Identifying chemokines as therapeutic targets in renal disease: Lessons from antagonist studies and knockout mice

Chemokines, in concert with cytokines and adhesion molecules, play multiple roles in local and systemic immune responses. In the kidney, the temporal and spatial expression of chemokines correlates with local renal damage and accumulation of chemokine receptor-bearing leukocytes. Chemokines play important roles in leukocyte trafficking and blocking chemokines can effectively reduce renal leukocyte recruitment and subsequent renal damage. However, recent data indicate that blocking chemokine or chemokine receptor activity in renal disease may also exacerbate renal inflammation under certain conditions. An increasing amount of data indicates additional roles of chemokines in the regulation of innate and adaptive immune responses, which may adversively affect the outcome of interventional studies. This review summarizes available in vivo studies on the blockade of chemokines and chemokine receptors in kidney diseases, with a special focus on the therapeutic potential of anti-chemokine strategies, including potential side effects, in renal disease. Copyright (C) 2004 S. Karger AG, Basel

Prompt and delayed secondary excitons in rare gas solids

Direct and indirect creation of excitons in rare gas solids has been investigated with reflectivity and luminescence spectroscopy. For the heavy rare gas solids Kr and Xe, new and more reliable exciton parameters have been deduced. With time-resolved luminescence spectroscopy, fast and delayed secondary-exciton creation has been established and separated. Thermalization of photocarriers and their delayed recombination have been analyzed, including a first attempt to investigate the influence of excitation density on the carrier dynamics. The existence of excitonic side bands of ionization limits Ei (either band gap or inner-shell ionization limits) in prompt secondary exciton creation has been established. The threshold energies of these side bands are given by Eth≈Ei nEex (n is integer, Eex is exciton energy). The side bands are ascribed to the formation of electronic polaron complexes, superimposed to inelastic scattering of photoelectrons

5d-4f luminescence of Ce3, Gd3 and Lu3 in LiCaAlF6

The emission and excitation spectra as well as decay kinetics of luminescence due to 5d4f transitions in Ce3, Gd3 and Lu3 ions doped into LiCaAlF6 crystals have been analyzed with high spectral and time resolution using synchrotron radiation for excitation. The rich fine structure originating from electronic origins of transitions and their phonon replica has been well resolved and identified. Experimental data are compared with the spectra simulated in the framework of the semiphenomenological models of the crystal field and the crystal lattice dynamics. © 2011 Elsevier B.V. All rights reserved

Vacuum-ultraviolet 5d-4f luminescence of Gd3+ and Lu3+ ions in fluoride matrices

The VUV 4 f n-1 5d-4 f n luminescence and luminescence excitation spectra of Gd3+ (n=7) in LiGdF4, GdF3, LiYF4: Gd3+, and YF3: Gd3+, and of Lu3+ (n=14) in LiLuF4, LuF3, and LiYF4: Lu3+ have been analyzed with high spectral resolution. In systems with intermediate electron-phonon coupling, zero-phonon lines, and phonon sidebands were observed. The excitation spectra of dilute systems exhibit rich fine structure originating from electronic origins of transitions and their phonon replica. Theoretical calculations explicitly taking into account a microscopic model of the crystal field and the crystal lattice vibrational spectra agree well with experimental data and are the basis for a safe analysis of the spectra. © 2007 The American Physical Society

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis

Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-alpha-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-alpha/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure

Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis

Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-alpha-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-alpha/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure