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 1,315 records · Page 73Linked to original sources
PubMed2001

Effect of n-3 and n-6 polyunsaturated fatty acids and their ethylesters on stimuli-dependent superoxide generation in neutrophils.

Polymorphonuclear leukocytes from healthy volunteers (HPMN) generated superoxide (O2*-) following treatment with various stimuli, such as phorbol myristate acetate (PMA), opsonized zymozan (OZ) and arachidonic acid (AA). Other types of n-3 polyunsaturated fatty acids (PUFAS), such as docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA), also stimulated O2*- generation. The free form of DHA enhanced the generation of O2*- induced by PMA but inhibited that induced by OZ. In contrast, the ethylester of DHA (DHA-E) inhibited O2*- generation induced by PMA but stimulated that induced by OZ. Similar effects were also observed with ethylesters of EPA (EPA-E), DPA (DPA-E) and AA (AA-E). High concentrations of DHA-E reduced the PMA-induced formation of superoxide without affecting the cellular activity of protein kinase C (PKC). Similar phenomena were also observed with oral neutrophils from healthy volunteers (OPMN). These results indicate that PUFAS and their esters affect 02*- generation in human PMN via different pathways, thereby modulating inflammatory reactions.

Electron Spin Resonance Spectroscopy↗
PubMed1998

[Overexpression of B7-1 amd B7-2 by LFA-1 positive lymphocytes in chronic inflammatory bowel diseases].

The B7/CD28 pathway is essential for initiating antigen-specific T-cell activation. LFA-1 (CD11a/CD18) is required for sufficient migration into inflammatory tissue. The aim of this study was to evaluate the role of B7 and LFA-1 in inflammatory bowel disease. Immunohistological single and double staining (PAP/APAAP) with monoclonal antibodies against HLA I/II, CD4, CD8, CD28, B7-1, B7-2, LFA-1 and CD68 were performed in tissue samples from patients with crohn's disease (n = 15), ulcerative colitis (n = 14), colorectal carcinoma (n = 5) and FAP (n = 3). The expression of B7-1 and B7-2 was generally much higher in ulcerative colitis and crohn's disease than in colorectal carcinoma and FAP. In crohn's disease multinucleated gigant cells in the granulomas express B7-1 and B7-2. Double staining showed a higher B7-1/B7-2 coexpression for CD4+ than for CD8+ T cells. In colitis ulcerosa and crohn's disease LFA-1 positive leucocytes showed a high coexpression of B7-1 and B7-2 in contrast to CD68 positive macrophages. These data suggest that overexpression of B7-1 and B7-2 on LFA-1 positive Leucocyts seems to play an important role in the pathogenesis of inflammatory bowel disease.

Adenomatous Polyposis Coli↗
PubMed2005

Discrimination of vanadium from zinc using gene profiling in human bronchial epithelial cells.

We hypothesized that gene expression profiling may discriminate vanadium from zinc in human bronchial epithelial cells (HBECs). RNA from HBECs exposed to vehicle, V (50 microM), or Zn (50 microM) for 4 hr (n = 4 paired experiments) was hybridized to Affymetrix Hu133A chips. Using one-class t-test with p < 0.01, we identified 140 and 76 genes with treatment:control ratios > or = 2.0 or < or = 0.5 for V and Zn, respectively. We then categorized these genes into functional pathways and compared the number of genes in each pathway between V and Zn using Fisher's exact test. Three pathways regulating gene transcription, inflammatory response, and cell proliferation distinguished V from Zn. When genes in these three pathways were matched with the 163 genes flagged by the same statistical filtration for V:Zn ratios, 12 genes were identified. The hierarchical clustering analysis showed that these 12 genes discriminated V from Zn and consisted of two clusters. Cluster 1 genes (ZBTB1, PML, ZNF44, SIX1, BCL6, ZNF450) were down-regulated by V and involved in gene transcription, whereas cluster 2 genes (IL8, IL1A, PTGS2, DTR, TNFAIP3, CXCL3) were up-regulated and linked to inflammatory response and cell proliferation. Also, metallothionein 1 genes (MT1F, MT1G, MT1K) were up-regulated by Zn only. Thus, using microarray analysis, we identified a small set of genes that may be used as biomarkers for discriminating V from Zn. The novel genes and pathways identified by the microarray may help us understand the pathogenesis of health effects caused by environmental V and Zn exposure.

