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After ischemic stroke, in the lesion core as well as in the ischemic penumbra, evolution of tissue damage and repair is strongly affected by neuroinflammatory events that involve activation of local specialized glial cells, release of inflammatory mediators, recruiting of systemic cells and vascular remodelling. To take advantage of this intricate response in the quest to devise new protective therapeutic strategies we need a better understanding of the territorial and temporal interplay between stroke-triggered inflammatory and cell death-inducing processes in both parenchymal and vascular brain cells. Our goal is to describe structural rearrangements and functional modifications occurring in glial and vascular cells early after an acute ischemic stroke. Low and high scale mapping of the glial activation on brain sections of mice subjected to 30 minutes middle cerebral artery occlusion (MCAO) was correlated with that of the neuronal cell death, with markers for microvascular changes and with markers for pro-inflammatory (IL-1β) and reparative (TGFβ1) cytokines. Our results illustrate a time-course of the neuroinflammatory response starting at early time-points (1 h) and up to one week after MCAO injury in mice, with an accurate spatial distribution of the observed phenomena.

Microglia cells, the resident macrophages of the central nervous system, are key actors for specific brain functions that are critical for development and health. Microglial reactivity and functions, even when immature, play a major role if the developing brain is subjected to abnormal perinatal events. Brain exposure to general anesthesia, surgery, or analgesic drugs during early infancy may adversely affect its maturation and plasticity after injury. A better understanding of the regulation of microglial activation in the developing brain and interactions with specific anesthetic drugs is expected to give novel insights into the mechanisms underlying their potential adverse effects. This review recapitulates the most frequent perinatal circumstances associated with exacerbated systemic inflammation and neuroinflammation together with the double-edged role of microglia associated with subsequent brain damage. A role for microglial reactivity in both potential anesthetic toxicity and neuroprotection is emerging. However, further preclinical experiments are needed to better understand regulatory mechanisms of the developing microglia, and interaction between anesthesia and neuroinflammation in the developing brain.

OBJECTIVE: Up to 30% of obese individuals are metabolically healthy. Metabolically healthy obese (MHO) individuals are characterized by having low abdominal adiposity, low inflammation level and low risk of developing metabolic comorbidity. In this study, we hypothesize that cardiorespiratory fitness (fitness) is a determinant factor for the MHO individuals and aim to investigate the associations between fitness, abdominal adiposity and low-grade inflammation within different BMI categories.METHOD: Data from 10,976 individuals from the general population, DANHES 2007-2008, on waist circumference, fitness and C-reactive protein (hsCRP) were analysed using multiple linear and median quantile regressions.RESULTS: In men, an inverse association between fitness (+5 mL min-1 kg-1) and waist circumference (-1.45 cm; 95% CI: -1.55 to -1.35 cm; pCONCLUSION: Fitness was found to be inversely associated with both abdominal adiposity and low-grade inflammation independent of BMI. These data suggest that, in spite of BMI, high fitness levels lead to a reduction in abdominal fat mass and low-grade inflammation.

