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PubMed2001

Typhlocolitis in NF-kappa B-deficient mice.

Activation of inflammatory gene expression by the transcription factor NF-kappaB is a central pathway in many inflammatory disorders, including colitis. Increased NF-kappaB activity has been linked with development of colitis in humans and animal models, thus it was unexpected when NF-kappaB-deficient mice developed spontaneous typhlocolitis. To further characterize this finding, we induced typhlocolitis in rederived NF-kappaB-deficient mice using intragastric infection with Helicobacter hepaticus. At 6 wk postinfection (PI), severe colitis with increased type 1 cytokine expression was seen in infected mice that lacked the p50 subunit of NF-kappaB and were also heterozygous for the p65 subunit of NF-kappaB(p50(-/-)p65(+/-)). Mice lacking the p50 subunit alone (p50(-/-)) were less severely affected, and wild-type mice and p65(+/-) mice were unaffected. T cell development in NF-kappaB-deficient mice was normal. These data indicate that p50 and p65 subunits of NF-kappaB have an unexpected role in inhibiting the development of colitis.

Animals↗

PubMed2004

Activated protein C in sepsis: emerging insights regarding its mechanism of action and clinical effectiveness.

PURPOSE OF REVIEW: Dysregulation of endogenous coagulant and anticoagulant systems is now believed to play an important role in the pathogenesis of sepsis and septic shock. Reductions in host activated protein C levels and resultant microvascular thrombosis provided a basis for the use of recombinant human activated protein C in sepsis. Although controversial, the findings from an initial phase III trial testing this agent resulted in its approval for use in patients with severe sepsis and high risk of death. This review highlights emerging insights into the biology of protein C and activated protein C in sepsis, summarizes additional analysis growing out of the phase III trial testing recombinant human activated protein C, and assesses the cost-effectiveness that the clinical use of the agent has had thus far. RECENT FINDINGS: Binding of activated protein C to the endothelial cell protein C receptor is recognized to result in a growing number of actions including increased activity of activated protein C itself and inhibition of both nuclear factor-kappaB, a central regulator in the host inflammatory response, and apoptosis. Additional analysis of the original phase III trial testing recombinant human activated protein C appears to emphasize one of the US Food and Drug Administration's original concerns regarding an association between severity of sepsis and this agent's effects. Postmarketing analysis and growing experience with other anticoagulant agents and corticosteroids in sepsis raise questions regarding the ultimate cost-effectiveness of activated protein C. SUMMARY: The protein C pathway is important both to coagulant and inflammatory pathways during sepsis. Based on emerging investigations, its actions appear to be increasingly complex ones. Despite potentially promising results in an initial phase III trial, the role of recombinant human activated protein C in the treatment of septic patients must continue to be evaluated.

Blood Coagulation↗

PubMed2006

Cytosolic phospholipase A alpha modulates NMDA neurotoxicity in mouse hippocampal cultures.

The arachidonic acid-specific cytosolic phospholipase A(2) alpha (cPLA(2)alpha) has been implicated in the generation of neurological injuries. cPLA(2)alpha-dependent neurological injury has been postulated to be mediated through inflammatory and eicosanoid pathways. We determined if cPLA(2)alpha amplifies the injury of a non-inflammatory, excitotoxic stimulus by modifying a well-described toxicity assay to measure the toxicity of N-methyl-d-aspartate (NMDA) in the CA1 region of organotypic, mouse hippocampal cultures. Hippocampal cultures from wild-type and cPLA(2)alpha knockout mice were exposed to 5, 7.5 or 10 microm NMDA for 1 h. Toxicity was measured 23 h later. Cultures derived from cPLA(2)alpha(-/-) mice and cultures treated with the selective inhibitor AACOCF(3) were significantly protected from NMDA toxicity, as compared with wild-type cultures. To determine if cPLA(2)alpha-dependent toxicity is cyclooxygenase (COX)-2 dependent, COX-2 and PGE(2) levels were measured 7 and 25 h after NMDA treatment. NMDA treatment failed to induce COX-2 protein or increase PGE(2) in the culture media in either genotype at either time. In contrast, phorbol 12-myristate 13-acetate and ionophore treatment caused robust induction of COX-2 and PGE(2) in both genotypes. We conclude that cPLA(2)alpha may have a hitherto unrecognized direct effect on excitatory neurotoxicity, suggesting that cPLA(2)alpha inhibition is a therapeutic candidate for treatment of the early, excitotoxic injury observed in stroke.

