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.

SourceResearch connectionFrom yearThrough year

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

At least 1,783 records · Page 99Linked to original sources

PubMed2007

TREM-1 promotes survival during septic shock in mice.

Triggering receptor expressed on myeloid (TREM)-1 is integral to the inflammatory response occurring during septic shock, although its precise function has yet to be determined. Here we show that in vivo silencing of TREM-1 using siRNA duplexes in a fecal peritonitis mouse model resulted in a blunted inflammatory response and increased mortality. This was associated with impaired bacterial clearance related to marked inhibition of the neutrophil oxidative burst. By contrast, TREM-1-silenced mice were highly resistant to a lethal endotoxin challenge, while partial silencing of TREM-1 in the bacterial peritonitis model produced a significant survival benefit. These data highlight the crucial role of the TREM-1 pathway in mounting an adequate inflammatory and cytotoxic response to polymicrobial sepsis, and both the therapeutic promise and potential risks of its modulation.

Animals↗

PubMed2004

Pre- and postnatal inflammatory mechanisms in chronic lung disease of preterm infants.

Epidemiological data suggest a strong association between chorioamnionitis and the development of chronic lung disease in preterm infants. Increased concentrations of proinflammatory cytokines present in the amniotic fluid and the systemic fetal circulation seem to be important mediators in the early inflammatory response by recruiting and activating inflammatory cells and by inducing pathways of lung injury. As a consequence vascular cell adhesion molecules are upregulated and a marked infiltration of neutrophils and macrophages as well as an increased expression of interleukin-8 mRNA in the bronchoalveolar epithelium and in the interstitial tissue takes place. These antenatal events may prime the lungs such that various injurious factors in the postnatal period provoke an excessive inflammatory response: oxygen toxicity, mechanical ventilation, inappropriate resuscitation, pulmonary and systemic infections, persistent ductus arteriosus. Besides proinflammatory cytokines, toxic oxygen radicals, lipid mediators and potent proteases may be responsible for acute and chronic lung injury. In general, an imbalance between pro- and anti-inflammatory factors can be considered as a hallmark of lung injury, and may considerably affect normal alveolarisation and pulmonary vascular development by inducing growth arrest of the immature lung.

Cell Adhesion Molecules↗

PubMed2005

Leishmania lipophosphoglycan activates the transcription factor activating protein 1 in J774A.1 macrophages through the extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase.

Leishmania donovani is an obligatory intracellular pathogen that resides and multiplies in the phagolysosomes of macrophages. The outcome of this infection depends on the balance between the host ability to activate macrophage killing and the parasite ability to suppress or evade this host immune response. Lipophosphoglycan (LPG) glycoconjugate, the surface molecule of the protozoan parasite is a virulence determinant and a major parasite molecule involved in this process. In this study, we examined the ability of Leishmania and its surface molecule, lipophosphoglycan to activate activating protein 1 (AP-1) through the mitogen-activated protein kinase (MAPK) cascade. We report here that the Leishmania surface molecule, lipophosphoglycan stimulates the simultaneous activation of all three classes of MAP kinases, extracellular signal-related kinases (ERKs), the c-jun amino-terminal kinase (JNK) and the p38 MAP kinase with differential kinetics in J774A.1 macrophage cell line. Furthermore, both L. donovani and its surface molecule lipophosphoglycan resulted in a dose- and time-dependent induction of AP-1 DNA-binding activity. We have also shown a dose-dependent increase of AP-1 binding activity in both low and high virulent strains of parasite. The use of inhibitors selective for ERK (PD98059) and p38 (SB203580) pathway showed that pre-incubation of cells with either SB203580 or PD98059 affected the binding activity of AP-1 suggesting that both p38 and ERK MAP kinase activation appear to be necessary for AP-1 activation by LPG. Lipophosphoglycan induced IL-12 production and generation of nitric oxide in murine macrophages. These results demonstrate that L. donovani LPG activates pro-inflammatory, endotoxin-like response pathway in J774A.1 macrophages and the interaction may play a pivotal role in the elimination of the parasite.

