Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Inflammatory pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2005

Inflammatory pathways and microvascular responses in the lung.

Neutrophil granulocytes constitute an important host defense mechanism, but may at the same time damage functional tissue and propagate acute organ failure. This balance is particularly vulnerable in the lung which provides a large surface area for invading pathogens and microorganisms, and simultaneously harbors a large pool of physiologically marginated neutrophils within its microvascular bed. Pathophysiological stimuli further amplify this accumulation of blood cells and promote the emigration of neutrophils into the pulmonary interstitium and the airspaces by different mechanisms depending on the pathophysiological stimulus, its route of entry into or site of production in the lung, and the time course of its action. Importantly, the pulmonary microvascular endothelium plays a key role in regulating not only sequestration and emigration of neutrophils, but by initiating the inflammatory response to a variety of diverse stimuli many of which do not directly target the circulating neutrophil, but elicit microvascular reactions by primarily acting on the endothelium. This review highlights the inflammatory process in the pulmonary microvasculature with special emphasis on the role of the pulmonary endothelium.

Animals↗
PubMed2007

An inflammatory pathway of IFN-gamma production in coronary atherosclerosis.

Inflammation is associated with the pathogenesis of coronary atherosclerosis, although the mechanisms remain unclear. We investigated whether cytokine secretion by innate immune responses could contribute to the production of proarteriosclerotic Th1-type cytokines in human coronary atherosclerosis. Cytokines were measured by ELISA in the plasma of patients with coronary atherosclerosis undergoing cardiac catheterization. IL-18 was detected in all subjects, whereas a subset of patients demonstrated a coordinated induction of other IFN-gamma-related cytokines. Specifically, elevated plasma levels of IL-12 correlated with that of IFN-gamma and IFN-gamma-inducible chemokines, defining an IFN-gamma axis that was activated independently of IL-6 or C-reactive protein. Systemic inflammation triggered by cardiopulmonary bypass increased plasma levels of the IFN-gamma axis, but not that of IL-18. Activation of the IFN-gamma axis was not associated with acute coronary syndromes, but portended increased morbidity and mortality after 1-year follow-up. IL-12 and IL-18, but not other monokines, elicited secretion of IFN-gamma and IFN-gamma-inducible chemokines in human atherosclerotic coronary arteries maintained in organ culture. T cells were the principal source of IFN-gamma in response to IL-12/IL-18 within the arterial wall. This inflammatory response did not require, but was synergistic with and primed for TCR signals. IL-12/IL-18-stimulated T cells displayed a cytokine-producing, nonproliferating, and noncytolytic phenotype, consistent with previous descriptions of lymphocytes in stable plaques. In contrast to cognate stimuli, IL-12/IL-18-dependent IFN-gamma secretion was prevented by a p38 MAPK inhibitor and not by cyclosporine. In conclusion, circulating IL-12 may provide a mechanistic link between inflammation and Th1-type cytokine production in coronary atherosclerosis.

Aged↗
PubMed1996

A physiologic anti-inflammatory pathway based on thrombomodulin expression and generation of activated protein C by human mononuclear phagocytes.

The endothelial molecule thrombomodulin (TM) regulates hemostasis by binding thrombin and promoting conversion of protein C to activated protein C (aPC). Apart from its anticoagulant actions, aPC modulates mononuclear phagocyte (M phi) activation, including TNF-alpha production, indicating interrelationships of the coagulation and immune systems. While the endothelium is considered to be the prime regulator of aPC generation, TM recently has been identified M phi and neutrophils. This study analyzes TM membrane expression by human blood monocytes, alveolar macrophages, and U937 cells cultured in the presence of various stimuli. All except U937 cell expressed high levels of surface TM. Surprisingly, stimulation with LPS or TNF-alpha further up-regulated TM expression by M phi, whereas cultured endothelial cells (EC) showed decreased TM expression. However, noninflammatory stimuli induced qualitatively similar changes in M phi and EC; all-trans retinoic acid and prostaglandin E up-regulated surface TM, and PMA decreased TM expression. Changes in M phi TM expression were accompanied by alteration in functional activity. Thus, LPS increased the TM cofactor activity of THP-1 cells by 27 +/- 6.9% (p < 0.05), and PMA decreased their cofactor activity by 53.2 +/- 11.5% (p < 0.05).In addition, in vivo relevance was demonstrated by the presence of TM on intragraft inflammatory M phi during cardiac rejection, whereas adjacent EC lacked TM expression. These studies demonstrate that expression of TM on human M phi is regulated differently to EC with respect to inflammatory stimuli, suggesting the potential for extravascular M phi to promote local production of aPC.