This special issue wants to contribute to a better understanding of cardiac involvement in sepsis. Sepsis is a complex syndrome that has recently been defined as “life-threatening organ dysfunction due to a dysregulated host response to infection” [1, 2]. It should be considered a major public health problem since it affects millions of people worldwide each year, and it accounts for most deaths in critically ill patients. The presence of myocardial dysfunction in sepsis is associated with higher mortality. A great attention has been dedicated to improving our knowledge and understanding of the intricate mechanisms underlying sepsis. However, data from the literature suggest the need to implement strategies to reliably measure sepsis morbidity and mortality. In fact, methods based on analyses of insurance claim data using sepsis-specific codes or separate codes for infection and organ dysfunction are unreliable in informing or measuring the effects of policy changes [3, 4], and the postmortem diagnosis of sepsis is often elusive since postmortem investigations lack certain pathognomonic macroscopic and histopathological findings [5, 6]. From a morphological and diagnostic point of view, the term “septic disease” has been created to describe the cardiac involvement in the syndrome. However, this definition, rather than describing a morphological finding, was instead referred to the clinical setting. Although in recent years the concept of septic cardiomyopathy has evolved and it involves pathological alterations of myocardial cells in response to the multiplicity of acting mechanism of damage, the importance of structural changes during sepsis is often overlooked. In patients with sepsis, death is usually the result of a progressive multiorgan dysfunction, overlooking the primary infection through the hyperinflammation. The cardiac involvement as fundamental part of septic multiorgan dysfunction syndrome has been discussed for a long time. C. Pomara et al. explored the state of current knowledge on the molecular and biohumoral mechanisms of sepsis and correlate them with our ability at postmortem diagnosis. The authors highlight that a complete methodological approach, integrating clinical data by means of autopsy and histological and laboratory findings aiming to identify and demonstrate the host response to infectious insult, is mandatory. Such an approach would be likely to produce an accurate objective surveillance of deaths due to sepsis and improve our knowledge of the clinical-pathological correlation in sepsis, thus contributing to the evaluation of the effectiveness of therapies. Sepsis is characterized by symptoms and manifestations of organ dysfunction that may lead to fatal outcome. Myocardial dysfunction in sepsis is mediated by a complex interplay among several factors that still remains incompletely understood [7]. Circulatory compromise and microcirculatory alterations may, in part, explain cardiac impairment in sepsis. However, in recent years increasing attention has been paid to the study of other possible pathways of myocardial dysfunction in sepsis. The effects of the host's immune-inflammatory response with particular focus on depressant molecules, complement molecules, cellular adhesion molecules, and altered intracellular energetic, dysregulated intracellular calcium fluxes have been called upon in the pathophysiology of myocardial depression in sepsis. Oxidative-nitrosative stress may contribute to cardiac dysfunction in sepsis, and mitochondria are one of the major sites for generation of reactive oxygen species and reactive nitrosative species as a detrimental side product of oxidative energy metabolism [8]. M. Neri et al. reviewed the evidence for a role of oxidative-nitrosative stress unbalance and mitochondria dysfunction in myocardial depression in sepsis. NADPH oxidase-derived reactive oxygen species, the role of mitochondria, and finally the involvement of nitric oxide and peroxynitrite as critical factors in mediating myocardial dysfunction in sepsis are discussed. Measurement of biomarkers is a potential approach to early prediction of the risk of mortality in patients with sepsis. Over the years, a great amount of molecules has been proposed as potential biological markers [9]. However, only 20% of these biomarkers have been assessed specifically in appropriate studies for use in the diagnosis of sepsis [10]. To date an ideal clinical and postmortem marker of sepsis does not exist. Proadrenomedullin and copeptin are peptides cosynthesized together with adrenomedullin and vasopressin in endothelial cells and pituitary gland, respectively. These peptides are increased during sepsis. They have vasoactive, immune modulating, and metabolic properties. It was recently reported that adrenomedullin plays a central role in initiating the hyperdynamic response during the early stages of sepsis and was a useful predictor for development of severe sepsis and septic shock [11, 12]. W. Hu et al. discuss the prognostic value of adrenomedullin and atrial and brain natriuretic peptides in uroseptic patients induced by ureteroscopy. In their research article the authors suggest that the prognostic value of adrenomedullin is superior to atrial and brain natriuretic peptides and that all these molecules are robust independent predictors of in-hospital death in uroseptic patients. They conclude that adrenomedullin and atrial and brain natriuretic peptides may participate in initiating the hyperdynamic response during the early stages of sepsis in uroseptic patients and that these biomarkers could be considered strong predictors of adverse outcome in patients with urosepsis. Finally, two articles of the special issue discuss the potential link existing between inflammatory status and cardiometabolic disorders. It has been well established that inflammation is also able to affect lipoprotein metabolism. However, the precise mechanisms pathophysiologically linking metabolic dysfunction and inflammation are still under investigation. The biological basis for these associations includes both systemic and local tissue effects. Metabolic Syndrome (MetS) is a constellation of diseases that include obesity, diabetes, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. These metabolic derangements trigger a persistent inflammatory cascade, whit recruitment of immune cells to the site of injury, and subsequent expression of cytokines and chemokines that amplify the inflammatory response [13]. A common link between inflammation and MetS has been suggested. In cardiometabolic disorders a high serum lipopolysaccharides activity has been demonstrated, thus suggesting a potential role of bacterial infections and immune response in their etiology [14]. One article discussed the serum adiponectin levels and the homeostasis model assessment-insulin resistance (HOMA-IR) that are reportedly associated with MetS. Y.-S. Ding et al. concluded that the adiponectin to HOMA-IR ratio (A/H) may be a better diagnostic marker for MetS than either HOMA-IR or adiponectin alone, and it may serve as an important biomarker to determine an increased risk for MetS in healthy middle-aged population. Y. Zhang et al. investigated the relationship between inflammatory markers and the atherogenic lipoprotein subfractions, and they hypothesized presence of heterogeneity in the relationship of systemic inflammatory markers with atherogenic lipoprotein subfractions, which would aid our understanding of their interplay in the pathogenesis of atherosclerotic disease. This special issue is dedicated to the cardiovascular involvement in sepsis. The high mortality associated with sepsis makes a thorough knowledge of its underlying mechanisms and its pathophysiological connections with the cardiometabolic disorders important.