Animals↗

PubMed1999

Apoptosis in Helicobacter pylori-associated gastric and duodenal ulcer disease is mediated via the Fas antigen pathway.

Increased mucosal apoptosis is seen in H. pylori-infected gastric tissue; however, the precise mechanism by which this organism triggers programmed cell death is poorly understood and is investigated in this study. One pathway for induction of apoptosis is the Fas Ag pathway. Normal gastric and small bowel tissue express low levels of Fas antigen and nondetectable levels of Fas ligand. Consequent to H. pylori infection, there is elevated expression of Fas antigen in mucosal cells concurrent with Fas ligand expressing lymphocytes. This prompted us to investigate the potential role of Fas in mediating H. pylori-related apoptosis. It has been shown that inflammatory cytokines are abundant in H. pylori-infected tissue and that cytokines regulate the expression of Fas Ag in various tissue types. Using cell culture, we examine the role of specific inflammatory cytokines in activating this pathway. This communication presents the first evidence to implicate the Fas pathway in mediating apoptosis in H. pylori-associated gastric and duodenal ulcer disease.

Apoptosis↗

PubMed2002

Tumour necrosis factor alpha up-regulates protein kinase R (PKR)-activating protein (PACT) and increases phosphorylation of PKR and eukaryotic initiation factor 2-alpha in articular chondrocytes.

Our previous analysis of the genes regulated in cartilage at the onset of spontaneous osteoarthritis in the guinea pig knee revealed up-regulation of the gene for protein kinase R (PKR)-activating protein (PACT), which encodes the cellular activator of the protein kinase, PKR. PACT and PKR are upstream components of a number of signal transduction and gene transcription pathways used by pro-inflammatory cytokines. We have investigated the role of PACT and PKR in articular cartilage degradation using cytokine treatment of bovine primary chondrocytes and cartilage explants. Tumour necrosis factor alpha increased expression of PACT protein after 3 h of treatment. Furthermore, increased phosphorylation of PKR and eukaryotic initiation factor 2-alpha was observed. The known role of PKR in cytokine-induced signalling pathways, together with our data showing cytokine regulation of PACT and PKR in chondrocytes, reveals a novel mechanism of cartilage degradation that may be important in the pathogenesis of arthritic diseases.

Animals↗

PubMed2006

Phosphatidylinositol 3-kinase-dependent suppression of the human inducible nitric-oxide synthase promoter is mediated by FKHRL1.

The synthesis of nitric oxide by inducible nitric-oxide synthase (iNOS) plays an important role in the innate immune response by promoting microbial killing and cell damage. In response to inflammatory cytokines and bacterial products, the human iNOS (hiNOS) gene undergoes rapid transcriptional activation via binding of stimulatory transcription factors (e.g. AP-1 and NF-kappaB) to its 5'-flanking region. However, maximal hiNOS promoter induction was suppressed via an unknown phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. We hypothesized that inhibition of the transcription factor FKHRL1 by the PI3K/protein kinase B pathway attenuates hiNOS promoter induction by bacterial lipopolysaccharide and interferon-gamma (LPS/IFN-gamma). Human lung epithelial adenocarcinoma (A549) cells were transiently transfected with an 8.3-kb hiNOS promoter luciferase reporter construct. Co-expression of dominant-negative protein kinase B potentiated LPS/IFN-gamma-stimulated hiNOS promoter activity. In response to LPS/IFN-gamma, FKHRL1 was phosphorylated in a PI3K- and time-dependent fashion. Co-expression of constitutively active FKHRL1 increased hiNOS promoter activity and mRNA levels. Dominant-negative siRNA expression showed that FKHRL1 was necessary for the inhibitory effects of PI3K on hiNOS induction. The same effect was observed upon mutation of a consensus FKHRL1-binding site in the hiNOS promoter. By gel-shift analysis, the corresponding oligonucleotide probe bound endogenous FKHRL1 in an LPS/IFN-gamma- and PI3K-sensitive fashion. Regulation of the hiNOS promoter by FKHRL1 represents a potentially important molecular mechanism by which the PI3K pathway might suppress pro-inflammatory and proapoptotic responses to cytokines and bacterial products.