Anti-Inflammatory Agents↗
PubMed2004

Direct ANP inhibition of hypoxia-induced inflammatory pathways in pulmonary microvascular and macrovascular endothelial monolayers.

Atrial natriuretic peptide (ANP) has been shown to reduce hypoxia-induced pulmonary vascular leak in vivo, but no explanation of a mechanism has been offered other than its vasodilatory and natriuretic actions. Recently, data have shown that ANP can protect endothelial barrier functions in TNF-alpha-stimulated human umbilical vein endothelial cells. Therefore, we hypothesized that ANP actions would inhibit pulmonary vascular leak by inhibition of TNF-alpha secretion and F-actin formation. Bovine pulmonary microvascular (MVEC) and macrovascular endothelial cell (LEC) monolayers were stimulated with hypoxia, TNF-alpha, or bacterial endotoxin (LPS) in the presence or absence of ANP, and albumin flux, NF-kappa B activation, TNF-alpha secretion, p38 mitogen-activated protein kinase (MAPK), and F-actin (stress fiber) formation were assessed. In Transwell cultures, ANP reduced hypoxia-induced permeability in MVEC and TNF-alpha-induced permeability in MVEC and LEC. ANP inhibited hypoxia and LPS increased NF-kappa B activation and TNF-alpha synthesis in MVEC and LEC. Hypoxia decreased activation of p38 MAPK in MVEC but increased activation of p38 MAPK and stress fiber formation in LEC; TNF-alpha had the opposite effect. ANP inhibited an activation of p38 MAPK in MVEC or LEC. These data indicate that in endothelial cell monolayers, hypoxia activates a signal cascade analogous to that initiated by inflammatory agents, and ANP has a direct cytoprotective effect on the pulmonary endothelium other than its vasodilatory and natriuretic properties. Furthermore, our data show that MVEC and LEC respond differently to hypoxia, TNF-alpha-stimulation, and ANP treatment.

Actins↗
PubMed1995

Interferon beta in the cytokine network: an anti-inflammatory pathway.

Interferons are cytokines and thus fulfil a vital role in communication between cells in their microenvironment. Type I interferons, the group to which interferon beta (IFN-beta) belongs, share several structural and functional properties by which they distinguish themselves from type II interferon or IFN-gamma. In particular, IFN-beta can be produced by many different cells while IFN-gamma is an exclusively lymphocytic cytokine, i.e. a lymphokine. IFN-beta is functionally linked to other cytokines as it can induced by some of them (e.g. interleukin I) and as its actions can be potentiated or antagonized by other cytokines. Such interactions can take place at several levels, e.g. at the level of signal transduction and transcription activation. Of potential interest for the role of IFN-beta in multiple sclerosis is its ability to function as a deactivator of mononuclear phagocytes, and hence as an inhibitor of inflammation.

Adjuvants, Immunologic↗
PubMed2004

Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation.

