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Cytokines that regulate autoimmune myocarditis.

A growing body of evidence suggests that autoimmune responses are involved in the pathogenesis of myocarditis and postinfectious cardiomyopathy. Autoimmunity may also arise after ischaemic or traumatic damage to heart tissue. Myocarditis leading to heart failure can be mimicked in rodents by immunisation with cardiac alpha myosin and peptides derived from it. Cytokines and chemokines, produced mainly by T-cells and antigen-presenting cells, control immune responses by acting as either potentiating or inhibitory agents. Gene targeting and experiments with antibodies and/or antagonists blocking cytokines and their receptors have uncovered mechanisms whereby such regulatory molecules are involved in the pathogenesis of myocarditis. Identification of regulatory key cytokines and the associated pro- or anti-inflammatory pathways involved in the pathogenesis of cardiac inflammation may have important implications for therapeutic strategies and vaccine design in the future.

Animals↗

Invasive monitoring of airway inflammation.

What we know: Ethical concerns have limited research involving invasive bronchoscopy techniques in young children. No longitudinal studies have been conducted to compare the findings of bronchial biopsy or bronchoalveolar lavage in young children with transient episodic wheeze versus asthma. Children with atopic asthma have more airway eosinophils and mast cells than children with viral-associated wheeze. Both neutrophilic and eosinophilic patterns of inflammation are present in asthma. What we need to know: Can we establish robust normal values for tissue and fluid samples obtained at bronchoscopy or bronchoalveolar lavage? Do biopsy specimens taken at the carina tell us about the pathological processes occurring in asthma? Can we use invasive procedures to predict which children with wheeze will continue to wheeze and develop a classical asthma phenotype? Can we use invasive procedures to guide asthma therapy? Can we expect airway inflammation to resolve with anti-inflammatory medication? Can we correlate invasive with non-invasive measures of inflammation? Can we use our understanding of pro- and anti-inflammatory pathways to develop new therapeutic interventions? Is there a presymptomatic phase of inflammation?

Adult↗

Nucleotide structure and characterization of the murine gene encoding the endothelial cell protein C receptor.

The nucleotide sequence of the entire gene encoding the murine endothelial cell receptor for activated protein C (EPCR) has been determined. A total of 5303 bp of DNA was sequenced that included 4 exons and three introns, which constituted the coding region of the gene, as well as 393 bp upstream of the first exon and 841 bp downstream of the last exon. From the locations of the introns in this gene and analysis of the exon structures, it is clear the EPCR gene is a member of the CD1 class of multiple histocompatibility proteins. and its cDNA sequence is nearly identical to that of CCD41, a centrosome-associated protein. All elements needed for RNA polymerase II-based transcription are predicted to exist in the 5' uncoded region of the gene, and potential 3' regulatory sequences for efficient polyadenylation have been located at their optimal locations. A variety of highly probable transcription factor binding sites have been located in the 5' region of the gene. These data suggest that the EPCR gene is under efficient transcriptional control, and support the finding that this gene product may be involved in the inflammatory pathway.

Animals↗

Noninflammatory expression of E-selectin is regulated by cell growth.

E-selectin, an endothelial-specific adhesion molecule best known for its role in leukocyte adhesion, is not detected in quiescent endothelial cells, but is induced by inflammatory stimuli. However, E-selectin is also expressed in proliferating endothelial cells under noninflammatory conditions in vivo and in vitro, suggesting that E-selectin is also regulated by growth signals. To investigate E-selectin expression in lipopolysaccharide-stimulated versus nonstimulated proliferating cells, we analyzed the distribution of E-selectin-positive human microvascular endothelial cells in G0/G1, S, and G2/M phases of the cell cycle under both conditions. Lipopolysaccharide treatment resulted in uniformly increased E-selectin expression in cells in G0/G1, S, and G2/M. In contrast, levels of E-selectin in nonstimulated proliferating cells showed a linear correlation with the percentage of cells in G2/M. E-selectin in proliferating endothelial cells was not reduced by addition of soluble tumor necrosis factor-alpha-receptor or soluble interleukin-1-receptor indicating that its expression was not due to endogenous production of either cytokine. In addition, E-selectin was increased in cells stimulated with basic fibroblast growth factor, a well-known mitogen for endothelial cells. E-selectin in proliferating endothelial cells is functional, as shown by E-selectin-dependent adhesion of the promyelocytic leukemia cell line HL-60 to subconfluent human microvascular endothelial cells. In summary, these studies indicate that E-selectin can be regulated by a non-inflammatory pathway that is related to the proliferative state of the endothelium.