Animals↗

PubMed1984

The acute inflammatory process, arachidonic acid metabolism and the mode of action of anti-inflammatory drugs.

Arachidonic acid is a polyunsaturated fatty acid covalently bound in esterified form in the cell membranes of most body cells. Following irritation or injury, arachidonic acid is released and oxygenated by enzyme systems leading to the formation of an important group of inflammatory mediators, the eicosanoids. It is now recognised that eicosanoid release is fundamental to the inflammatory process. For example, the prostaglandins and other prostanoids, products of the cyclooxygenase enzyme pathway, have potent inflammatory properties and prostaglandin E2 is readily detectable in equine acute inflammatory exudates. The administration of nonsteroidal anti-inflammatory drugs results in inhibition of prostaglandin synthesis and this explains the mode of action of agents such as phenylbutazone and flunixin. Lipoxygenase enzymes metabolise arachidonic acid to a group of noncyclised eicosanoids, the leukotrienes, some of which are also important inflammatory mediators. They are probably of particular importance in leucocyte-mediated aspects of chronic inflammation. Currently available non-steroidal anti-inflammatory drugs, however, do not inhibit lipoxygenase activity. In the light of recent evidence, the inflammatory process is re-examined and the important emerging roles of both cyclo-oxygenase and lipoxygenase derived eicosanoids are explored. The mode of action of current and future anti-inflammatory drugs offered to the equine clinician can be explained by their interference with arachidonic acid metabolism.

Adrenal Cortex Hormones↗

PubMed2002

Novel therapeutic targets for acute pancreatitis and associated multiple organ dysfunction syndrome.

Acute pancreatitis is a common clinical condition. The exact mechanisms by which diverse etiological factors induce an attack are unclear but once the disease process is initiated, common inflammatory and repair pathways are invoked. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction; if marked, this leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicemia, severe burns and trauma. Potentially, there is a therapeutic window between symptom onset and the development of distant organ damage in acute pancreatitis, when anti-inflammatory therapy may be of use. Recent studies conducted by us and other investigators have established the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, CINC/GRO-alpha, MCP-1, PAF, IL-10, CD40L, C5a, ICAM-1, and Substance P in acute pancreatitis and the resultant MODS. It is reasonable to speculate that elucidation of the key mediators in acute pancreatitis coupled with the discovery of specific inhibitors will make it possible to develop a clinically effective anti-inflammatory therapy.

Acute Disease↗

PubMed2000

Inhibition of MAP kinase kinase (MEK) results in an anti-inflammatory response in vivo.

The MAP kinase pathway has been well-characterized as a cascade of sequential protein phosphorylation events leading to the upregulation of a variety of genes in response to growth factors and mitogens. We are interested in the role of these kinases in inflammation and have thus examined their activity in vivo using TPA-induced ear edema in the mouse as a model of inflammation. We show that the activities of both ERK-1 and ERK-2 are upregulated in this model in response to TPA. Increased levels of ERK phosphorylation are measurable as early as 15 min poststimulation and reach a level 8-fold over controls at 4 h. In contrast, minimal activation of JNK or p38 is observed. Topical treatment of ears with the MEK inhibitor, U0126, prevents ERK phosphorylation and ear swelling in a dose-dependent manner in this model. These results suggest that the MEK/ERK pathway is important during an inflammatory response in vivo.

Animals↗

PubMed2005

Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock.

Septic shock is initiated by a systemic inflammatory response to microbial infection that frequently leads to impaired perfusion and multiple organ failure. Because of its high risk of death, septic shock is a major problem particularly for patients in the intensive care unit. In general, bacterial lipopolysaccharide (LPS) is a strong activator of various immune responses and stimulates monocytes/macrophages to release a variety of inflammatory cytokines. However, overproduction of inflammatory factors in response to bacterial infections is known to cause septic shock, similar to that induced by LPS. Studies of LPS-signaling pathways and downstream inflammatory cytokines may have critical implications in the treatment of sepsis. In recent years, there has been significant progress in understanding the signaling pathways activated by LPS and its receptor Toll-like receptor 4 (TLR4), as well as by tumor necrosis factor alpha (TNFalpha), a potent inflammatory cytokine induced by LPS stimulation. This review briefly summarizes our current knowledge of these signaling pathways and critical signal transducers. Characterization of key signal transducers may allow us to identify tractable, novel targets for the therapeutic interventions of sepsis.