BACKGROUND AND AIMS: Recent evidence suggests that toll-like receptors (TLRs) recognize certain viruses. We reported that hepatitis C virus (HCV) core and nonstructural 3 (NS3) proteins activate inflammatory pathways in monocytes. The aim of this study was to investigate the role of TLRs in innate immune cell activation by core and NS3 proteins. METHODS: Human monocytes, human embryonic kidney cells transfected with TLR2, and peritoneal macrophages from TLR2, MyD88 knockout, and wild-type mice were studied to determine intracellular signaling and proinflammatory cytokine induction by HCV proteins. RESULTS: HCV core and NS3 proteins triggered inflammatory cell activation via the pattern recognition receptor TLR2 and failed to activate macrophages from TLR2 or MyD88-deficient mice. HCV core and NS3 induced interleukin (IL)-1 receptor-associated kinase (IRAK) activity, phosphorylation of p38, extracellular regulated (ERK), and c-jun N-terminal (JNK) kinases and induced AP-1 activation. Activation of nuclear factor-kappaB by core and NS3 was associated with increased IkappaBalpha phosphorylation. TLR2-mediated cell activation was dependent on the conformation of core and NS3 proteins and required sequences in the regions of aa 2-122 in core and aa 1450-1643 in NS3. Although cellular uptake of core and NS3 proteins was independent of TLR2 expression, cell activation required TLR2. HCV core protein and TLR2 showed intracellular colocalization. The hyper-elevated TNF-alpha induction by TLR2 ligands in monocytes of HCV-infected patients was not due to increased TLR2 expression. CONCLUSIONS: HCV core and NS3 proteins trigger inflammatory pathways via TLR2 that may affect viral recognition and contribute to activation of the innate immune system.

Animals↗
PubMed2001

Oxidative signalling and inflammatory pathways in Alzheimer's disease.

It is well established that inflammation and oxidative stress are key components of the pathology of Alzheimer's disease (AD), but how early in the pathological cascade these processes are involved or which specific molecular components are key, has not been fully elucidated. This paper describes the pharmacological approach to understand the molecular components of inflammation and oxidative stress on the activation of microglial cells and neuronal cell viability. We have shown that activation of microglia with the 42-amino-acid form of the beta-amyloid peptide (A beta 42) activates the production of cyclooxygenase-2, the inducible form of nitric oxide synthase and tumour necrosis factor-alpha and there appears to be little interactive feedback between these three mediators. Moreover, we explore the effects of a series of salen-manganese complexes, EUK-8, -134 and -189, which are known to possess both superoxide and catalase activity. These compounds are able to protect cells from insults produced by hydrogen peroxide or peroxynitrite. Moreover, EUK-134 was also able to limit the output of prostaglandin E2 from activated microglial cells. The mechanisms underlying these effects are discussed. Together, these data support a pivotal role for oxidative stress and inflammation as key mediators of the pathological cascade in AD and provide some ideas about possible therapeutic targets.

Alzheimer Disease↗
PubMed2005

The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation.

The Injury Hypothesis, first published in 1994 and modified several times between 1996 and 2002, holds that the reactive oxygen species-mediated reperfusion injury to allografts initiates and induces the alloimmune response and contributes to alloatherogenesis. Recent experimental and clinical evidence in support of the concept is presented suggesting that (1) reactive oxygen species-mediated allograft injury activates the innate immune system of the donor and recipient; (2) injury-induced putative endogenous ligands of Toll-like receptors (TLRs) of host origin such as heat shock proteins interact with and activate TLR4-bearing dendritic cells that mature and induce the adaptive alloimmune response (acute rejection), and interact with and activate TLR4-bearing vascular cells contributing to the development of alloatherosclerosis (chronic rejection); and (3) TLR4-triggered signaling, involved in the establishment of a reperfusion injury, seems to use myeloid differentiation marker 88-independent, Toll/interleukin-1 receptor domain containing adaptor inducing interferon-beta-dependent pathways that are associated with the maturation of dendritic cells and induction of interferon-inducible genes.

Animals↗
PubMed2025

Inflammatory pathways and immune dysregulation in pediatric postoperative septic shock: A study integrating transcriptomics, machine learning and molecular docking.

