Inflammatory response: pathway across the blood-brain barrier.
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Animals↗
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Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors on renal function.
Pleiotropic, or non-lipid-dependent, effects mediated by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have important clinical implications for the cardiovascular (CV) system. Atherosclerosis is an inflammatory process accompanied by increases in levels of plasma inflammatory markers and accumulation of immune cells within atherosclerotic plaques. Statins not only decrease serum lipid levels, but also inhibit signaling molecules at several points in inflammatory pathways. The anti-inflammatory effects and improved endothelial function associated with statin therapy are thought to be partly responsible for the reduction in CV morbidity and mortality. In analogy, patients with chronic kidney disease administered statins for CV risk reduction show evidence of improved renal function. However, whether statins confer similar protective benefits on the kidney has not been established. Several lines of evidence suggest that similar etiologic and pathological processes may be involved in CV and chronic kidney diseases. If inflammation and functional changes in the renovascular endothelium contribute to the progression of kidney disease, statins are likely to be effective in the treatment of renal disease. In this review, we critically consider emerging data indicating that statins may modulate renal function by altering the inflammatory response of the kidney and renal vasculature to dyslipidemia. Whether the amelioration of renal function by statins is separable from the lipid-lowering effects of these drugs still remains to be delineated. Other questions that remain to be addressed and issues that should be investigated also are presented.
Animals↗
Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia.
The capsaicin-sensitive vanilloid receptor (VR1) was recently shown to play an important role in inflammatory pain (hyperalgesia), but the underlying mechanism is unknown. We hypothesized that pain-producing inflammatory mediators activate capsaicin receptors by inducing the production of fatty acid agonists of VR1. This study demonstrates that bradykinin, acting at B2 bradykinin receptors, excites sensory nerve endings by activating capsaicin receptors via production of 12-lipoxygenase metabolites of arachidonic acid. This finding identifies a mechanism that might be targeted in the development of new therapeutic strategies for the treatment of inflammatory pain.
Animals↗
Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways.
Type I interleukin-1 receptor is the prototype for a family of proteins, which play a central role in early responses to injury and infection. The similarity of function across the family is reflected in similarity in signaling: all members tested couple to activation of NFkappaB and stress kinases. The coupling to these pathways is mediated by a 200-residue intracellular domain (the Toll/interleukin-1 receptor domain), in which sequence conservation is primarily confined to three short motifs (boxes 1, 2, and 3) located at amino acid residue positions 10 (box 1), 60 (box 2), and 170 (box 3). We have analyzed the contribution of these motifs to function by alanine scanning mutagenesis of the human interleukin-1 receptor type I. Mutant receptors were tested for expression, ligand binding, activation of receptor-associated kinase(s), NFkappaB, stress kinases, and transcription. Mutations in all three motifs led to low cell surface expression. Mutants in box 3 were, however, wild type for signaling, whereas mutants in boxes 1 and 2 were defective. We conclude that the conserved motifs box 1 and box 2 mediate the coupling of molecules in the family to inflammation signaling pathways.
Amino Acid Sequence↗
Key inflammatory signaling pathways are regulated by the proteasome.
Lipopolysaccharide (LPS) is a major structural component of all Gram-negative organisms and has been implicated in Gram-negative sepsis and septic shock. In the present study, Affymetrix microarray analysis of RNA derived from murine macrophages treated with LPS in the absence or presence of the proteasome inhibitor lactacystin revealed that the vast majority of genes regulated by LPS is under control of the proteasome. Analysis of the data has revealed that the products of these genes participate in 14 distinct signaling pathways. This represents a novel approach to the identification of signaling pathways that are both toll-like receptor 4- and proteasome-dependent and may lead to the development of new drug targets in Gram-negative sepsis and septic shock.
Acetylcysteine↗
Distinct inflammatory gene pathways induced by particles.