Cell Adhesion↗

Modulation of cytochrome P-450 gene expression in endotoxemic mice is tissue specific and peroxisome proliferator-activated receptor-alpha dependent.

Administration of the bacterial endotoxin lipopolysaccharide (LPS) causes induction of cytochrome P-450 (CYP) 4A mRNAs in rat liver and kidney. Because induction of the CYP4A subfamily by chemicals requires peroxisome proliferator-activated receptor-alpha (PPARalpha), we determined whether CYP4A induction by LPS also requires PPARalpha by comparing the responses of PPARalpha-null (-/-) and wild-type (+/+) mice. Renal expression of CYP4A10, CYP4A14, and acyl-CoA oxidase was induced by LPS treatment in (+/+) mice, and these effects were absent in the (-/-) mice. In contrast, hepatic expression of CYP4A10 was down-regulated in the (+/+) animals, and no significant induction of acyl-CoA oxidase or CYP4A14 was detected in liver. Expression of the peroxisomal bifunctional enzyme was not significantly affected by LPS treatment. These results indicate that PPARalpha is activated in mouse kidney after LPS treatment and that this leads to modulation of some PPARalpha-regulated genes. However, the species and tissue specificity of these effects suggest that inflammatory pathways may modulate the induction via PPARalpha. Mice pair fed with LPS-treated mice showed no induction of renal CYP4A10 or CYP4A14, indicating that renal CYP4A induction during endotoxemia is not due to hypophagia. Down-regulation of CYP2A5, CYP2C29, and CYP3A11 by LPS was attenuated or blocked in the (-/-) mice, suggesting a role for PPARalpha in CYP down-regulation as well. Finally, we found that clofibrate caused an acute induction of two hepatic acute-phase mRNAs that was only partially dependent on PPARalpha.

Animals↗

Secretory mucosal immune mechanisms.

Mucosal immune mechanisms in the airways are the first specific line of defense, protecting the body from pathogens. The respiratory epithelium actively transports locally produced dimeric IgA in the respiratory secretions by transcytosis, through the pIgR. S-IgA production therefore requires epithelial integrity. S-IgA at the epithelial level is active in several non-inflammatory pathways including intracellular neutralization of virus, antigen excretion, binding to bacterial adhesins. Local IgA production is regulated by various growth factors and cytokines of both epithelial and non-epithelial origin. The respiratory epithelium is thought to play a crucial role in this process. In addition, in chronic airway inflammation, IgA production demonstrates a correlation with eosinophil activation both in vitro and in vivo. While increased IgA and S-IgA production is reported in asthmatics, decreased SC production has been documented in CF and COPD patients, further impairing their local defense mechanisms.

Bronchi↗

Ischemic cardiovascular disease and Helicobacter pylori. Where is the link?

Coronary heart disease (CHD) is the leading cause of death in western countries. Although several major risk factors have been identified, they fail to account for all the epidemiological variants of the disease, thus warranting research into novel causal agents. Cardiovascular diseases have long been associated with chronic infections acting through the activation of inflammatory pathways, and antibiotic therapy has been shown to produce a dramatic decrease in the rate of disease recurrence in patients with a history of myocardial infarction or unstable angina. The link between Helicobacter pylori (H. pylori) infection and CHD, first described by Mendall et al. in 1994, has been the subject of a multitude of epidemiological and clinical studies; however, these have been so heterogeneous that not two of them are based on a comparable selection of patients and focused on the same kind of disease, e.g. stable coronary heart disease or acute myocardial infarction. Evidence from animal studies supports the thesis that H. pylori plays an extremely important role in the acute phase of myocardial infarction: the bacterium causes platelet aggregation and induces pro-coagulant activity in experimentally infected mice. H. pylori may also contribute to atherosclerosis through an auto-immune process against endothelial cells or an increased concentration of homocysteine in the blood due to decreased levels of folic acid and cobalamin. The exact role of H. pylori cannot yet be fully assessed: there is a clear and present need for further studies with appropriate epidemiological and clinical approaches to investigate through prospective and interventional trial the possible causal relationship between H. pylori and CHD.