Bronchi↗
PubMed2003

Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.

It has been much disputed whether or not stress can cause hair loss (telogen effluvium) in a clinically relevant manner. Despite the paramount psychosocial importance of hair in human society, this central, yet enigmatic and controversial problem of clinically applied stress research has not been systematically studied in appropriate animal models. We now show that psychoemotional stress indeed alters actual hair follicle (HF) cycling in vivo, ie, prematurely terminates the normal duration of active hair growth (anagen) in mice. Further, inflammatory events deleterious to the HF are present in the HF environment of stressed mice (perifollicular macrophage cluster, excessive mast cell activation). This provides the first solid pathophysiological mechanism for how stress may actually cause telogen effluvium, ie, by hair cycle manipulation and neuroimmunological events that combine to terminate anagen. Furthermore, we show that most of these hair growth-inhibitory effects of stress can be reproduced by the proteotypic stress-related neuropeptide substance P in nonstressed mice, and can be counteracted effectively by co-administration of a specific substance P receptor antagonist in stressed mice. This offers the first convincing rationale how stress-induced hair loss in men may be pharmacologically managed effectively.

Acoustic Stimulation↗
PubMed2003

The proteasome system and proteasome inhibitors in stroke: controlling the inflammatory response.

The ubiquitin-proteasome pathway (UPP) is a predominantly non-lysosomal protein degradation pathway responsible for degrading many critical regulatory proteins (e.g., nuclear factor-kappa B). This pathway is widely known for its ubiquitous role in immune and inflammatory responses, control of cell growth and apoptosis. These roles are apparent in the nervous system, but neurons and their neighboring cells also employ the UPP for distinct functions, ranging from development to the co-ordination of cellular responses, injury of the nervous system and brain-specific processes such as aging and memory. Promising results from preclinical studies in animal models indicate that the use of specific proteasome inhibitors to manipulate UPP may prove valuable in treating such conditions as ischemic stroke.

Animals↗
PubMed2004

Myocardial fibrosis and diastolic dysfunction in deoxycorticosterone acetate-salt hypertensive rats is ameliorated by the peroxisome proliferator-activated receptor-alpha activator fenofibrate, partly by suppressing inflammatory responses associated with the nuclear factor-kappa-B pathway.

OBJECTIVES: We sought to clarify that a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activator inhibits myocardial fibrosis and its resultant diastolic dysfunction in hypertensive heart disease, as well as to investigate whether inflammatory mediators through the nuclear factor (NF)-kappa-B pathway are involved in the effects. BACKGROUND: Patients with hypertensive heart disease often have diastolic heart failure without systolic dysfunction. Meanwhile, it has been well established in atherosclerosis that PPAR-alpha activation negatively regulates early inflammation. In hypertensive hearts, however, it is still unclear whether PPAR-alpha activation inhibits inflammation and fibrosis. METHODS: Twenty-one rats were randomly separated into the following three groups: deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with a PPAR-alpha activator, fenofibrate (80 mg/kg/day for 5 weeks); DOCA-salt rats treated with vehicle only; and uni-nephrectomized rats as normotensive controls. RESULTS: Fenofibrate significantly inhibited the elevation of left ventricular end-diastolic pressure and the reduction of the magnitude of the negative maximum rate of left ventricular pressure rise and decline, corrected by left ventricular pressure (-dP/dt(max)/P), which are indicators of diastolic dysfunction. Next, fenofibrate prevented myocardial fibrosis and reduced the hydroxyproline content and procollagen I and III messenger ribonucleic acid expression. Finally, inflammatory gene expression associated with NF-kappa-B (interleukin-6, cyclooxygenase-2, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1), which is upregulated in DOCA-salt rats, was significantly suppressed by fenofibrate. Activation of NF-kappa-B and expression of I-kappa-B-alpha in DOCA-salt rats were normalized by fenofibrate. CONCLUSIONS: A PPAR-alpha activator reduced myocardial fibrosis and prevented the development of diastolic dysfunction in DOCA-salt rats. The effects of a PPAR-alpha activator may be mediated partly by prevention of inflammatory mediators through the NF-kappa-B pathway. These results suggest that treatment with PPAR-alpha activators will improve diastolic dysfunction in hypertensive heart disease.