Androstadienes↗

PubMed1996

Preventing the inflammatory response to open-heart surgery: the role of aprotinin and other protease inhibitors.

This review discusses the role of protease inhibition in reducing or preventing certain of the deleterious effects of major surgery. The ability of agents such as aprotinin to inhibit bleeding and reduce the need for donor blood transfusions is now well established. What is less well recognized is that aprotinin is not simply an antifibrinolytic but is a polyvalent enzyme inhibitor of many of the enzymes which are involved in inflammatory and hemostatic processes. Inappropriate activation of these pathways is considered to be important in the genesis of the inflammatory response to open-heart surgery. The first part of the article reviews aspects of the inflammatory and hemostatic systems which have a common basis and which utilize proteolytic actions for their control. In the later part of the review, the effect of a period of cardiopulmonary bypass on organ and tissues is discussed together with the effects of protease inhibition to prevent any abnormal or inappropriate response to the stimulus. Consideration of these aspects will hopefully allow a more rational and scientific approach to the uses, possible benefits and perceived or real safety issues following administration of these agents.

Animals↗

PubMed2000

The involvement of phospholipase C in crystal induced human neutrophil activation.

OBJECTIVE: To investigate the involvement of phospholipase C (PLC) in the signal transduction pathway leading to neutrophil activation by inflammatory microcrystals. METHODS: Neutrophil chemiluminescence, superoxide anion generation, and degranulation responses to opsonized crystals were measured in the presence of U73122, a specific inhibitor of PLC. Phospholipase Cgamma2 (PLCgamma2) activity was measured by Western blotting. RESULTS: U73122 was shown to inhibit neutrophil activation induced by plasma opsonized crystals of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate. The IC50 for inhibition of crystal induced respiratory burst (measured by chemiluminescence) was roughly 3 microM. No inhibition of crystal induced respiratory burst was observed using U73343, an inactive analog of U73122. These results show the pivotal role of PLC in neutrophil respiratory burst activation by both crystals. Superoxide anion generation and degranulation responses of neutrophils to CPPD crystals were also strongly inhibited by U73122 at a concentration of 10 microM, supporting the concept of direct involvement of PLC in signal transduction pathways leading to crystal induced oxidase activation and degranulation responses. CPPD crystals caused a sustained increase in the tyrosine phosphorylation levels of PLCgamma2 in neutrophils. CONCLUSION: We conclude that PLC plays a central role in signal transduction pathways leading to respiratory burst and degranulation responses in neutrophils activated by inflammatory microcrystals, and that PLCgamma2 may be the isoform involved in these pathways.

Calcium↗

PubMed1997

The stress-activated c-Jun protein kinase (JNK) is stimulated by lipoxygenase pathway product 12-HETE in RIN m5F cells.

Cytokine induced pancreatic beta-cell destruction seen in Type 1 diabetes and islet graft rejection involves multiple intracellular signaling pathways that directly or indirectly lead to inflammatory damage or programmed cell death. IL-1beta has been shown to stimulate the 12-lipoxygenase pathway product 12-HETE, in RIN m5F cells; however, the precise role of 12-LO activation in mediating cytokine effects is not clear. Since the stress-activated protein kinase, JNK, has been linked to cytokine mediated inflammatory actions, we studied the effect of two LO products, 12-HETE and 15-HETE, on JNK activity. We demonstrate that 1 nM 12-HETE stimulates JNK activity, while 1 nM 15-HETE, the 15-lipoxygenase pathway product, does not. These results suggest 12-HETE is a novel upstream signal for IL-1beta induced JNK activation in RIN m5F cells.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed2002

Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer known. IBC carries a guarded prognosis primarily due to rapid onset of disease, typically within six months, and the propensity of tumor emboli to invade the dermal lymphatics and spread systemically. Although the clinical manifestations of IBC have been well documented, until recently little was known about the genetic mechanisms underlying the disease. In a comprehensive study aimed at identifying the molecular mechanisms responsible for the unique IBC phenotype, our laboratory identified overexpression of RhoC GTPase in over 90% of IBC tumors in contrast to 36% of stage-matched non-IBC tumors. We also demonstrated that overexpression of RhoC GTPase in human mammary epithelial (HME) cells nearly recapitulated the IBC phenotype with regards to invasion, motility and angiogenesis. In the current study we sought to delineate which signaling pathways were responsible for each aspect of the IBC phenotype. Using well-established inhibitors to the mitogen activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) pathways. We found that activation of the MAPK pathway was responsible for motility, invasion and production of angiogenic factors. In contrast, growth under anchorage independent conditions was dependent on the PI3K pathway.

ADP Ribose Transferases↗

PubMed2004

Corticothalamic modulation on formalin-induced change of VPM thalamic activities.

Spontaneous activities of single cells were extracellularly recorded in ventral posterior medial (VPM) thalamus of anesthetized rats to characterize the corticothalamic modulation on formalin-induced changes of spontaneous thalamic firing. Formalin injected into the peripheral receptive field, dose-dependently induced the reversible facilitation of spontaneous activities of VPM. However, when the primary somatosensory (SI) cortex was inactivated by muscimol, the pattern of formalin-induced changes of VPM firing was altered. This altered responsiveness included both first and second phase of facilitated spontaneous activities. Bicuculline infused into SI cortex did not alter the pattern of formalin-induced thalamic changes. These results suggest that the pain reactivity of VPM thalamus may be modulated by cortex via corticothalamic pathway during the generation of inflammatory pain.

Animals↗

PubMed1998

Soluble mediators and the interaction of drugs in IBD.

The chronic idiopathic bowel diseases (IBD) - Crohn's disease and ulcerative colitis - are considered to be the result of an unrestrained inflammatory reaction. Although an explanation for the etiopathogenesis has still not emerged, the explosion of information on the inflammatory process is expected to yield a multitude of drugs targeted at particular elements of the inflammatory process. The final common pathway of immune activation in IBD is the local influx of monocytes, macrophages and polymorphonuclear neutrophils (PMNs). The processes which account for the recruitment of these cells include cytokine generation, complement activation and eicosanoid biosynthesis. Once the influx of PMNs and macrophages occurs, an increased production of platelet-activating factor (PAF) and leukotrienes (LTs), in particular LTB(4), results in the secondary amplification of the inflammatory response, which provides the clinical manifestations of IBD. Other important soluble mediators of inflammation include complement-derived and chemotactic peptides, specific adhesion molecules, neuropeptides and reactive metabolites of oxygen and nitrogen. Current established therapies, such as glucocorticoids and 5-aminosalicylic acid (5-ASA), inhibit raised concentrations of these interdependent soluble mediators of inflammation, which may amplify one another or have parallel effects. Future medical options for treatment of IBD aim at removing perpetuating antigens or inhibiting the entry of inflammatory cells by manipulating adhesion molecules, by blocking the proinflammatory molecules, or by preserving endogenous suppressive molecules or correcting genetic defects. However, it remains to be defined whether targeting multiinflammatory actions or a single key pivotal process is the better therapeutic strategy and whether subgroups of IBD with different clinical courses will require different treatment approaches.

Journal Article↗

PubMed2006

Carbohydrate recognition systems in autoimmunity.