Animals↗

Coagulation and inflammation.

Severe infection induces both activation of the coagulation system and multiple other inflammatory mediator cascades. This concise review summarizes the current knowledge of mechanisms that are considered to contribute to the procoagulant response to sepsis. Furthermore, evidence is discussed that mediators traditionally involved in the regulation of the hemostatic balance may also influence other inflammatory pathways.

Animals↗

Fire and ICE: the role of pyrin domain-containing proteins in inflammation and apoptosis.

The genetic bases for several human autoinflammatory syndromes have recently been identified, and the mutated proteins responsible for these diseases are rapidly being characterized. Here, we examine two of these newly identified proteins, pyrin (also called marenostrin, product of the familial Mediterranean fever locus, MEFV) and cryopyrin (product of the CAIS1 locus, and mutated in familial cold urticaria, Muckle Wells syndrome and chronic infantile neurological cutaneous and articular syndrome). Both pyrin and cryopyrin contain an N-terminal domain that encodes a death domain-related structure, now known as the pyrin domain, or PyD. We trace the molecular interactions mediated by these PyDs, examine the evolution of the family of molecules containing this domain, and discuss the function of PyD-containing proteins and their homologues. Synthesis of the available data indicates that both pyrin and cryopyrin interact via their PyDs with a common adaptor protein, ASC. ASC itself participates in at least three important cellular processes: apoptosis, recruitment and activation of pro-caspase-1 (with associated processing and secretion of IL-1beta), and activation of NF-kappaB (a transcription factor involved in both initiation and resolution of the inflammatory response). Through PyD:PyD interactions, pyrin and cryopyrin, as well as several related, but still uncharacterized PyD containing proteins, appear to modulate the activity of all three of these processes, each of which plays a crucial role in the inflammatory pathways that characterize the innate immune system.

Apoptosis↗

Treatment of the SpA-like disease in HLA B27 transgenic animals.

A major involvement of the immune system and of microbial flora in the HLA-B27 transgenic rat model of spondylarthropathy was demonstrated. The role of inflammatory pathways, such as cytokines and inducible nitric oxide synthase (iNOS) was investigated. Treatment with IL-10 failed to improve established disease, whereas such improvement was achieved with IL-11. In contrast, aggravation was observed after treatment with selective inhibitor of iNOS.

Animals↗

Cytokines in chronic heart failure: possible interaction in the neurohormonal and the cytokine system at the cAMP level?

In recent years, the pathophysiological concept of chronic heart failure (CHF) has changed from an isolated hemodynamic view to a more complex concept involving neuroendocrine and inflammatory pathways. New therapeutic strategies, such as beta-blocker therapy, are based on these new concepts and provide clinical evidence for a clinical benefit in patients with CHF. The survival benefit of beta-blocker therapy in CHF has been related to neurohumoral regulation. Thus, evidence evolved showing that following beta-blocker therapy cytokine levels in CHF patients are altered. We have shown that the levels of soluble TNF receptor type 2 correlated well with cAMP in leukocytes. Data from clinical studies in adult and infant CHF patients have demonstrated that beta-blocker therapy is accompanied by altered cytokine, cytokine antagonist, and/or soluble cytokine receptor levels. These alterations may result from a dysregulated interaction of beta-adrenergic pathways and the cytokine system, and are possibly related to cAMP-dependent regulation of the release or shedding of these mediators.