This study elucidates the molecular and immune regulatory mechanisms of pediatric postoperative septic shock. Transcriptomic data were obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using the limma package, and gene co-expression modules were constructed using Weighted Gene Co-expression Network Analysis. Functional enrichment was performed via gene set enrichment analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. Immune cell infiltration was assessed using ESTIMATE and CIBERSORT. Mendelian randomization was applied to explore causal relationships between gene expression and septic shock. Feature genes were selected using machine learning algorithms, and a diagnostic nomogram model was constructed. Finally, molecular docking analysis was performed to screen and evaluate the binding affinity of traditional Chinese medicine monomers to core target proteins. A total of 1331 differentially expressed genes were identified, and the turquoise module was strongly correlated with septic shock. Enrichment analysis revealed significant activation of IL-6/JAK/STAT3, TNF-&#x3b1;/NF-&#x3ba;B, and PI3K/Akt/mTOR pathways. Immune infiltration analysis indicated suppressed immune scores and imbalances in neutrophils, macrophages, T cells, and B cells. Mendelian randomization confirmed causal associations for 6 genes, including PIM3. The predictive model based on feature genes demonstrated high diagnostic performance. Molecular docking suggested that quercetin and astramembrannin I could stably bind PIM3. This study systematically identified core genes, dysregulated immune pathways, and candidate small-molecule interventions in pediatric septic shock, providing novel insights for early diagnosis and targeted therapy.

Humans↗
PubMed2005

AIDS-related vasculopathy: evidence for oxidative and inflammatory pathways in murine and human AIDS.

Increased life expectancy of human immunodeficiency virus (HIV)-positive patients has led to evidence of complications apparently not directly related to immunodeficiency or opportunistic infection, including increased cardiovascular risk. We tested the hypothesis that vascular dysfunction occurs in the murine acquired immune deficiency syndrome (AIDS) model and evaluated potential mechanisms in murine AIDS tissues and relevant human HIV/AIDS vascular tissues. We also investigated endothelial activation and/or endothelial protein nitration and their association with time-dependent vascular dysfunction. At 1 and 5 wk of murine AIDS, statistically significant decreases in KCl contractility and time-dependent contractile deficits in response to phenylephrine were observed. The maximal response (E(max)) was reduced by approximately 40% at 10 wk, and EC(50) values were significantly changed: 102 +/- 7.3 ng for control vs. 190 +/- 37 and 130 +/- 22 ng at 5 and 10 wk, respectively (P < 0.05). Endothelium-dependent relaxation to ACh was decreased (EC(50) = 120 +/- 27 and 343 +/- 94 nM for control and at 10 wk, respectively), whereas the response to an exogenous nitric oxide donor, sodium nitroprusside, remained unchanged, suggesting a specific endothelial dysfunction. Histochemical investigations of the same vascular tissues as well as corresponding coronary endothelium showed an increase in protein 3-nitrotyrosine, intercellular adhesion molecule, and nitric oxide synthase isoforms 2 and 3. These findings were corroborated in concurrent experiments in a cohort of well-cataloged human cardiac microvascular tissues. We have demonstrated, for the first time, a specific functional vasculopathy with endothelial involvement in a murine model of AIDS that was also associated with and correlated to increased oxidative stress and specific endothelial activation. This finding was echoed in a relevant population of human HIV/AIDS patients. Research into sources and intracellular targets of oxidants in this disease could provide important mechanistic insights and may reveal new therapeutic opportunities for this increasingly important cardiovascular disease state.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Statins promote potent systemic antioxidant effects through specific inflammatory pathways.

BACKGROUND: The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO2Tyr), a modification generated by nitric oxide-derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported. METHODS AND RESULTS: As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO2Tyr, and dityrosine (30%, 25%, and 32%, respectively; P<0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%, P<0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively; P>0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins. CONCLUSIONS: Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide-derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.

Antioxidants↗
PubMed2006

Differential activation of inflammatory pathways in A549 type II pneumocytes by Streptococcus pneumoniae strains with different adherence properties.

BACKGROUND: Adherence of Streptococcus pneumoniae bacteria to lung cells is a first step in the progression from asymptomatic carriage to pneumonia. Adherence abilities vary widely among S. pneumoniae patient isolates. In this study, the binding properties of S. pneumoniae isolates and the effects of binding on activation of the Nuclear Factor-Kappa-B (NFkappaB) pathway and cytokine secretion by type II pneumocytes were measured. METHODS: Mechanisms of high- and low-binding S. pneumoniae adherence to A549 cells were investigated by blocking putative receptors on bacteria and host cells with antibody and by eluting choline-binding proteins off of bacterial surfaces. NFkappaB activation was measured by western blot and immunocytochemistry and cytokine secretion was detected by a protein array. RESULTS: This study shows that S. pneumoniae isolates from pneumonia patients (n = 298) can vary by as much as 1000-fold in their ability to bind to human lung epithelial cells. This difference resulted in differential activation of the NFkappaB pathway. High-, but not low-binding S. pneumoniae used Choline-binding protein A (CbpA) to bind to complement component C3 on epithelial cell surfaces. Interleukin-8 (IL-8) was the only cytokine secreted by cells treated with either low- or high-binding S. pneumoniae. CONCLUSION: These results indicate that S. pneumoniae clinical isolates are not homogeneous in their interaction with host epithelial cells. The differential activation of host cells by high- and low-binding S. pneumoniae strains could have implications for the treatment of pneumococcal pneumonia and for vaccine development.