The immune system is a complex functional network of diverse cells and soluble molecules orchestrating innate and adaptive immunity. Biological information, to run these intricate interactions, is not only stored in protein sequences but also in the structure of the glycan part of the glycoconjugates. The spatially accessible carbohydrate structures that contribute to the cell's glycome are decoded by versatile recognition systems in order to maintain the immune homeostasis of an organism. Microbial carbohydrate structures are recognized by pathogen associated molecular pattern (PAMP) receptors of innate immunity including C-type lectins such as MBL, the tandem-repeat-type macrophage mannose receptor, DC-SIGN or dectin-1 of dendritic cells, certain TLRS or the TCR of NKT cells. Natural autoantibodies, a long known effector branch of this network-based operation, are effective to home in on non-self and self-glycosylation also. The recirculating pool of mammalian immune cells is recruited to inflammatory sites by a reaction pathway involving the self-carbohydrate-binding selectins as initial recognition step. Galectins, further key sensors reading the high-density sugar code, exert regulatory functions on activated T cells, among other activities. Autoimmune diseases are being associated with defined changes of glycosylation. This correlation deserves to be thoroughly studied on the levels of structural mimicry and dysregulation as well as effector molecules to devise innovative anti-inflammatory strategies. This review briefly summarizes data on sensor systems for carbohydrate epitopes and implications for autoimmunity.

Animals↗

PubMed2026

Necroptosis in alveolar epithelium orchestrates lung ischemia-reperfusion injury: a multi-omics study.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is a leading cause of early morbidity and mortality following lung transplantation and other cardiopulmonary procedures. It is characterized by acute sterile inflammation driven by regulated cell death (RCD). While various RCD modalities, including apoptosis, necroptosis, pyroptosis, and ferroptosis, have been implicated in lung injury, their relative contributions and distinct activation patterns in LIRI remain poorly defined. METHODS: We employed an integrated multi-omics approach combining transcriptomics and proteomics with histological and functional validations in a murine hilar clamping model of LIRI. Key findings were further corroborated using single-cell RNA sequencing (scRNA-seq) data from human lung transplant recipients. The functional role of necroptosis was validated using pharmacological inhibitors (Nec-1, GSK'872) and Mlkl-deficient (Mlkl-/-) mice. RESULTS: LIRI triggered acute, time-dependent lung injury peaking within 24 h of reperfusion. Although transcriptomic profiling suggested broad activation of multiple RCD pathways, proteomic and biochemical analyses revealed a distinct landscape in our experimental setting: markers of apoptosis, pyroptosis, and ferroptosis were either downregulated or showed no significant positive correlation with injury severity and inflammatory peaks. In contrast, the necroptotic pathway emerged as a highly activated modality. Specifically, necroptosis, marked by phosphorylated RIPK1, RIPK3, and MLKL, was localized primarily in alveolar epithelial cells, correlated strongly with cytokine release and histological lung injury, and preceded the inflammatory response. Pharmacological inhibition or genetic ablation of necroptosis significantly attenuated tissue damage and inflammation. This pronounced necroptotic signature appeared distinct from the broad multi-pathway activation observed in lipopolysaccharide (LPS)-induced lung injury. Translational analysis of human scRNA-seq data further confirmed the selective upregulation of necroptosis signatures in alveolar type 2 (AT2) cells following lung transplantation. CONCLUSION: Our multi-omics analysis identifies necroptosis, particularly in alveolar epithelial cells, as a critical driver of sterile inflammation and tissue injury in the early phase of LIRI. Targeting alveolar epithelial necroptosis may represent a precise and promising therapeutic strategy for lung transplantation and ischemia-reperfusion-associated pulmonary disorders.

Animals↗

PubMed2002

The upregulation of CC chemokine receptor 7 and the increased migration of maturing dendritic cells to macrophage inflammatory protein 3beta and secondary lymphoid chemokine is mediated by the p38 stress-activated protein kinase pathway.