Purpose of review This systematic review reports the most recent literature regarding the effects of physical exercise on muscle strength, body composition, physical functioning and inflammation in older adults. All articles were assessed for methodological quality and where possible effect size was calculated. Recent findings Thirty-four articles were included - four involving frail, 24 healthy and five older adults with a specific disease. One reported on both frail and nonfrail patients. Several types of exercise were used: resistance training, aerobic training, combined resistance training and aerobic training and others. In frail older persons, moderate-to-large beneficial exercise effects were noted on inflammation, muscle strength and physical functioning. In healthy older persons, effects of resistance training (most frequently investigated) on inflammation or muscle strength can be influenced by the exercise modalities (intensity and rest interval between sets). Muscle strength seemed the most frequently used outcome measure, with moderate-to-large effects obtained regardless the exercise intervention studied. Similar effects were found in patients with specific diseases. Summary Exercise has moderate-to-large effects on muscle strength, body composition, physical functioning and inflammation in older adults. Future studies should focus on the influence of specific exercise modalities and target the frail population more.

OBJECTIVE Pancreatic β-cells exposed to proinflammatory cytokines display alterations in gene expression resulting in defective insulin secretion and apoptosis. MicroRNAs are small noncoding RNAs emerging as key regulators of gene expression. Here, we evaluated the contribution of microRNAs to cytokine-mediated β-cell cytotoxicity. RESEARCH DESIGN AND METHODS We used global microarray profiling and real-time PCR analysis to detect changes in microRNA expression in β-cells exposed to cytokines and in islets of pre-diabetic NOD mice. We assessed the involvement of the microRNAs affected in cytokine-mediated β-cell failure by modifying their expression in insulin-secreting MIN6 cells. RESULTS We found that IL-1β and TNF-α induce the expression of miR-21, miR-34a, and miR-146a both in MIN6 cells and human pancreatic islets. We further show an increase of these microRNAs in islets of NOD mice during development of pre-diabetic insulitis. Blocking miR-21, miR-34a, or miR-146a function using antisense molecules did not restore insulin-promoter activity but prevented the reduction in glucose-induced insulin secretion observed upon IL-1β exposure. Moreover, anti–miR-34a and anti–miR-146a treatment protected MIN6 cells from cytokine-triggered cell death. CONCLUSIONS Our data identify miR-21, miR-34a, and miR-146a as novel players in β-cell failure elicited in vitro and in vivo by proinflammatory cytokines, notably during the development of peri-insulitis that precedes overt diabetes in NOD mice.

Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)α, PPARβ/δ and PPARγ are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARα are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARα also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARγ controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARβ/δ increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARβ/δ ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARα favours skin healing during the inflammatory phase that follows injury, whilst PPARβ/δ enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in many inflammatory reactions and disorders, and it has become evident that it also affects glucose homeostasis. The protein is produced by pancreatic beta cells and can promote the release of insulin. It also modulates glucose uptake, glycolysis and insulin resistance in insulin target cells such as the adipocyte, myocyte and cardiomyocyte. Possessing both immunological and endocrinological properties, MIF has been associated with the development of type 1 and type 2 diabetes, and it may be important in the setting of islet transplantation. The present review summarises our current knowledge, based on clinical and research data, on the impact of MIF on both physiological and pathological aspects of glucose metabolism.

Fas ligand (FasL) exerts potent proapoptotic and proinflammatory actions on epidermal keratinocytes and has been implicated in the pathogenesis of eczema, toxic epidermal necrolysis, and drug-induced skin eruptions. We used reconstructed human epidermis to investigate the mechanisms of FasL-induced inflammatory responses and their relationships with FasL-triggered caspase activity. Caspase activity was a potent antagonist of the pro-inflammatory gene expression triggered by FasL prior to the onset of cell death. Furthermore, we found that FasL-stimulated autocrine production of epidermal growth factor receptor (EGFR) ligands, and the subsequent activation of EGFR and ERK1 and ERK2 mitogen-activated protein kinases, were obligatory extracellular steps for the FasL-induced expression of a subset of inflammatory mediators, including CXCL8/interleukin (IL)-8, ICAM-1, IL-1alpha, IL-1beta, CCL20/MIP-3alpha, and thymic stromal lymphopoietin. These results expand the known physiological role of EGFR and its ligands from promoting keratinocyte mitogenesis and survival to mediating FasL-induced epidermal inflammation.