Animals↗
PubMed2006

Mitogen activated protein kinase p38 pathway is an important component of the anti-inflammatory response in Mycobacterium avium subsp. paratuberculosis-infected bovine monocytes.

We investigated the role of cell signaling through the mitogen-activated protein kinase-p38 (MAPK p38) pathway on the antimicrobial functions and cytokine expression by bovine monocytes after ingestion of Mycobacterium avium subsp. paratuberculosis. We evaluated the dynamic secretion of interleukin (IL)-10, IL-12 and tumor necrosis factor-alpha (TNF-alpha) as well as phagosome acidification and organism killing at several time points after in vitro infection of bovine monocytes with M. avium subsp. paratuberculosis. Monocytes treated with M. avium subsp. paratuberculosis had a significant increase in IL-10 expression at 2, 4, and 6h post-infection and an increase expression of TNF-alpha at 2, 4, 6, and 24h post-infection. In contrast, IL-12 expression did not increase at any time point post-infection. Moreover, MAPK p38 was rapidly phosphorylated at 10 and 60 min after M. avium subsp. paratuberculosis ingestion. Chemical inhibition of the MAPK p38 signaling pathway (SB203580) resulted in decreased expression of IL-10 and increased expression of IL-12 at 6h post-infection. Chemically blocking the MAPK p38 pathway also increased acidification of phagosomes as well as increasing the capacity of macrophages to kill organisms. Taken together, these results indicated that selective activation of MAPK p38 may be a major mechanism exploited by M. avium subsp. paratuberculosis to circumvent the antimycobacterial effects of mononuclear phagocytes.

Animals↗
PubMed2003

Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia.

Inflammatory and procoagulant host responses are closely related in sepsis. The protein C pathway serves as a regulatory pathway with anti-inflammatory and anticoagulant properties. Recently, recombinant human activated protein C (rhAPC) was shown to reduce mortality in severe sepsis. Nevertheless, the effects of rhAPC in humans are still ill defined. The infusion of low endotoxin doses into humans provides a standardized model to study inflammatory and hemostatic mechanisms. Thus, we investigated whether rhAPC acts as an anticoagulant or anti-inflammatory drug in human endotoxemia. There were 24 volunteers randomized to receive either 24 microg/kg per hour rhAPC or placebo intravenously for 8 hours. Lipopolysaccharide (LPS, 2 ng/kg) was administered 2 hours after starting the infusions. rhAPC decreased basal tissue factor (TF)-mRNA expression, and thrombin formation and action. In contrast, rhAPC did not significantly blunt LPS-induced thrombin generation. Consistently, rhAPC did not reduce LPS-induced levels of TF-mRNA or D-dimer and had no effect on fibrinolytic activity or inflammation. Finally, endogenous APC formation was enhanced during endotoxemia and appeared to be associated with inflammation rather than thrombin formation. In conclusion, even low-grade endotoxemia induces significant protein C activation. Infusion of rhAPC decreases "spontaneous" activation of coagulation but does not blunt LPS-induced, TF-mediated coagulation in healthy volunteers, which is in contrast to a number of anticoagulants.