Adaptor Proteins, Signal Transducing↗

PubMed1998

CSF-1 (M-CSF) enhances the inflammatory response of fibronectin-primed macrophages: pathways involved in activation of the cytokine network.

We have previously reported that the priming of thioglycollate-elicited peritoneal macrophages (PMphi), as a representative population of mononuclear phagocytes (MNP), by macrophage-colony-stimulating factor (M-CSF or CSF-1) rendered these cells more susceptible to secondary stimulation by extracellular matrix (ECM) proteins, in particular fibronectin (FN), and that at least two beta1 integrins, VLA 4 (alpha4beta1 or CD49d) and VLA 5 (alpha5beta1 or CD49e), regulate IL-6 gene expression when PMphi come into contact with FN. In this report, we focused our attention on resident PMphi, as a more mature/differentiated MNP subpopulation. By using granulocyte-macrophage colony-stimulating factor (GM-CSF)- and IL-6-knockout (null) mice, we demonstrated that the cooperative effect between CSF-1 and FN in IL-6 release was a result of a sequential stimulation of the GM-CSF, but not the TNF-alpha, gene via interaction with VLA 5. We also showed that regardless of the presence or absence of CSF-1 or FN, IL-6 inhibits GM-CSF and TNF-alpha gene expression in an autocrine manner. The observed effects were specific because CSF-1 enhanced VLA 5 expression and blocking FN-treated resident PMphi in vitro with VLA 5 monoclonal antibodies inhibited the IL-6 response. We found that treatment of resident PMphi with the protein kinase C inhibitor, staurosporine, and the activator, phorbol myristate acetate (PMA), resulted in marked modulation of either FN- or FN/CSF-1-induced cytokine release. An increased level of VLA 5 expression was observed in PMA-treated resident PMphi. We concluded that in inflammatory processes, CSF-1 drives a number of pathways involved in the regulation of the expression of several genes and renders MNP highly susceptible to stimulation by ECM proteins that transform the MNP into secretory inflammatory cells.

Animals↗

PubMed2026

Exploring shared biomarkers and their mechanisms in thyroid cancer and systemic lupus erythematosus via bioinformatics analysis.

BACKGROUND: Systemic lupus erythematosus (SLE), an autoimmune disorder, is linked to a heightened risk of multiple malignancies, including thyroid cancer. Thyroid cancer is the most prevalent malignancy of the endocrine system, and its autoimmune-related pathological features render it an optimal subject for investigating the mechanisms of their comorbidity. The molecular mechanisms underlying this comorbidity are still ambiguous. The accurate diagnosis and treatment of thyroid cancer urgently necessitate innovative molecular targets that extend beyond conventional pathological characteristics. This study seeks to employ integrated bioinformatics approaches to elucidate potential shared molecular mechanisms and immunological features between thyroid cancer and systemic lupus erythematosus (SLE), aiming to enhance understanding of their comorbidity and identify novel intervention targets. METHODS: This study initially acquired gene expression data for TC and SLE from the GEO database and subsequently screened and identified differentially expressed genes (DEGs) shared by both diseases. Subsequently, we conducted Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome functional enrichment analyses on these 46 shared differentially expressed genes (DEGs) and further assessed the activation status of pertinent pathways using Gene Set Enrichment Analysis (GSEA). Subsequently, we employed CIBERSORTx to examine immune infiltration patterns and developed protein-protein interaction networks utilising the STRING database. We identified hub genes utilising the MCODE and cytoHubba plugins and visualised the findings with Cytoscape software. We additionally assessed the diagnostic efficacy of these core hub genes in an independent dataset utilising ROC curves and investigated their prognostic relevance in thyroid cancer through Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression. Ultimately, we employed the Network Analyst platform to forecast transcription factor-gene and miRNA-gene regulatory networks and identified potential targeted therapeutic compounds utilising the DSigDB database. RESULTS: This study identified 46 differentially expressed genes (DEGs) commonly linked to thyroid cancer and systemic lupus erythematosus (SLE), which were significantly enriched in signalling pathways associated with immune-inflammatory activation, type I interferon responses, and complement pathway activation. Moreover, GSEA findings validated that immune-inflammatory and autoimmune-related pathways are markedly activated in both conditions. Twelve hub genes were discerned through protein-protein interaction networks. Analysis of immune infiltration indicated that thyroid cancer and systemic lupus erythematosus exhibit a shared characteristic of innate immune dysregulation, marked by the infiltration of myeloid cells (neutrophils, M0/M2 macrophages). Receiver operating characteristic (ROC) curve analysis identified six significant core hub genes with substantial diagnostic value: C1QB, LCN2, C1QC, LTF, VSIG4, and C3AR1. Univariate survival analysis indicated that elevated expression of C1QC and C3AR1 significantly enhances overall survival in thyroid cancer patients; however, multivariate COX regression analysis revealed that their independent prognostic significance necessitates further validation. This study predicted the interaction networks of transcription factors and miRNAs regulating key genes, with LCN2 demonstrating the highest connectivity to miRNAs, and identified candidate therapeutic compounds linked to it. CONCLUSION: This study employed bioinformatics analysis to identify critical shared hub genes and molecular pathways connecting thyroid cancer and systemic lupus erythematosus, offering novel insights into their shared pathogenesis and the advancement of targeted biomarkers and therapeutic strategies.