Comment on: Bratisl Lek Listy. 2006;107(1-2):3-8.

Journal of the American College of Cardiology

Local injury induces a complex orchestrated response to stimulate healing of injured tissues, cellular regeneration and phagocytosis. Practically, inflammation is defined as a defense process whereby fluid and white blood cells accumulate at a site of injury. The balance of cytokines, chemokines, and growth factors is likely to play a key role in regulating important cell functions such as migration, proliferation, and matrix synthesis during the process of inflammation. Hence, the initiation, maintenance, and resolution of innate responses depend upon cellular communication. A process similar to tissue repair and subsequent scarring is found in a variety of fibrotic diseases. This may occur in a single organ such as liver, kidneys, pancreas, lung, skin, and heart, but fibrosis may also have a more generalized distribution such as in atherosclerosis. The purpose of this review is to summarize recent advances on the contribution of gap junction-mediated intercellular communication in the modulation of the inflammatory response and tissue repair.

We have examined the effects of a novel GABA(B) agonist, CGP35024, in models of chronic neuropathic (partial sciatic ligation) and inflammatory (Freund's complete adjuvant) pain in the rat, and its inhibitory action on spinal transmission in vitro. The effects of CGP35024 were compared with L-baclofen and gabapentin. CGP35024 and L-baclofen reversed neuropathic mechanical hyperalgesia following single subcutaneous or intrathecal administration, but did not affect inflammatory mechanical hyperalgesia. Gabapentin only moderately affected neuropathic hyperalgesia following a single administration by either route, but produced significant reversal following daily administration for 5 days. It was only weakly active against inflammatory hyperalgesia following single or repeated administration. The antihyperalgesic effects of L-baclofen and CGP35024, but not gabapentin, were blocked by the selective GABA(B) receptor antagonist CGP56433A. CGP35024 was seven times more potent against neuropathic hyperalgesia than in the rotarod test for motor co-ordination, whilst L-baclofen was approximately equipotent in the two tests. In the isolated hemisected spinal cord from the rat, CGP35024, L-baclofen and gabapentin all inhibited capsaicin-evoked ventral root potentials (VRPs). CGP35024 and L-baclofen, but not gabapentin, also inhibited the polysynaptic and monosynaptic phases of electrically-evoked VRPs, as well as the 'wind-up' response to repetitive stimulation. These data indicate that CGP35024 and L-baclofen modulate nociceptive transmission in the spinal cord to inhibit neuropathic hyperalgesia, and that CGP35024 has a therapeutic window for antihyperalgesia over spasmolysis.

Animal models based on knock-out or transgenic technology are widely used in basic and applied biomedical research. An alternative to these approaches is the generation of xenogeneic transplantation models allowing the in-vivo investigation of cell types and organs. In the field of dermatology transplantation of human skin onto mice lacking functional B and T cells (SCID mice) and subsequent manipulation of these grafts yielded new insights in many different aspects of skin biology. This review highlights some of the applications of this versatile model focussing on phenomena relevant for the subject of dermatology.

Thiazolidinediones (TZDs) represent insulin sensitizing drugs that are being increasingly used for the treatment of type 2 diabetes. These agents have also pleiotropic properties that possibly contribute to their favorable cardiovascular effects. In particular, TZDs have anti-inflammatory and anti-oxidant potential while they modulate cardiovascular remodeling. On the other hand, atrial electrical and structural remodeling constitutes the substrate for atrial fibrillation (AF) development and perpetuation. Of note, inflammation and oxidative stress have been recently implicated in the pathogenesis of AF while non-channel blocking drugs with pleiotropic properties, including anti-inflammatory and anti-oxidant, seem to favorably affect atrial remodeling. It is therefore reasonable to assume that TZDs may have a role in the management of AF. Despite some limited observations, no study to date has examined the effect of TZDs therapy on AF development. In addition, the role of these agents in atrial remodeling has not been clarified yet. Int J Cardiol

