In mice, administration of murine anti-myeloperoxidase (MPO) IgG induces pauci-immune necrotizing crescentic glomerulonephritis. Recent studies in this model indicate a crucial role for complement activation in disease induction. Here, we investigated the effect of pretreatment or intervention with a C5-inhibiting monoclonal antibody (BB5.1) in the mouse model of anti-MPO IgG-induced glomerulonephritis. Mice received BB5.1 8 h before or 1 day after disease induction with anti-MPO IgG and lipopolysaccharide. Mice were killed after 1 or 7 days. Control antibody-pretreated mice developed hematuria, leukocyturia and albuminuria, and glomerulonephritis with a mean of 21.0+/-8.8% glomerular crescents and 12.8+/-5.5% glomerular capillary necrosis. BB5.1 pretreatment prevented disease development, as evidenced by the absence of urinary abnormalities, a marked reduction in glomerular neutrophil influx at day 1 and normal renal morphology at day 7. Importantly, BB5.1 administration 1 day after disease induction also resulted in a marked attenuation of urinary abnormalities and a more than 80% reduction in glomerular crescent formation. In conclusion, inhibition of C5 activation attenuates disease development in a mouse model of anti-MPO IgG-induced glomerulonephritis. These results favor further investigations into the role of complement activation in human MPO-anti-neutrophil cytoplasmic autoantibody-mediated glomerulonephritis, and indicate that inhibition of C5 activation is a potential therapeutic approach in this disease.

The endothelium plays a pivotal role in the progression of solid tumors and is considered a highly relevant target for therapy. However, it emerges that current clinical angiogenesis inhibitors that act through inhibition of tumor-derived growth factors are prone to inducing drug resistance. Therefore, markers of tumor endothelial cells (ECs) themselves provide attractive novel therapeutic targets. In a screen for markers of tumor angiogenesis, we recently identified high-mobility group box 1 (HMGB1), known to act as proinflammatory cytokine and chromatin-binding molecule. Here we report on the role of HMGB1 in angiogenesis by showing that its overexpression is associated with an increased angiogenic potential of ECs. HMGB1 stimulates the expression of players in vascular endothelial growth factor and platelet-derived growth factor signaling, both in vitro and in vivo. Importantly, we show that HMGB1 triggers and helps to sustain this proangiogenic gene expression program in ECs, additionally characterized by increased activity of matrix metalloproteinases, integrins and nuclear factor-κB. Moreover, we found that HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of HMGB1 expression, and that of its receptors, RAGE (receptor for advanced glycation end products) and Toll-like receptor 4 (TLR4). Interference in HMGB1 expression and/or function using knockdown approaches and antibody-mediated targeting to break this vicious circle resulted in inhibited migration and sprouting of ECs. Using different in vivo models, therapeutic efficacy of HMGB1 targeting was confirmed. First, we demonstrated induction of HMGB1 expression in the chicken embryo chorioallantoic membrane (CAM) neovasculature following both photodynamic therapy and tumor challenge. We subsequently showed that anti-HMGB1 antibodies inhibited vessel density in both models, accompanied by a reduced vascular expression of angiogenic growth factor receptors. Collectively, these data identify HMGB1 as an important modulator of tumor angiogenesis and suggest the feasibility of targeting HMGB1 for multi-level cancer treatment.

Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic wasting, in part associated with a chronic inflammatory response. The aim of this study was to investigate cross-sectionally and prospectively the potential role of leptin in relation to systemic inflammation in the regulation of the energy balance in COPD. Body composition by deuterium dilution, resting energy expenditure (REE) by indirect calorimetry, and plasma concentrations of leptin and soluble tumor necrosis factor (TNF) receptors (sTNF-R) 55 and 75 by ELISA were measured in 27 male patients with emphysema and 15 male patients with chronic bronchitis (disease-subtype defined by high-resolution computed tomography [HRCT]). Emphysematous patients were characterized by a lower body mass index due to a lower fat mass (FM) (p = 0.001) and by lower mean (detectable) leptin concentrations (p = 0.020) compared with bronchitic patients. Leptin was exponentially related to FM in emphysema (r = 0.74, p < 0.001) and in chronic bronchitis (r = 0.80, p = 0.001). Furthermore, a significant partial correlation coefficient between leptin and sTNF-R55 adjusted for FM and oral corticosteroid use was seen in emphysema (r = 0.81, p < 0.001) but not in chronic bronchitis. In 17 predominantly emphysematous depleted male patients with COPD, baseline plasma leptin divided by FM was in addition logarithmically inversely related to baseline dietary intake (r = -0.50, p = 0.047) and to the degree of weight change after 8 wk of nutritional support (r = -0.60, p = 0.017). This proposed cytokine-leptin link in pulmonary cachexia may explain the poor response to nutritional support in some of the cachectic patients with COPD and may open a novel approach in combating this significant comorbidity in COPD. Schols AMWJ, Creutzberg EC, Buurman WA, Campfield LA, Saris WHM, Wouters EFM. Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease.

Abdominal aortic aneurysm (AAA) is an important health problem. Elective surgical treatment is recommended on the basis of an individual's risk of rupture, which is predicted by AAA diameter. However, the natural history of AAA differs between patients and a reliable and individual predictor of AAA progression (growth and expansion rates) has not been established. Several circulating biomarkers are candidates for an AAA diagnostic tool. However, they have yet to meet the triad of biomarker criteria: biological plausibility, correlation with AAA progression, and prediction of treatment effect on disease outcome. Circulating levels of markers of extracellular matrix degeneration, such as elastin peptides, aminoterminal propeptide of type III procollagen, elastase-alpha1-antitrypsin complexes, matrix metalloproteinase 9, cystatin C, plasmin-antiplasmin complexes and tissue plasminogen activator, have been correlated with AAA progression and have biological plausibility. Although studies of these markers have shown promising results, they have not yet led to a clinically applicable biomarker. In future studies, adjustment for initial AAA size, smoking history and the measurement error for determination of AAA size, among other variables, should be taken into account. A large, prospective, standardized, follow-up study will be needed to investigate multiple circulating biomarkers for their potential role in the prediction of AAA progression, followed by a study to investigate the effect of treatment on the circulating levels of biomarkers.