Bioinformatics analysis↗

PubMed1987

Description, mechanisms and control of reactions to treatment in the human filariases.

Since diethylcarbamazine at the dosages used to treat filarial infections has little direct toxicity, most of the post-treatment reactions (termed Mazzotti reactions in onchocerciasis) result from the immunological inflammatory mechanisms activated in the process of clearing and killing the skin-swelling or blood-borne microfilariae. These reactions may be either localized to the skin, eyes or lymphatics or generalized systemically (e.g. headache, fever, adenopathy, arthralgia, tachypnoea, tachycardia, hypotension and even death). The occurrence and intensity of such reactions can be shown to be related to the intensity of infection. It had previously been speculated that the best candidates for triggering these post-treatment reactions were activation of complement, immediate hypersensitivity responses mediated by immunoglobulin E, and degranulation of eosinophils with resultant inflammatory reactivity. Recent detailed studies have given little support to the primacy of either complement or immediate hypersensitivity responses in triggering such reactions, but eosinophil degranulation with the release of inflammatory mediators into the tissues and peripheral blood is extremely prominent in all patients undergoing post-treatment reactions and develops with a time course generally consistent with what would be required of an initiator of such reactions. Other inflammatory mediators and pathways may be involved (e.g. kinins, prostaglandins, immune complexes, leukotrienes, platelets and parasite-derived inflammatory molecules), but there is currently no evidence to implicate any of these mechanisms as initiators of the response. Symptomatic treatment of these post-treatment reactions with analgesics, antipyretics, antihypotensive agents etc. has been successful, but their prevention has been achieved only with the broadly anti-inflammatory corticosteroids.

Animals↗

PubMed2004

Suppression of inducible nitric oxide synthase and cyclooxygenase-2 in downregulating nuclear factor-kappa B pathway by Garcinol.

Garcinol is a polyisoprenylated benzophenone derivative of Garcinia indica fruit rind and other species. Recent studies have demonstrated that garcinol exhibited antioxidative effects in vitro. In this study, we found that garcinol inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-activated macrophages. Western blot analyzes and gel-shift assays revealed that garcinol strongly blocks the activation of eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B)-induced by LPS. Moreover, transient transfection experiments showed that garcinol inhibited the NF-kappa B-dependent transcriptional activity. Based on these data, we demonstrated that inhibition of LPS-induced NF-kappa B activation occurred through suppressing the phosphorylation of I kappa B alpha and p38 mitogen-activated kinase (MAPK). Garcinol also lowers the LPS-induced increase of intracellular reactive oxygen species (ROS), which contributes to the activation of NF-kappa B. The NF-kappa B signaling pathway leads to inflammatory reaction and our results suggest that garcinol suppresses the expression of iNOS in this pathway.