The biologic response to particulate load after arthroplasty has not been fully characterized but is believed mediated by proinflammatory cytokines released from mononuclear cells in the periprosthetic region. To investigate the contribution of lymphocytes to expression of proinflammatory genes induced by metal particles, we compared gene expression of mononuclear cells in response to metal and polymethylmethacrylate particles using cDNA microarray profiling. Peripheral blood mononuclear cells and monocytes were stimulated with polymethylmethacrylate and titanium particles of clinically relevant sizes. Polymethylmethacrylate elicited a six- to 12-fold increase in gene expression of tumor necrosis factor alpha, interleukin 1alpha, interleukin 1beta, interleukin 6, and interleukin 8 in purified monocytes and unfractionated peripheral blood mononuclear cells. Although the effect of titanium on stimulation of purified monocytes was modest, stimulation of lymphocyte-containing peripheral blood mononuclear cells by titanium particles resulted in monocyte-derived proinflammatory cytokine expression. In contrast to polymethylmethacrylate, titanium particles stimulated increased expression of T lymphocyte-derived cytokines, including interleukin 2, interferon gamma, interleukin 9, and interleukin 22, in peripheral blood mononuclear cell cultures. The induction of T cell activation by titanium particles suggests lymphocytes may contribute to the inflammation that mediates osteolysis in patients with metallic particulate debris after total joint replacement.
Cell Survival↗
Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin.
During neonatal hyperbilirubinaemia, astrocytes activated by unconjugated bilirubin (UCB) may contribute to brain toxicity through the production of cytokines. As a first step in addressing the signal transduction cascades involved in the UCB-induced astroglial immunological response, we tested whether tumour necrosis factor (TNF)-alpha receptor 1 (TNFR1), mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) would be activated in astrocytes exposed to UCB, and examined the profile of cytokine production. Astrocyte cultures stimulated with UCB showed a rapid rise in TNFR1 protein levels, followed by activation of the MAPKs p38, Jun N-terminal kinase1/2 and extracellular signal-regulated kinase1/2, and NF-kappaB. Interestingly, the induction of these signal effectors preceded the early up-regulation of TNF-alpha and interleukin (IL)-1beta mRNAs, and later secretion of TNF-alpha, IL-1beta and IL-6. Treatment of astrocytes with UCB also induced cell death, with levels comparable to those obtained after exposure of astrocytes to recombinant TNF-alpha and IL-1beta. Moreover, loss of cell viability and cytokine secretion were reduced when the NF-kappaB signal transduction pathway was inhibited, suggesting a key role for NF-kappaB in the astroglial response to UCB. These results demonstrate the complexity of the molecular mechanisms involved in cell injury by UCB during hyperbilirubinaemia and provide a basis for the development of novel therapeutic strategies.
Animals↗
The CD40/CD40L costimulatory pathway in inflammatory bowel disease.
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Animals↗
Macrophage migration inhibitory factor: controller of systemic inflammation.
Macrophage migration inhibitory factor (MIF) is a cytokine that is secreted by the anterior pituitary and immune cells in response to surgical stress, injury, and sepsis. This cytokine appears to be a critical regulator of the inflammatory pathways, leading to systemic inflammatory response syndrome and subsequent multiple organ dysfunction syndrome. This report provides an integrated scheme describing the manner by which MIF controls the neurohormonal response and the adaptive immune system, namely the T-helper (Th)1 and Th2 lymphocytes, which results in the release of pro-inflammatory cytokines and the anti-inflammatory cytokine interleukin-10. The development of systemic inflammatory response syndrome and subsequent development of multiple organ dysfunction syndrome appear to be related to MIF levels and the balance of Th1 and Th2 function.
Humans↗
The roles of insulin and hyperglycemia in sepsis pathogenesis.
Hyperglycemia is a risk marker of morbidity and mortality in acute critical illness, and insulin therapy seems to be beneficial in this patient group. Whether this is true for a population of sepsis patients, as such, has not been investigated in clinical trials, but evidence from in vitro studies and experimental sepsis suggests that this may be the case. The endocrinology of septic patients is characterized by a shift in the balance between insulin and its counter-regulatory hormones favoring the latter. This leads to prominent metabolic derangements composed of high release and low use of glucose, amino acids, and free fatty acids (FFA), resulting in increased blood levels of these substrates. Circulating, proinflammatory mediators further enhance this state of global catabolism. Increased levels of glucose and FFA have distinct effects on inflammatory signaling leading to additional release of proinflammatory mediators and endothelial and neutrophil dysfunction. Insulin has the inherent capability to counteract the metabolic changes observed in septic patients. Concomitantly, insulin therapy may act as a modulator of inflammatory pathways inhibiting the unspecific, inflammatory activation caused by metabolic substrates. Given these properties, insulin could conceivably be serving a dual purpose for the benefit of septic patients.
Endocrine System↗
[Cross-talk between iNOS and COX-2 pathways in inflammatory response and anti-inflammatory effect of insulin].
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Animals↗
Modulation of inflammatory activation pathways in the Lewis-to-F-344 rat chronic cardiac rejection model.
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Animals↗
Activation of the NF-kappaB pathway by inflammatory stimuli in human neutrophils.