Adrenergic beta-Antagonists↗

Association of an interleukin-1beta gene polymorphism at position -511 with Alzheimer's disease.

Inflammation is thought to promote neuronal cell death in Alzheimer's disease (AD). The proinflammatory interleukin-1 is a main component in inflammatory pathways and is overexpressed in the brain of AD patients. Investigation of different polymorphisms in the interleukin-1 genes (IL-1alpha -889, IL-1beta -511, IL-1beta +3953) revealed associations between specific alleles and AD in that they increased the risk or modified the age at onset of AD. However, there are controversial findings from other studies which revealed no significant associations between these polymorphisms and AD; thus further evaluation of the association of IL-1 gene polymorphisms with AD and their role in pathogenesis is needed. In this study we examined the distribution of the IL-1beta -511 alleles in AD patients and a control sample of healthy individuals. An additional control population of non-demented depressive inpatients was recruited to exclude a confounding bias. The cerebrospinal fluid (CSF) levels of Abeta42 in AD patients were investigated to assess the influence of IL-1beta -511 genotypes. We found no significant association of the IL-1beta -511 polymorphism with AD, suggesting that the IL-1beta -511 polymorphism is no risk factor for AD. However, we found the Abeta42 CSF levels to be lower in carriers of the IL-1beta CC-genotype compared to carriers of the T-allele. Even though IL-1beta -511 polymorphism did not influence the risk of AD it might have a pathophysiological influence on the disease process.

Aged↗

The relationship of obesity to the metabolic syndrome.

Obese patients with the metabolic syndrome generally have a visceral (apple-shaped) fat distribution and are at an increased risk of macrovascular disease, while those with peripheral (pear-shaped) obesity tend not to have metabolic abnormalities and are at less risk. This difference appears to be related to the differing metabolic functions (and secretory products) of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), as well as the fact that VAT drains directly into the liver. Thus, it appears that increased VAT, but not SAT, is associated with both hepatic and peripheral biochemical abnormalities leading to insulin resistance and the associated metabolic syndrome. Insulin resistance is associated with VAT products, such as free fatty acids and their metabolites, as well as cytokines, such as tumour necrosis factor alpha (TNF-alpha). These factors may activate components of the inflammatory pathway such as nuclear factor kappa-B (NFkappaB), and inhibit insulin signalling. Insulin resistance is further associated with decreased levels of another tissue product, adiponectin. The incidence and prevalence of obesity is increasing at an unprecedented rate. The classic treatment of obesity is weight loss via lifestyle modification. However, prevention of obesity comorbidity can also be achieved by modifying the mechanisms by which obesity causes these comorbid conditions. For instance, it is now known that the peroxisome proliferator-activated receptor (PPAR) family of transcriptional regulators are crucial in regulating adipose tissue development and metabolism; this helps explain why compounds with PPARgamma agonist activity, e.g. thiazolidinediones, increase insulin action through their effects in regulating adipose tissue metabolism.

Adiponectin↗

[Erythropoietin--a new therapy in cerebral ischemia?].

Erythropoietin (EPO) is a cytokine which is commonly associated with its central role in erythropoiesis. The clinical applications of the recombinant hormone are currently restricted to the treatment of anemia in renal failure and cancer. Recent studies, however, have suggested a new role for EPO as an anti-inflammatory and neuroprotective drug. EPO and its receptor are expressed in neurons, glial cells and brain capillary endothelial cells, and the system is upregulated in conditions of cerebral ischaemia and hypoxia. Animal studies have now established that intracerebroventricular administration of recombinant EPO exerts neuroprotection in models of stroke. The mechanisms appear to involve an upregulation of specific anti-apoptotic and anti-inflammatory pathways. In addition, neurotrophic and angiogenetic effects of EPO may contribute in a long latency protection. Interestingly, also systemic administration of recombinant EPO ameliorates neuronal damage after brain ischaemia, and prevents the loss of autoregulation of cerebral blood flow following experimental subarachnoid haemorrhage. Recombinant human EPO is a safe and non-toxic drug, and clinical studies are currently investigating the neuroprotective potential of EPO in humans.