Animals↗

PubMed2004

Selective modulation of microglial signal transduction by PACAP.

We have investigated the possible effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on signal transduction pathways associated with inflammatory activation of BV-2 mouse microglia cells. Pretreatment of the cells with PACAP resulted in a significant decrease in LPS- or IFNgamma-induced NO production as well as iNOS and IL-1beta mRNA levels. The inhibitory effect of PACAP appeared to be mediated through an increase in intracellular cAMP. PACAP inhibition of LPS-induced NO production was accompanied by inhibition of p38 MAPK activation, but not ERK, JNK, or NF-kappaB. IFNgamma-induced STAT-1 activation or IRF-1 induction was not significantly influenced by PACAP. Therefore, PACAP appears to suppress inflammatory activation of BV-2 microglia via specific inhibition of LPS-induced p38 MAPK pathway.

Animals↗

PubMed2003

Prostaglandins inhibit 5-lipoxygenase-activating protein expression and leukotriene B4 production from dendritic cells via an IL-10-dependent mechanism.

PGs produced from arachidonic acid by the action of cyclooxygenase enzymes play a pivotal role in the regulation of both inflammatory and immune responses. Because leukotriene B4 (LTB4), a product of 5-lipoxygenase (5-LO) pathway, can exert numerous immunoregulatory and proinflammatory activities, we examined the effects of PGs on LTB4 release from dendritic cells (DC) and from peritoneal macrophages. In concentration-dependent manner, PGE1 and PGE2 inhibited the production of LTB4 from DC, but not from peritoneal macrophage, with an IC50 of 0.04 microM. The same effect was observed with MK-886, a 5-LO-activating protein (FLAP)-specific inhibitor. The decreased release of LTB4 was associated with an enhanced level of IL-10. Furthermore, the inhibition of LTB4 synthesis by PGs was significantly reversed by anti-IL-10, suggesting the involvement of an IL-10-dependent mechanism. Hence, we examined the effects of exogenous IL-10 on the 5-LO pathway. We demonstrate that IL-10 suppresses the production of LTB4 from DC by inhibiting FLAP protein expression without any effect on 5-LO and cytosolic phospholipase A2. Taken together, our results suggest links between DC cyclooxygenase and 5-LO pathways during the inflammatory response, and FLAP is a key target for the PG-induced IL-10-suppressive effects.

5-Lipoxygenase-Activating Proteins↗

PubMed2005

Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells.

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. In vascular diseases, such as atherosclerosis, inflammation plays an important role in the pathogenesis of the disease. We examined the role of LPL in modulating tumor necrosis factor-alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-mediated inflammatory cytokine signal transduction pathways in human aortic endothelial cells (HAECs). LPL significantly suppressed TNF-alpha-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase. In contrast, LPL synergistically enhanced IFN-gamma-induced gene expression in HAECs. To elucidate the molecular mechanisms of LPL action, we investigated the role of transcription factors nuclear factor kappa B (NF-kappaB) and signal transducer and activator of transcription factor 1 (Stat1). The anti-inflammatory response of LPL in suppressing TNF-alpha-induced gene expression was a result of its inhibition of NF-kappaB activity by the abrogation of IkappaB-alpha degradation and phosphorylation of the p65 subunit. Although LPL alone had no effect on Stat1 activation, LPL enhanced IFN-gamma-induced phosphorylation of Stat1 on tyrosine 701 and serine 727, as well as Stat1-mediated transactivation. The synergistic effect of LPL on IFN-gamma-induced Stat1 activation was mediated by enhanced activation of the tyrosine kinase JAK2 and was abrogated by LY294002, a specific inhibitor of the phosphatidylinositol 3'-kinase pathway. Our studies indicate that LPL has differential effects on several inflammatory pathways known to be important in atherosclerosis.

Aorta↗

PubMed2006

TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease.

The CD40/CD40 ligand (CD40L) pathway is involved in Crohn's disease (CD) pathogenesis. In the patients' circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-alpha action, but because TNF-alpha modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-alpha-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-alpha and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

Adult↗

PubMed1985

Eicosanoids as bioregulators in clinical medicine.

