Proteinase-activated receptors induce nonoxidative, antimicrobial peptides and increased antimicrobial activity in human mononuclear phagocytes.

As thrombin and SFLLRNPNDKYEPF (SFLLRN-14), a synthetic ligand, mainly of the proteinase-activated receptor-1 (PAR-1), induce in monocytes the synthesis and secretion of chemokines, the PAR pathway can be viewed as a mononuclear phagocyte-activating principle. Classically, antimicrobial activity of mononuclear phagocytes is the measure for activation. Here, we investigated whether thrombin or SFLLRN-14 increases the antimicrobial activity of human monocytes and compared these effects to those of IFN-gamma.

CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin.

CD163 mediates the internalization of hemoglobin-haptoglobin (Hb-Hp) complexes by macrophages. Because Hp binding capacity is exhausted during severe hemolysis, an Hp-independent Hb-clearance pathway is presumed to exist. We demonstrate that Hb interacts efficiently with CD163 in the absence of Hp.

Regulated expression of platelet factor 4 in human monocytes--role of PARs as a quantitatively important monocyte activation pathway.

Human mononuclear phagocytes have recently been shown to express constitutively and even more so, upon stimulation with bacteria, fungi, lipopolysaccharide (LPS), zymosan, or thrombin platelet basic protein (PBP). This CXC chemokine as well as platelet factor 4 (PF4), which is located genomically at a short distance from the PBP, were previously considered to be specific markers for the megakaryocyte cell lineage. Both chemokines have signaling and antimicrobial activity.

Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome.

Reactive hemophagocytic syndrome (RHS) is a disease of overwhelming macrophage activity triggered by infection, malignancy or autoimmune disorders. Currently used laboratory markers for the quantitative assessment of monocyte/macrophage activation lack lineage-restricted expression patterns and thus specificity. Serum levels of the macrophage specific scavenger receptor CD163 were determined by enzyme-linked immunosorbent assay (ELISA) and were found to be highly increased in patients with RHS (median 39.

Gene expression profiling of inflamed human endothelial cells and influence of activated protein C.

Background: During systemic inflammation, activation of vascular endothelium by proinflammatory cytokines leads to hypotension, microvascular thrombosis, and organ damage. Recent data suggest a link between coagulation and inflammation through the activated protein C (APC) pathway. We studied gene expression profiles in human coronary artery endothelial cells (HCAECs) exposed to proinflammatory stimuli and the influence of APC on expression of candidate genes regulated by these stimuli.

Induction and antimicrobial activity of platelet basic protein derivatives in human monocytes.

The antimicrobial activity of a number of chemokines has recently come into focus of research about innate immunity. We have previously shown that platelet basic protein (PBP), which gives rise to several antimicrobial peptides of platelets, is also expressed in human monocytes. In the present studies, we show that exposure of human monocytes to bacteria or microbial components (lipopolysaccharide and zymosan) induces a several-fold greater expression of derivates of PBP.

Functional tetrahydrobiopterin synthesis in human platelets.

Background: Previous studies have provided evidence for the importance of platelet-derived nitric oxide (NO) for the regulation of hemostasis. Tetrahydrobiopterin (BH4) is an essential cofactor and regulator of NO synthase activity in the vasculature; however, it is as yet unknown whether platelets dispose over a functional BH4 synthesis.

Methods And Results: We quantified mRNA expression of genes involved in BH4 synthesis, measured enzymatic activities, and determined intraplatelet levels of pteridines in platelets from healthy volunteers and from patients treated for prolonged periods of time with glucocorticoids.

Constitutive and regulated expression of platelet basic protein in human monocytes.

Platelet basic protein (PBP) and several of its derivatives are known for their broad range of functions as signaling molecules and cationic antimicrobial peptides and were considered hitherto megakaryocyte- and platelet-specific. In search of glucocorticoid-regulated antimicrobial systems of monocytes, we found a 15-fold down-regulation of PBP mRNA by differential display. Regulation was confirmed in vivo even at low prednisone doses.

Listeria species escape from the phagosomes of interleukin-4-deactivated human macrophages independent of listeriolysin.

Listeria monocytogenes is the causative agent of infections like sepsis and meningitis, especially in immunocompromised hosts. Human macrophages are able to phagocytose and digest L. monocytogenes but IL-4 prevents human macrophages from killing the bacteria, the mechanisms of which are unknown.

Critical role of interleukin-1beta for transcriptional regulation of endothelial 6-pyruvoyltetrahydropterin synthase.

Objective: Synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases, is strongly induced on immunostimulation in vascular endothelial cells (VECs). Expression of GTP cyclohydrolase I (GTPCH), the first enzyme in BH4 biosynthesis, is regulated by cytokines and considered rate-limiting. Herein we investigated the molecular mechanism and relevance of cytokine-dependent regulation of 6-pyruvoyltetrahydropterin synthase (PTPS), the second enzyme in BH4 synthesis, in human coronary artery endothelial cells (HCAECs).

Continuous infusion of escalated doses of amphotericin B deoxycholate: an open-label observational study.

Amphotericin B deoxycholate (AmB-d) remains a mainstay of antifungal therapy for immunocompromised patients, despite being associated with significant therapy-related toxicity. Because continuous infusion of AmB-d is better tolerated than traditional administration over 2-6 hours, we evaluated escalation of the AmB-d dose in 33 patients (31 of whom were neutropenic), for whom the initial dosage of AmB-d (1 mg/kg/day) was gradually increased to 2.0 mg/kg/day when renal function remained stable and the drug was tolerated.

Nephrotoxicity of cyclosporine A and amphotericin B-deoxycholate as continuous infusion in allogenic stem cell transplantation.

Background: Nephrotoxicity is an important side effect of amphothericin B deoxycholate (ampho B) and cyclosporine A (CsA). The combined administration of these drugs is frequent in patients with haematological diseases undergoing allogeneic stem cell transplantation.

Aim: To assess the additional renal toxicity of ampho B given as a continuous infusion in addition to CsA.

Induction of the CD163-dependent haemoglobin uptake by macrophages as a novel anti-inflammatory action of glucocorticoids.

Highly efficient systems remove toxic and pro-inflammatory haemoglobin (Hb) from the circulation and local sites of tissue damage. Macrophages are major Hb-clearing cells; CD163 was recently recognized as the specific haemoglobin-haptoglobin scavenger receptor (HSR). We show that dexamethasone strongly induced the specific uptake of haemoglobin-haptoglobin complexes, CD163 mRNA transcription (13-fold) and cell surface expression (10-fold) by human macrophages.

Host-parasite relation in invasive aspergillosis.

Invasive aspergillosis has become one of the most important infectious complications of intensive modern medicine often limiting the success of oncological treatments and transplantation. The rationale for this is found in the effects of immunosuppressive therapies and to a lesser degree underlying disease processes as well as in properties of the fungus. The double pronged nature of host defenses directed against spores and hyphae of Aspergilli is affected by glucocorticoids and myeloablative therapy.

Assessment of digital clubbing in medical inpatients by digital photography and computerized analysis.

Background: Digital clubbing has been associated with a large number of disorders. To overcome the limitation of subjective clinical assessment, several objective measurements have been developed among which the hyponychial angle was considered most accurate for quantification of finger clubbing.

Methods And Results: Here we investigated hyponychial angles in 123 healthy subjects and 515 medical inpatients from a tertiary hospital.