Animals↗

A study on the serum levels of interleukin-1beta in bronchial asthma.

Mononuclear phagocytes can be activated through an immunoglobulin E (IgE)- specific mechanism to release pro-inflammatory cytokine like interleukin-1beta (IL-1beta). The present study was conducted to show the inter-relationship between these two parameters in the serum of asthmatic patients. The study included 30 patients of asthma and 10 as control. Out of these 30 cases, 20 patients had stable and 10 had acute asthma. Of the 20 stable patients, 9 were allergic and 11 were non-allergic to either of the 12 allergens used for skin prick test. Serum IgE and IL-1beta levels were measured by enzyme linked immunosorbent assay (ELISA). Total serum IgE levels increased significantly (p < 0.05) in asthma [200.5 +/- 30.91 IU/ml, mean +/- standard error of mean (SEM)] in comparison with the controls (18.15 +/- 4.35 IU/ml). Serum IL-1beta level was higher in allergic (1.94 +/- 0.63 pg/ml) than in non-allergic patients (0.64 +/- 0.21 pg/ml) but it was not statistically significant (p > 0.05). The study suggests involvement of IgE and IL-1beta in the pathophysiology of allergic asthmatic condition. Further studies are required to delineate the inflammatory pathway in asthma and determine stages at which therapeutic interventions can be done.

Acute Disease↗

Treatment of glomerular endothelial dysfunction in steroid-resistant nephrosis with Ganoderma lucidum, vitamins C, E and vasodilators.

Glomerular endothelial dysfunction is believed to be responsible for the proteinuria and nephronal damage, namely tubulointerstitial fibrosis and glomerulosclerosis, observed in severe nephrosis such as focal segmental glomerulosclerosis. A dysfunctioning glomerular endothelium is likely to be induced by oxidative stress and oxidized LDL as well as altered immunocirculatory balance with a defective anti-inflammatory pathway. A defective release of vasodilator inconjunction with enhanced production of angiotensin II induces hemodynamic maladjustment by preferential constriction at the efferent arteriole. Such a hemodynamic maladjustment exerts two significant hemodynamic impacts. Close to the efferent constriction, it induces intraglomerular hypertension and glomerulosclerosis. Far from the efferent constriction, it reduces peritubular capillary flow, which eventually leads to tubulointerstitial fibrosis. Treatment with a vasodilator improves the hemodynamic maladjustment but does not completely suppress proteinuria. A successful suppression of proteinuria is accomplished by using Ganoderma lucidum and vitamins C and E. The beneficial effect of Ganoderma lucidum appears to be multifactorial, including the modulation of immunocirculatory balance, antilipid, vasodilator, antiplatelet and improved hemorheology. Together with vitamins C and E, this helps to neutralize oxidative stress and suppress the toxic effect to the glomerular endothelial function.

Adrenal Cortex Hormones↗

Biochemistry of serine protease inhibitors and their mechanisms of action: a review.

Cardiopulmonary bypass (CPB) activates and disrupts the hemostatic and inflammatory systems, which, in turn, makes an impact on the clinical outcome of patients. Postoperative bleeding is one common complication of CPB. Many techniques have been used to reduce post-operative bleeding, and pharmacological agents have demonstrated the greatest efficacy. In particular, the serine protease inhibitor, aprotinin, consistently reduces post-operative bleeding. The hemostatic mechanism of action of aprotinin; however, remains to be elucidated fully. The purpose of this review is to discuss the probable mechanisms of aprotinin action from the perspective of its interactions within the hemostatic and inflammatory pathways.

Aprotinin↗

Fever, cytokines and shock.

Septic shock is a complex event with activation of many inflammatory pathways. Recent advances have begun to make some sense of the pathophysiological events. This review describes the historical background to the contemporary concepts and outlines the important role that cytokines probably have in the pathophysiology of septic shock. A consequence of the changing understanding of septic shock is that new therapeutic interventions are becoming available.

Cytokines↗