Formation of eicosanoids in stimulated cells and tissues is a ubiquitous phenomenon, but the precise physiologic or pathophysiologic role of these autacoids has not yet been defined. In contrast, understanding of synthetic mechanisms, metabolism, and catabolism of eicosanoids seems to have surpassed understanding of their pharmacologic actions. Early clinical research involving eicosanoids focused on reactions of the cyclo-oxygenase pathway, which are inhibitable by nonsteroidal anti-inflammatory drugs. The lipoxygenase pathway, which appears to be an important component of the allergic and inflammatory response, represents a new area of clinical research.

Arachidonic Acids↗

PubMed2001

Activated protein C versus protein C in severe sepsis.

OBJECTIVE: To delineate critical differences between activated protein C (APC) and its precursor, protein C, with regard to plasma levels in health and in severe sepsis, and to discuss the implications of these differences as they relate to treatment strategies in patients with severe sepsis. DATA SOURCE/STUDY SELECTION: Published literature including abstracts, manuscripts, and review articles reporting studies in both experimental animal models and humans that provide an understanding of the relationship and the critical differences between circulating levels of APC and protein C. DATA EXTRACTION AND SYNTHESIS: The protein C pathway represents one of the major regulatory systems of hemostasis, exhibiting antithrombotic, profibrinolytic and anti-inflammatory properties. This pathway also plays a critical role in the pathophysiology of severe sepsis. Central to this pathway is the vitamin K-dependent serine protease, APC, and its precursor, protein C. The conversion of protein C to APC is dependent on the complex of thrombin and thrombomodulin, an integral endothelial surface receptor. The conversion of protein C to APC is further augmented by another endothelial surface protein, the endothelial protein C receptor. There are limited published data on APC levels in health and disease, probably due to the complexity of the assay methodology for measuring APC and the absence of commercially available diagnostic kits. In animals and humans with normal functioning endothelium, circulating levels of APC (1-3 ng/mL) are positively correlated with protein C (4000-5000 ng/mL) concentration and the amount of thrombin generated. In patients with severe sepsis, there is a generalized endothelial dysfunction, contributing to multiple organ failure with increased morbidity and mortality. Persistently low protein C levels are related to poor prognosis. Key to understanding the treatment strategy with APC or protein C is knowledge of the functional status of the endothelium and, specifically, whether the microvasculature in patients with severe sepsis can support the conversion of protein C to APC. To date, only APC (drotrecogin alfa [activated]) has been shown to reduce mortality in severe sepsis in a large, phase 3, placebo-controlled, double-blind international trial. In contrast, no data, other than open-label case studies, are available for evaluation of the effects of protein C in the treatment of severe sepsis. CONCLUSION: The limited data available indicate that lower levels of protein C in sepsis occur in the absence of appreciable conversion to APC. These observations indicate that treatment with APC may be more efficacious than protein C in severe sepsis, where generalized endothelial dysfunction may impair conversion of protein C to APC. Additional research is required to confirm these observations.

Animals↗

PubMed2000

[Rheumatic disorders. Overview].

Of all rheumatic diseases, osteoarthritis (OA) and rheumatoid arthritis (RA) are the most frequently occurring. Although they differ in pathophysiology and the molecular mechanisms responsible for the destruction of cartilage (since RA is an inflammatory disease and OA is not), there are, however, a certain number of similarities and common pathways in the inflammatory processes of both diseases: mild inflammatory phenomena have been observed during OA, and both interleukin-1 and tumour necrosis factor-alpha seem to play key roles, as in RA. Although there is a dramatic difference between the 2 diseases in the intensity of inflammation, the inflammatory process is responsible for the synthesis of metalloproteinases and free oxygen radicals, and, subsequently, for progressive cartilage destruction. Both OA and RA engender important costs for the healthcare system. Direct costs result from practitioner visits, drug purchase and management, drug-related adverse effects, management or hospital care; indirect costs are linked to progressive functional disability. Although RA leads to significant individual costs, OA is more problematical for the healthcare system, since its prevalence is far higher than that of RA. Thus, rheumatic diseases have become a major public health problem. Optimal therapeutic strategies need to be determined in order to define the most effective procedure for controlling disease symptoms such as pain, stopping or slowing down disease progression and, finally, keeping patients active. But it is of paramount importance that the gain in efficacy be associated with a gain in drug safety.

Animals↗