Activated neutrophils have the ability to upregulate the expression of many genes, in particular those encoding cytokines and chemokines, and to subsequently release the corresponding proteins. Although little is known to date concerning the regulation of gene transcription in neutrophils, it is noteworthy that many of these genes depend on the activation of transcription factors, such as NF-kappaB, for inducible expression. We therefore investigated whether NF-kappaB/Rel proteins are expressed in human neutrophils, as well as their fate on cell activation. We now report that dimers consisting of p50 NFkappaB1, p65 RelA, and/or c-Rel are present in neutrophils and that the greater part of these protein complexes is physically associated with cytoplasmic IkappaB-alpha in resting cells. Following neutrophil stimulation with proinflammatory agonists (such as lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], and fMet-Leu-Phe) that induce the production of cytokines and chemokines in these cells, NF-kappaB/Rel proteins translocated to nuclear fractions, resulting in a transient induction of NF-kappaB DNA binding activity, as determined in gel mobility shift assays. The onset of both processes was found to be closely paralleled by, and dependent on, IkappaB-alpha degradation. Proinflammatory neutrophil stimuli also promoted the accumulation of IkappaB-alpha mRNA transcripts, resulting in the reexpression of the IkappaB-alpha protein. To our knowledge, this constitutes the first indication that NF-kappaB activation may underlie the action of proinflammatory stimuli towards human neutrophil gene expression and, as such, adds a new facet to our understanding of neutrophil biology.
Base Sequence↗
Activation of peroxisome proliferator-activated receptors in human airway smooth muscle cells has a superior anti-inflammatory profile to corticosteroids: relevance for chronic obstructive pulmonary disease therapy.
Airway smooth muscle is actively involved in the inflammatory process in diseases such as chronic obstructive pulmonary disease and asthma by 1) contributing to airway narrowing through hyperplasia and hypertrophy and 2) the release of GM-CSF and G-CSF, which promotes the survival and activation of infiltrating leukocytes. Thus, the identification of novel anti-inflammatory pathways in airway smooth muscle will have important implications for the treatment of inflammatory airway disease. This study identifies such a pathway in the activation of peroxisome proliferator-activated receptors (PPARs). PPAR ligands are known therapeutic agents in the treatment of diabetes; however, their role in human airway disease is unknown. We demonstrate, for the first time, that human airway smooth muscle cells express PPAR alpha and -gamma subtypes. Activation of PPAR gamma by natural and synthetic ligands inhibits serum-induced cell growth more effectively than does the steroid dexamethasone, and induces apoptosis. Moreover, PPAR gamma activation, like dexamethasone, inhibits the release of GM-CSF. However, PPAR gamma ligands, but not dexamethasone, similarly inhibits G-CSF release. These results reveal a novel anti-inflammatory pathway in human airway smooth muscle, where PPAR gamma activation has additional anti-inflammatory effects to those of steroids. Hence, PPAR ligands might act as potential treatments in human respiratory diseases.
Adolescent↗
Genetic inflammatory factors predict restenosis after percutaneous coronary interventions.
BACKGROUND: Restenosis is a negative effect of percutaneous coronary intervention (PCI). No clinical factors are available that allow good risk stratification. However, evidence exists that genetic factors are important in the restenotic process as well as in the process of inflammation, a pivotal factor in restenosis. Association studies have identified genes that may predispose to restenosis, but confirmation by large prospective studies is lacking. Our aim was to identify polymorphisms and haplotypes in genes involved in inflammatory pathways that predispose to restenosis. METHODS AND RESULTS: The GENetic DEterminants of Restenosis (GENDER) project is a multicenter prospective study, including 3104 consecutive patients after successful PCI. Forty-eight polymorphisms in 34 genes in pathways possibly involved in the inflammatory process were analyzed. The 16Gly variant of the beta2-adrenergic receptor gave an increased risk of target vessel revascularization (TVR). The rare alleles of the CD14 gene (-260T/T), colony-stimulating factor 2 gene (117Thr/Thr), and eotaxin gene (-1328A/A) were associated with decreased risk of TVR. However, through the use of multiple testing corrections with permutation analysis, the probability of finding 4 significant markers by chance was 12%. CONCLUSIONS: Polymorphisms in 4 genes considered involved in the inflammatory reaction showed an association with TVR after PCI. Our results may contribute to the unraveling of the restenotic process. Given the explorative nature of this analysis, our results need to be replicated in other studies.