Using the p38 stress-activated protein kinase (p38SAPK) inhibitor, SB203580, increased responsiveness of monocyte-derived dendritic cells (MoDCs) to secondary lymphoid chemokine (SLC) and macrophage inflammatory protein 3beta (MIP3beta), following lipopolysaccharide-induced MoDC maturation, was shown to be mediated by the p38SAPK pathway. This was due to the complete abrogation of upregulation of CC chemokine receptor 7, the receptor for MIP3beta/SLC. Once mature, MoDCs utilized both the p38SAPK and phosphoinositide-3 kinase pathways to migrate in response to SLC or MIP3beta. These findings have implications for the mechanism of action of p38SAPK inhibitors, currently in use in clinical trials for patients with autoimmune diseases.

Angiogenesis Inhibitors↗

PubMed1986

Dermatosis in magnesium-deficient hairless rats: effects of steroidal and non-steroidal anti-inflammatory drugs.

Dermatosis in magnesium-deficient hairless rats has been described as a reproducible model of skin inflammation. It was therefore felt of interest to search for the effects of various anti-inflammatory compounds on this model. Results showed that 1) Dexamethasone acetate completely abolished the rash, 2) Indomethacin, a Non-Steroidal Anti-Inflammatory Drug (NSAID), inhibitor of the cyclooxygenase pathway was quite inactive, 3) Benoxaprofen, a NSAID inhibitor of both cyclooxygenase and lipoxygenase pathways only slightly modified the development of the pathology. Activity of steroidal anti-inflammatory drugs on this model may be related to their immunosuppressive effects.

Animals↗

PubMed2006

How to modulate inflammatory cytokines in liver diseases.

Most acute and chronic liver diseases are characterized by inflammatory processes with enhanced expression of various pro- and anti-inflammatory cytokines in the liver. These cytokines are the driving force of many inflammatory liver disorders often resulting in fibrosis and cirrhosis. Severe alcoholic hepatitis is a prototypic tumor necrosis factor-alpha (TNF-alpha)-associated disease. This knowledge has recently led to pilot studies with promising results investigating specific anti-TNF drugs such as infliximab or etanercept in the treatment of this disease, although a recently performed controlled French study did show a potential detrimental effect of this approach. Anti-TNF treatment strategies might also improve chronic hepatitis C infection as shown by one controlled trial using etanercept administered subcutaneously for 24 weeks. Furthermore, several case reports suggest that TNF-alpha neutralization is not harmful to patients chronically infected with this virus. In contrast, neutralization of TNF-alpha worsens and might even be associated with fatalities in chronic hepatitis B infection. Anti-inflammatory cytokines such as interleukin-10 (IL-10) have also been tried in patients with chronic liver diseases. Whereas IL-10 administered to patients with chronic hepatitis C virus infection shows indeed anti-inflammatory effects in the liver, it seems to act as a proviral agent thereby limiting its clinical utility. Another cytokine with major anti-inflammatory potential is the adipokine adiponectin, as its administration is beneficial in many experimental models of liver injury. Interference with cytokine pathways and/or administration of anti-inflammatory cytokines will be of major interest in the future therapy of many liver diseases.

Adiponectin↗

PubMed2003

Transcriptional repression of atherogenic inflammation: modulation by PPARdelta.

The formation of an atherosclerotic lesion is mediated by lipid-laden macrophages (foam cells), which also establish chronic inflammation associated with lesion progression. The peroxisome proliferator-activated receptor (PPAR) gamma promotes lipid uptake and efflux in these atherogenic cells. In contrast, we found that the closely related receptor PPARdelta controls the inflammatory status of the macrophage. Deletion of PPARdelta from foam cells increased the availability of inflammatory suppressors, which in turn reduced atherosclerotic lesion area by more than 50%. We propose an unconventional ligand-dependent transcriptional pathway in which PPARdelta controls an inflammatory switch through its association and disassociation with transcriptional repressors. PPARdelta and its ligands may thus serve as therapeutic targets to attenuate inflammation and slow the progression of atherosclerosis.

Animals↗