The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

Fibroblasts in cancer

LTP and LTD: an embarrassment of riches.

Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)

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Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.

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Cellular and molecular mechanisms of fibrosis.

Die Glykosphingolipide Globotrihexosylceramid (Gb3, CD77) und Isoglobotrihexosylceramid (iGb3) sind Isomere, welche sich nur in einer glykosidischen Bindung unterscheiden. Beide wurden in unterschiedlichen Prozessen der angeborenen und erworbenen Immunitat beschrieben.

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Glykosphingolipide Gb3 und iGb3

Panarteritis nodosa, Wegener's granulomatosis and idiopathic necrotizing glomerulonephritis, regarded by some as a vasculitis restricted to the glomerulus, are those forms of primary vasculitis most often encountered in renal biopsy. The histopathologic differential diagnosis can be difficult and has to rely on the finding of vascular inflammation in preglomerular vessels and of granulomata. In a majority of renal biopsies only a necrotizing and crescentic glomerulonephritis without inflammation of arteries or arterioles can be seen. Also the clinical manifestation of these three diseases can be very similar. A new impetus for the differential diagnosis of vasculitis was the discovery of antineutrophilic cytoplasmic antibodies (ANCA). In alcohol fixed leukocytes a cytoplasmic immunofluorescence (c-ANCA) represents an autoantibody to a serine protease of 29 kD - probably Protease 3-, and a perinuclear stain (p-ANCA), often a reaction against myeloperoxidase. ANCA antibodies seem to be a useful marker for the diagnosis of Wegener's granulomatosis, although ANCA positive tests have also been obtained in microscopic panarteritis nodosa and seemingly even in lupus nephritis. ANCA autoantibodies apparently are a reliable parameter to assess activity of the vasculitic process, and may thus be helpful in therapeutic decisions. Despite of current aggressive immunosuppressive therapy long term survival of patients or their kidneys still is rather bleak, in case a severe renal vasculitic process is diagnosed. Extracapillary proliferation (crescents) in more than 50% of glomeruli is also associated with an increased mortality.

Vasculitis of the kidney

Preclinical evaluation of a diabody-based 177Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model

Die membranose Glomerulonephritis (MGN) ist durch eine Proteinurie > 3,5 g/d und weitere Symptome des nephrotischen Syndroms gekennzeichnet. In vielen Fallen ist die Atiologie idiopathisch. Ob und wie die MGN zu behandeln ist, bleibt kontrovers. Trotz der Therapie mit Kortikosteroiden, Ciclosporin oder Alkylanzien entwickeln bis zu 40% der Patienten eine terminale Niereninsuffizienz. Ein 40-jahriger Patient mit nierenbioptisch gesicherter idiopathischer MGN wurde aufgrund der hohen initialen Proteinurie von 22 g/d bei einer normalen Nierenfunktion mit Chlorambucil und Prednisolon behandelt. Da das nephrotische Syndrom nach 6 Monaten persistierte, wurde eine Ciclosporintherapie begonnen. Die Proteinurie konnte durch diese Therapie bis auf 4 g/d gesenkt werden. Diese Therapie wurde nach 17 Monaten beendet, und es kam zum schnellen Wiederauftreten des nephrotischen Syndroms. Eine erneute Nierenbiopsie zeigte eine MGN im Stadium II, teils III nach Ehrenreich & Churg ohne wesentlichen chronischen tubulointerstitiellen Schaden. Eine Therapie mit ACE-Hemmern und AT1-Rezeptor-Antagonisten sowie die erneute Ciclosporingabe reduzierten nochmals die Proteinurie. Ciclosporin wurde nach insgesamt 24 Monaten abgesetzt. 5 Monate danach kam es zu einem erneuten Rezidiv der Erkrankung mit einer Proteinurie bis 34 g/d. Der monoklonale Anti-CD20-Antikorper Rituximab wurde in einer Dosis von 4 × 375 mg/m2 alle 4 Wochen zusatzlich zu einer Prednisolontherapie verabreicht. Nach 4 Wochen reduzierte sich die Proteinurie auf 780 mg/d, 4 Monate nach Therapieende betrug sie < 150 mg/d. Die Nierenfunktion blieb allerdings reduziert (Kreatininclearance 65 ml/min, Stadium 2 nach K/DOQI). 2 Jahre nach Beendigung der Rituximabgabe ist die Proteinurie in anhaltend stabiler Remission (< 150 mg/d). Die Nierenfunktion verschlechterte sich jedoch weiter (Kreatininclearance 45 ml/min, Stadium 3 nach K/DOQI). Rituximab eroffnet die Moglichkeit einer zielgerichteten Therapie der idiopathischen MGN. Auf der Basis der existierenden Evidenz kann Rituximab als eine neue Therapieoption der MGN, wahrscheinlich noch vor dem Einsatz zytotoxischer Substanzen und hochdosierter Prednisolongaben, die das Risiko schwerer Nebenwirkungen haben, empfohlen werden. Langzeitergebnisse dieser Therapie sind allerdings noch nicht verfugbar.

Hermann Josef Gröne

Papers

Glykosphingolipide Gb3 und iGb3

Vasculitis of the kidney

Preclinical evaluation of a diabody-based 177Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model

Behandlung der idiopathischen membranösen glomerulonephritis. Ist der anti-CD20-antikörper rituximab eine sinnvolle therapieoption?

Sp048unraveling the mechanism of action of glucocorticoids in glomerulonephritis