Bacterial Adhesion↗
PubMed1999

The engineered human anti-tumor necrosis factor-alpha antibody CDP571 inhibits inflammatory pathways but not T cell activation in patients with rheumatoid arthritis.

OBJECTIVE: We investigated the effect of an engineered human anti-tumor necrosis factor-alpha antibody, CDP571, on immune functions as well as bone and cartilage turnover in patients with rheumatoid arthritis (RA) in a placebo controlled trial. We also assessed the effects of repeated treatment with CDP571 in an open label continuation study. METHOD: Thirty-six patients were treated with either placebo or 0.1, 1, or 10 mg/kg of CDP571 given as an intravenous infusion. The followup period was 8 weeks. Lymphocyte phenotype, soluble CD4 (sCD4), soluble interleukin 2 receptor (sIL-2R), IL-6, and stromelysin levels in the blood were measured before and after treatment; bone and cartilage markers (pyridinoline, deoxypyridinoline, N-terminal telopeptide) were similarly assessed in the urine. Patients who completed a placebo controlled trial of CDP571 were offered further treatment with CDP571. They received a maximum of 2 further doses of 1 mg/kg (7 patients) or 10 mg/kg (9 patients) in an open study. RESULTS: Plasma IL-6 level was statistically significantly reduced in the 1 and 10 mg/kg groups. In the 10 mg/kg group, there were also reductions in plasma stromelysin and urine bone markers, although there was no change in sCD4 and sIL-2R levels. Repeat doses of CDP571 were well tolerated and continued to suppress the acute phase response and disease activity. CONCLUSION: Treatment with 10 mg/kg of CDP571 reduced IL-6 and surrogate markers of bone turnover in RA, suggesting that CDP571 might prevent joint damage in RA. Since there was no effect on lymphocyte markers despite the marked reduction in inflammation, CDP571 appears to have no effect on ongoing CD4 T cell activation.

Antibodies↗
PubMed2002

Pathways of inflammatory activation in Alzheimer's disease: potential targets for disease modifying drugs.

In the human brain several cell types are capable of initiating and amplifying a brain specific inflammatory response involving the synthesis of cytokines, prostaglandins and oxygen free radicals. In Alzheimer's disease (AD), signs of an inflammatory activation of microglia and astroglia are present inside and outside amyloid deposits. Cell culture and animal models suggest an interactive relationship between inflammatory activation, reduced neuronal functioning and deposition of amyloid. The activation of inflammation-associated enzymes such as p38 mitogen-activated protein kinase (p38 MAPK) and cycloxygenase-2 (COX-2) is not restricted to glial cells but also found in neurons and may contribute to intraneuronal damage. Epidemiological studies have shown a reduced risk of AD among users of anti-inflammatory drugs. Therefore, anti-inflammatory drugs have become the focus of several new treatment strategies. Small clinical trials with non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and diclofenac showed a trend for a disease modifying effect, while clinical trials with steroids did not show a beneficial effect. NSAIDs may not only act on COX-2 but also inhibit COX-1 activity or activate peroxisome proliferator-activated receptor gamma (PPAR gamma). Among promising new strategies to reduce the inflammatory activation in the CNS interfering with intracellular pro-inflammatory pathways has been shown to be effective in various cell culture and animal models. Inhibitors of p38MAPK and PPAR gamma agonists may be suitable agents to suppress inflammatory activation in AD.

Alzheimer Disease↗