activation of vascular SMC. The data show a novel link between the proatherogenic vasoactive peptide ANG II and cell-cell contact-mediated inflammatory pathways and implicate options for the prevention and therapy of atherosclerotic disease.

Angiotensin II stimulates matrix metalloproteinase secretion in human vascular smooth muscle cells via nuclear factor-kappaB and activator protein 1 in a redox-sensitive manner.

The renin-angiotensin system contributes to atherogenesis. Matrix metalloproteinases (MMP) are thought to participate in plaque destabilization through degradation of extracellular matrix. This study tested whether angiotensin II (ANG II) induces MMP in human vascular smooth muscle cells (SMC). ANG II induced expression of MMP-1, -3, and -9, but not of MMP-2 in SMC. The expression of MMP-1, a key enzyme for collagen degradation, was studied in detail. SMC stimulated with ANG II concentration-dependently released enzymatically active MMP-1. The ANG II type 1 receptor antagonists losartan and candesartan blocked ANG-II-induced MMP-1 release. Inhibition experiments with actinomycin D suggest ANG-II-induced MMP-1 mRNA regulation at the transcriptional level. Decoy oligodeoxynucleotides against nuclear factor-kappaB and activator protein 1 inhibited MMP-1 secretion, demonstrating participation of these transcription factors in MMP-1 transcription. Stimulation of MMP-1 by ANG II depended on cyclooxygenase 2. The antioxidants pyrrolidine dithiocarbamate and N-acetylcysteine, the flavin protein inhibitor diphenylene iodonium, and the NADP(H) oxidase inhibitor apocynin blocked MMP-1 release, suggesting a redox-sensitive mechanism involving NADP(H) oxidase. The reactive oxygen species (ROS) donor 2,3-dimethoxy-1,4-naphthoquinone induced MMP-1 secretion and enhanced ANG-II-stimulated MMP-1 expression. These findings indicate that ROS may increase their own production by activation of NADP(H) oxidase. The capability of ANG II to induce functionally active MMP in human SMC may contribute to the altered plaque composition seen in complicated stages of atherosclerosis.

Ultrasound contrast agents can influence the respiratory burst activity of human neutrophil granulocytes.

Activated leucocytes can bind and, subsequently, phagocytose microbubbles that are used as ultrasound (US) contrast agents. The purpose of this study was to investigate whether or not microbubbles can influence the inflammatory response of human neutrophil granulocytes. Granulocytes isolated from healthy volunteers were activated with various stimuli, for example, the bacterial peptide N-formyl-methyonyl-leucyl-phenylalanine (fMLP), the calcium ionophore A23187, the protein kinase C activator phorbol myristate acetate (PMA) and the cytokine tumor necrosis factor alpha (TNF-alpha), and incubated with albumin or phospholipid microbubbles. Neutrophil respiratory burst activity and elastase release were quantified. Albumin (Optison) and phospholipid (SonoVue) contrast agents induced an extensive oxidative response of human granulocytes to all the stimuli used, and these effects could be significantly impaired by preincubation of the cells with cytochalasin B. Left heart contrast agents used for contrast-enhanced US assessment can activate human neutrophil granulocytes, inducing an extensive respiratory burst to secondary stimuli. The potential clinical relevance of this effect needs to be elucidated.