Acute Disease↗
PubMed1999

[The role of MAP kinases and inducible transcription factors in the regulation of cell death and survival].

Cell growth and survival are constantly promoted and modulated by a variety of extracellular stimuli. Modules of sequentially activating protein kinases serve as important routes for the intracellular transmission of signals from diverse stimuli to nucleus. The Raf signaling involving Mitogen-Activated Protein (MAP) kinases is a key element of mitogenic stimulation. The c-Jun N-terminal kinases (JNKs) are activated in cells in response to cytokines, stress or proapoptotic stimuli, indicating that this signaling pathway may contribute to inflammatory and cell death phenomena. Cross-talk between different MAP kinase signaling pathways determines cellular responses in stress, apoptosis and normal physiological processes.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2006

Effects of brief cutaneous JP-8 jet fuel exposures on time course of gene expression in the epidermis.

The jet fuel jet propulsion fuel 8 (JP-8) has been shown to cause an inflammatory response in the skin, which is characterized histologically by erythema, edema, and hyperplasia. Studies in laboratory animal skin and cultured keratinocytes have identified a variety of changes in protein levels related to inflammation, oxidative damage, apoptosis, and cellular growth. Most of these studies have focused on prolonged exposures and subsequent effects. In an attempt to understand the earliest responses of the skin to JP-8, we have investigated changes in gene expression in the epidermis for up to 8 h after a 1-h cutaneous exposure in rats. After exposure, we separated the epidermis from the rest of the skin with a cryotome and isolated total mRNA. Gene expression was studied with microarray techniques, and changes from sham treatments were analyzed and characterized. We found consistent twofold increases in gene expression of 27 transcripts at 1, 4, and 8 h after the beginning of the 1-h exposure that were related primarily to structural proteins, cell signaling, inflammatory mediators, growth factors, and enzymes. Analysis of pathways changed showed that several signaling pathways were increased at 1 h and that the most significant changes at 8 h were in metabolic pathways, many of which were downregulated. These results confirm and expand many of the previous molecular studies with JP-8. Based on the 1-h changes in gene expression, we hypothesize that the trigger of the JP-8-induced, epidermal stress response is a physical disruption of osmotic, oxidative, and membrane stability which activates gene expression in the signaling pathways and results in the inflammatory, apoptotic, and growth responses that have been previously identified.

Administration, Cutaneous↗
PubMed2002

Soluble fibrinogen modulates neutrophil functionality through the activation of an extracellular signal-regulated kinase-dependent pathway.

The integrin family not only mediates the recruitment of polymorphonuclear leukocytes (PMN) to sites of inflammation but also regulates several effector functions by binding to specific ligands. We have recently demonstrated that soluble fibrinogen (sFbg) is able to trigger an activating signal in PMN through an integrin-dependent mechanism. This activation results in degranulation, phagocytosis enhancement, and apoptosis delay. The aim of the present work was to further elucidate the molecular events that follow sFbg interaction with CD11b in human PMN, and the participation of this signaling pathway in the regulation of neutrophil functionality. We demonstrate that sFbg triggers a cascade of intracellular signals that lead to focal adhesion kinase and extracellular signal-regulated kinase 1/2 tyrosine phosphorylation. The activation of this mitogen-activated protein kinase pathway plays a central role in the sFbg modulation of secondary granule degranulation, Ab-dependent phagocytosis, and apoptosis. However, fibrinogen-induced secretory vesicle degranulation occurs independently of the signaling transduction pathways investigated herein. In the context of an inflammatory process, the intracellular signal pathway activated by sFbg may be an early event influencing the functionality of PMN.

Apoptosis↗
PubMed2003

Study of the pathogenesis of paralytic ileus in animal models of experimentally induced postoperative and septic ileus.