Amino Acid Substitution↗
Release of lipopolysaccharide toxicity-modulating proteins in patients undergoing cardiopulmonary bypass using noncoated and heparin-coated extracorporeal circuits. A clinical pilot study.
STUDY OBJECTIVE: Cardiopulmonary bypass (CPB) induces a generalized inflammatory response, including activation of leukocytes, contributing to postoperative morbidity. The inflammatory pathways leading to this systemic inflammatory response syndrome are considered identical to those involved in septic shock. Therefore, we studied the release of bactericidal/permeability-increasing protein (BPI), lipopolysaccharide binding protein (LBP), and soluble CD14 (sCD14)-all proteins that modulate the effects of lipopolysaccharide (LPS)-in patients undergoing CPB. In addition, the effect of heparin coating of the extracorporeal bypass circuit on the release of these parameters was assessed. DESIGN: Prospective, randomized clinical pilot study. SETTING: Cardiothoracic Surgery Department in a university hospital. PATIENTS: Fourteen patients undergoing elective coronary artery bypass grafting were included. Seven patients underwent CPB using a standard, noncoated extracorporeal circuit, and seven patients had CPB using a heparin-coated extracorporeal circuit (Duraflo II). INTERVENTIONS: Blood samples were taken after induction of anesthesia, just before aortic crossclamping, and 0, 0.5, 1.5, 3, 6, 12, and 24 h after declamping. MEASUREMENTS AND RESULTS: CPB with a noncoated extracorporeal circuit induced a sharp increase in neutrophil-derived BPI, manifest directly after release of the aortic crossclamp, which was significantly attenuated using a heparin-coated system. Also, CPB induced a gradual increase of the acute-phase reactant LBP, which was identical in the noncoated and heparin-coated groups. Systemic release of sCD14 after crossclamp release was significantly higher in the noncoated group compared with the heparin-coated group, but did not rise above baseline levels. CONCLUSIONS: These data confirm that CPB-induced leukocyte activation is attenuated using a heparin-treated extracorporeal circuit and point to the possible role of LPS toxicity-modulating proteins in the systemic inflammatory response after bypass surgery.
Acute-Phase Proteins↗
The role of leukotriene inhibitors in allergic rhinitis and paranasal sinusitis.
Leukotrienes (LTs) have been known in the field of immunology since the 1930s. At that time they were referred to as the slow reacting substance of anaphylaxis. However, they were not characterised until the 1980s, when they were noted to be formed during the breakdown of arachidonic acid (AA) by the enzyme 5-lipoxygenase (5-LO). There are five types of LT: LTA(4), LTB(4), LTC(4), LTD(4) and LTE(4). LTs are so called because the molecules were originally isolated from leukocytes and their carbon backbones contain 3 double bonds in series (a trion). This structural information provided the key to the oxidative pathway of lipometabolism, known as the 5-LO pathway. LTs are classified as inflammatory mediators. They are produced by a number of cell types, particularly mast cells, eosinophils, basophils, macrophages and monocytes. With the identification disorders associated with inflammatory pathways, such as asthma, allergic rhinitis and paranasal sinusitis, the LTs have been implicated in the pathogenesis of these conditions and have become targets for therapeutic modulation. In this review we will look at the biological effects of LTs, how they are formed, their role in asthma patients, the first therapeutic use of LT inhibitors and finally LTs with reference to the paranasal sinus areas.
Clinical Trials as Topic↗
Inflammation, blood pressure, and stroke: an opportunity to target primary prevention?
Promising findings suggest that systemic inflammation and neuroinflammation are central features in cerebrovascular disease. Inflammatory mechanisms are also important participants in the pathophysiology of hypertension. Markers of inflammation have been shown to be upregulated in different forms of cerebrovascular disease, and to correlate with vascular risk. The inhibitor nuclear factor-kB/nuclear factor-kB system is considered a major intracellular inflammatory pathway, mediating most of the vascular inflammatory responses. Increasing evidence indicates that hypertension, through the vasoactive peptides angiotensin and endothelin-1, promotes and accelerates the atherosclerotic process via inflammatory mechanisms. Proinflammatory properties of angiotensin II have been demonstrated. The identification of useful markers of inflammation, of new therapeutic targets to interfere with these mechanisms, and the evaluation of the efficacy of anti-inflammatory treatments will allow progress in our ability to combat cerebrovascular disease and the complications of hypertension. Whether these targets will be useful in the development of risk prediction strategies or therapies for the treatment of stroke in humans is far from clear.
Biomarkers↗