Susceptibility to arthritis in the Lewis rat is associated with a defect of the hypothalamic-pituitary-adrenal axis. We examined the pituitary corticotropes of both intact and dexamethasone-treated male and female inflammatory-disease-susceptible Lewis and inflammatory-disease-resistant Fischer rats. We determined adrenocorticotropin levels in the media from primary cultures of anterior pituitary cells of both strains. In other experiments we have measured intracellular cyclic adenosine monophosphate and inositol monophosphate accumulation. Cells were incubated with corticotropin-releasing hormone, arginine vasopressin, forskolin, phorbol myristate acetate, or thyrotropin-releasing hormone. Corticotropin-releasing hormone stimulated adrenocorticotropin secretion from both male and female Lewis rat pituitary cells in a concentration-dependent manner. Basal and stimulated adrenocorticotropin levels in cells from Lewis rats were lower than those measured in the incubation media of Fischer rat dispersed pituitary cells. Arginine vasopressin, as well as forskolin and phorbol myristate acetate, induced a significant release of adrenocorticotropin from pituitary cells of both strains. Incubation with corticotropin-releasing hormone did not produce a significant accumulation of intracellular cyclic adenosine monophosphate in Lewis rat dispersed pituicytes of both sexes. On the other hand, forskolin induced a significant increase of intracellular cyclic adenosine monophosphate in the same cultures. Finally, inositol monophosphate accumulation was comparable in pituitary cells from both Lewis and Fischer rats of both sexes incubated with thyrotropin-releasing hormone. Adrenocorticotropin secretion from pituitary cells of male Lewis rats treated in vivo with dexamethasone was either reduced or abolished following incubation with different secretagogues. A defect in pituitary adrenocorticotropin secretion could be among the causes of the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in the Lewis rat. Such a defect appears to be associated with dysfunction of receptor-coupled events related to adenylate cyclase.

Angiogenesis, the generation of new capillaries from existing blood vessels, is rarely observed in the healthy organism, but can present during various paediatric diseases. In this review, we describe recent progress in the understanding of pathological angiogenesis and approaches for an improved therapy of angiogenic childhood diseases. Eur J Pediatr

The susceptibility of female Lewis (LEW/N) rats to the development of streptococcal cell wall (SCW)-induced arthritis and other autoimmune phenomena is associated with the inability of their hypothalamic-pituitary-adrenal (HPA) axis to adequately respond to inflammatory stimuli. In contrast, resistance to the development of SCW-induced arthritis and other inflammatory autoimmune manifestations in histocompatible female Fischer rats (F344/N) is related to their intact HPA axis response to inflammatory mediators. To evaluate the mechanism and the specificity of the HPA axis defect in LEW/N rats, we examined the ability of three major excitatory neurotransmitter systems to activate the HPA axis in both Lewis and Fisher rats. The responsiveness of plasma ACTH and corticosterone to the cholinergic muscarinic receptor agonist arecoline, the alpha 1-adrenergic receptor agonist methoxamine and the serotonin (5-HT) type 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane were significantly blunted and/or abolished in LEW/N compared to F344/N rats. To localize the HPA axis defect to the hypothalamic CRH neuron, we evaluated the ability of explanted hypothalami from the two strains to secrete immunoreactive CRH in vitro, in response to acetylcholine (ACh), norepinephrine (NE), 5-HT and the 5-HT agonist quipazine. LEW/N hypothalami released less immunoreactive CRH (iCRH) in response to ACh, NE, 5-HT and quipazine than F344/N hypothalami. The dose-response curves of these compounds in the former were shifted to the right and/or abolished, suggesting decreased sensitivity of LEW/N hypothalami to these neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)

The involvement of tumor necrosis factor alpha (TNF alpha) in the regulation of acute-phase protein synthesis is currently under discussion. In this study the effect of human recombinant TNF alpha on the regulation of the 4 acute-phase proteins alpha 2-macroglobulin, albumin, alpha 1-proteinase inhibitor and alpha 1-acute-phase globulin was investigated in rat hepatocyte primary cultures. No changes in synthesis of any of the 4 proteins were observed. However, an acute-phase response similar to that in vivo could be generated by conditioned media from human monocytes containing natural TNF alpha. This response remained unchanged after neutralizing TNF alpha activity by the addition of a specific antibody to TNF alpha. It is concluded that the hepatocyte-stimulating activity synthesized by human monocytes is different from TNF alpha.