Paralytic ileus is defined as an inhibition of propulsive intestinal motility. Postoperative ileus is the most common type, however, also during sepsis and critical illness paralytic ileus is a common finding. The pathogenesis of paralytic ileus is still debated. It is believed to result from the activation of inhibitory neural reflex pathways and activation of inflammatory processes. It is generally accepted that postoperative ileus results from the activation of an inhibitory neural reflex pathway. In our rat model we showed that different degrees of nociceptive stimulation activate different reflex pathways: laparatomy activates an adrenergic inhibitory reflex pathway, whereas manipulation results in additional activation of inhibitory NANC neurons releasing NO and VIP as neurotransmitters. We also demonstrated that blockade of the afferent limb of the reflex pathway by peripheral kappa-opioid agonists or by non-steroidal anti-inflammatory drugs ameliorated postoperative ileus. However, the use of prokinetics lead to disappointing results. In the murine septic model we demonstrated an important role for activation of inducible NO synthase in the endotoxin-induced delay in gastric emptying and small intestinal transit. We hypothesise that activation of the residential macrophages in the gut wall leads to the production of iNOS and other inflammatory mediators. These mediators will attract more inflammatory cells and influence smooth muscle contractility. Next, we provide evidence that production of iNOS results in the activation of guanylyl cyclase leading to the production of cGMP and smooth muscle relaxation. However, a parallel mechanism of action for NO via oxidative stress needs further investigation.

Animals↗
PubMed1990

Activation of the alternative pathway of complement in psoriatic lesional skin.

The complement system may play an important role in the inflammatory reaction of psoriasis. While the classical pathway of the complement has been shown to be activated in psoriasis, there have been few reports on the involvement of the alternative pathway in the inflammatory reactions in psoriasis. Complement fragments, C4d and Bb, are released at the time of the classical and alternative pathway activation, respectively. The presence of the C4d or Bb fragment, therefore, denotes a preceding complement activation through the classical and/or alternative pathway. In the present study, we have measured the levels of C4d and Bb in psoriatic scale extracts using enzyme immunoassay techniques. The scales of these dermatoses contained higher levels of C4d and Bb detectable by enzyme immunoassay than those in the stratum corneum of noninflammatory skin. These results suggest that the alternative as well as the classical pathway of complement are activated in psoriatic lesional skin.

Complement Activation↗
PubMed2005

Fludarabine induces pro-inflammatory activation of human monocytic cells through a MAPK/ERK pathway.

Fludarabine is a nucleoside analogue that has been successfully employed for the treatment of low-grade lymphoid malignancies and, more recently, in nonmyeloablative preparative regimens for stem cell transplantation, due to its strong cytotoxic activity on lymphocytes. In this paper, we show that fludarabine can also induce pro-inflammatory stimulation of monocytic cells, as evaluated by increased expression of ICAM-1 and IL-8 release. To study the mechanisms involved, we employed selective inhibitors of MAPK and NF-kappaB pathways, both of which have been implicated in the modulation of ICAM-1 and IL-8. Our results showed that fludarabine effects were mediated through the activation of ERK and were independent on p38, JNK or NF-kappaB pathways. By Western blotting analysis we corroborated that fludarabine induced a rapid activation of ERK that was sustained for at least 30 min. Moreover, pro-inflammatory activation of monocytic cells by fludarabine was largely attenuated by coadministration of the free radical scavenger N-acetylcysteine suggesting the involvement of reactive oxygen species in fludarabine effects. Finally, we showed that fludarabine induced the activation of the transcription factor AP-1 not only in monocytic cells but also in non-proliferating lymphocytes from chronic lymphocytic leukemia. It is possible that some of fludarabine side effects in vivo may be attributed to cell activation/differentiation rather than induction of apoptosis.

Antineoplastic Agents↗
PubMed1999

[Intracellular signalization and inflammation: variations for an intracellular symphony. 1st movement].

Inflammatory response involves complex signalling pathways at cellular and molecular levels. During the cellular activation, intracellular substrates are subsequently phosphorylated for inducing transcription and synthesis of various inflammatory and/or anti-inflammatory mediators. This review focuses on the description of the main mechanisms involved in the activation signalling pathways that occur during inflammatory processes.

Acute Disease↗
PubMed2006

Antioxidant and cytoprotective properties of high-density lipoproteins in vascular cells.

Beside their key role in the regulation of cholesterol homeostasis, HDL exhibit antioxidant and anti-inflammatory properties that participate to their general antiatherogenic effect. The purpose of this review is to summarize the recent findings on antioxidant activity and cytoprotective cell signalling elicited by HDL against oxidized LDL and proatherogenic agents in vascular cells. HDL exhibit an antioxidant activity efficient to prevent LDL oxidation, or to inactivate newly formed lipid oxidation products. The antioxidant ability of HDL is due to the apoprotein moiety and to the presence of associated enzymes, paraoxonase and PAF-Acetyl Hydrolase. HDL prevent the intracellular oxidative stress and the inflammatory response elicited by oxidized LDL (ox-LDL), by inhibiting the NFkappaB signalling pathway, and the subsequent inflammatory events (expression of adhesion molecules, recruitment and proliferation of mononuclear cells within the vascular wall). HDL prevent ox-LDL-mediated cell activation and proliferation, this being also attributed to the presence in HDL of sphingosine-1 phosphate which modulates the migration and survival of vascular cells. Lastly, HDL inhibit apoptosis elicited by ox-LDL in vascular cells. Recent evidences indicate that, beside their strong antiatherogenic properties, HDL could exert their protective effect in diseases generally associated to inflammatory events.

Animals↗
PubMed2005

Gene expression profiling of dexamethasone-treated RBL-2H3 cells: induction of anti-inflammatory molecules.

Glucocorticoids are well known for their anti-inflammatory effect through the regulation of gene expression in many types of immune cells, including mast cells. However, the genes that are involved in suppression of mast cell-mediated inflammation by glucocorticoids have not been fully identified. Therefore, we examined the dexamethasone (Dex)-responsive genes in RBL-2H3 mast cells using a high-density oligonucleotide microarray technique. Gene expression profiling revealed that the antigen-induced up-regulation of pro-inflammatory factors, including monocyte chemoattractant protein-1, was markedly inhibited by 100 nM Dex. On the other hand, Dex treatment itself caused the substantial up-regulation of many genes, including phenylethanolamine-N-methyl transferase (PNMT) and cytokine-inducible SH2-containing protein (CISH), in the mast cells. The expression of these two genes significantly increased 6 h after Dex exposure and lasted for more than 24 h. Considering that PNMT is the rate-determining enzyme in epinephrine synthesis and that CISH is a suppressor of cytokine signaling, these Dex-responsive genes may be potential anti-inflammatory factors. Thus, gene expression profiling suggested that Dex might exert its anti-inflammatory effect through two pathways in mast cells: the suppression and induction of potentially pro- and anti-inflammatory factors, respectively.

Animals↗
PubMed2003

Cytokine induction of prolactin receptors mediates prolactin inhibition of nitric oxide synthesis in pulmonary fibroblasts.

Prolactin (PRL) has been implicated as a modulator of immune function, and some of its actions may be linked to NO synthesis. Because NO acts as a mediator of inflammation, we speculated that an inflammatory milieu could unmask pathways by which PRL could affect NO synthesis. Here, we show that pro-inflammatory cytokines induce the expression of PRL receptors in pulmonary fibroblasts, allowing PRL to inhibit cytokine-induced NO production and the expression of the inducible nitric oxide synthase (iNOS). Inhibition of iNOS expression by PRL correlates with the phosphorylation of STAT-5b (signal transducer and activator of transcription 5b) and the suppression of expression of IRF-1 (interferon regulatory factor 1), a transcription factor for iNOS. These results reveal previously unrecognized mechanisms by which PRL and PRL receptors may play significant modulatory roles during immune-inflammatory processes.

Animals↗