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 1,189 records · Page 66Linked to original sources
PubMed2003

Emerging treatments for asthma.

Despite the availability of a great number of medications, the asthma epidemic is continuing to increase. It is obvious that a high, unmet medical need remains and innovative therapeutic agents are urgently required. Existing therapies, such as beta-agonists and corticosteroids, provide relief for sufferers of mild-to-moderate asthma, reversing the acute bronchoconstriction and decreasing the inflammation. However, these therapies provide little relief for chronic asthmatics. Asthma is a manifestation of an imbalance in cytokine and signalling pathways that mediate inflammatory and structural changes within the lung. New therapies need to be developed to target these changes. Emerging treatments for asthma include strategies to alter the cytokine/chemokine balance, to skew the cytokine profile away from a T helper (Th)2 response and towards a Th1 response. Strategies designed to do this include therapeutic antibodies or small molecule inhibitors targeted towards IL-13, IL-4 or their receptors, and the Th1 cytokine IL-12. Much interest has focused on the signalling pathways involved in asthma. Among these, the mitogen-activated protein kinase (MAPK) pathway members c-Jun N-terminal kinase (JNK) and p38 have gathered much interest, in addition to the transcription factors nuclear factor kappaB (NF-kappa B), activator protein-1 (AP-1) and signal transducer and activator of transcription (STAT)-6. This review aims to summarise the emerging treatments for chronic asthma, from early discovery, to late clinical stages, and discuss the therapeutic rationale behind these treatments. Much is still to be learned about the mechanisms involved in the development and treatment of chronic asthma; however, much promise lies in the future of these new therapeutics.

Animals↗
PubMed2001

[Atherothrombosis and inflammation].

Alterations of coagulation, fibrinolysis, platelets and low grade inflammation are causal pathophysiological factors in atherosclerosis. Considerable activation of several involved pathways occurs during the acute progression of atherosclerotic lesions, which is characterized by an occluding thrombus, and local and systemic inflammatory reactions as in patients with acute coronary syndromes. These patients become clinically compromised due to the reduction in coronary flow. Furthermore, a frequent occurrence of non-occluding thrombi may be assumed as a progression factor in atherosclerotic diseases. Both the extrinsic and the intrinsic pathway of coagulation are involved, resulting in a hypercoagulative state. Furthermore, an inflammatory acute phase reaction occurs in addition to the activation of several other inflammatory pathways in patients with unstable angina pectoris or acute myocardial infarction. Exposure of tissue factor by the ruptured plaque together with a systemic hypercoagulative state, local and systemic inflammation as well as stimulated platelets and endothelial dysfunction are involved in the pathophysiology of acute coronary syndromes. In the following paper the current knowledge on activation of these pathways and on the various complex interactions is discussed.

Coronary Artery Disease↗
PubMed2003

Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock.

The lack of efficacy of anti-inflammatory drugs, anti-coagulants, anti-oxidants, etc. in critically ill patients has shifted interest towards developing alternative treatments. Since inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) were found to be beneficial in many pathophysiological conditions associated with oxidative stress and PARP-1 knock-out mice proved to be resistant to bacterial lipopolysaccharide (LPS)-induced septic shock, PARP inhibitors are candidates for such a role. In this study, the mechanism of the protective effect of a potent PARP-1 inhibitor, PJ34 was studied in LPS-induced (20mg/kg, i.p.) septic shock in mice. We demonstrated a significant inflammatory response by magnetic resonance imaging in the dorsal subcutaneous region, in the abdominal regions around the kidneys and in the inter-intestinal cavities. We have found necrotic and apoptotic histological changes as well as obstructed blood vessels in the liver and small intestine. Additionally, we have detected elevated tumor necrosis factor-alpha levels in the serum and nuclear factor kappa B activation in liver of LPS-treated mice. Pre-treating the animals with PJ34 (10mg/kg, i.p.), before the LPS challenge, besides rescuing the animals from LPS-induced death, attenuated all these changes presumably by activating the phosphatidylinositol 3-kinase-Akt/protein kinase B cytoprotective pathway.

Animals↗
PubMed1999

Linkage analysis of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the rat identifies a locus controlling demyelination on chromosome 18.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) with a complex etiology comprising a genetically determined predisposition and a suspected auto- immune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS, which can be used to define susceptibility loci for autoimmune neuroinflammation. We have recently established a chronic relapsing EAE model characterized by inflammation and focal demyelination in the CNS by immunizing a variety of rat strains with the CNS-specific myelin oligodendrocyte glycoprotein (MOG). This model is more MS-like than any other rodent EAE model described up to now. Here we present the first systematic genome search for chromosomal regions linked to phenotypes of MOG-induced EAE in a (DA x ACI) F(2)intercross. A genome-wide significant susceptibility locus linked to demyelination was identified on chromosome 18. This region has not been described in inflammatory diseases affecting other organs and the responsible gene or genes may thus be nervous system specific. Other chromosomal regions showing suggestive linkage to phenotypes of MOG-induced EAE were identified on chromosomes 10, 12 and 13. The chromosome 10 and 12 regions have previously been linked to arthritis in DA rats, suggesting that they harbour immunoregulatory genes controlling general susceptibility to autoimmune diseases. We conclude that identification of susceptibility genes for MOG-induced EAE on rat chromosomes 10, 12, 13 and 18 may disclose important disease pathways for chronic inflammatory demyelinating diseases of the CNS such as MS.

Animals↗
PubMed2000

Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors.

Previous studies have established that cardiomyocytes express protease-activated receptor (PAR)-1, a high-affinity receptor for thrombin, which is also activated by the tethered-ligand domain sequence (SFLLRN) and which promotes inositol trisphosphate accumulation, stimulates extracellular signal-regulated protein kinase, and modulates contractile function. A single previous report identified PAR-1 as a hypertrophic stimulus, but there have been no subsequent investigations of the mechanism. This study reveals the coexpression of PAR-1 and PAR-2 (a second PAR, which is activated by trypsin/tryptase but not thrombin) by Northern blot analysis and compares their signaling properties in neonatal rat ventricular cardiomyocytes. SFLLRN and SLIGRL (an agonist peptide for PAR-2) promote inositol trisphosphate accumulation, stimulate mitogen-activated protein kinases (extracellular signal-regulated protein kinase and p38-mitogen-activated protein kinase), elevate calcium concentration, and increase spontaneous automaticity. SFLLRN (but not SLIGRL) also activates c-Jun NH(2)-terminal kinase and AKT. In keeping with their linkage to pathways that have been associated with growth and/or survival, SFLLRN and SLIGRL both induce hypertrophy. However, PAR agonists promote cell elongation, a morphology that is distinct from the uniform increase in cell dimension induced by alpha(1)-adrenergic receptor activation. These studies provide novel evidence that cardiomyocytes coexpress 2 functional PARs, which link to a common set of signals that culminate in changes in contractile function and hypertrophic growth. PAR actions may assume clinical importance in the border zone surrounding an infarction, where local proteolysis of PARs by serine proteases generated during inflammatory or thrombogenic pathways would elevate calcium concentration (setting the stage for arrhythmias), promote hypertrophic growth, and/or influence cardiomyocyte survival.

Animals↗
PubMed2005

Synergistic induction of tissue factor by coagulation factor Xa and TNF: evidence for involvement of negative regulatory signaling cascades.

Enzymes of the blood coagulation pathway enhance the inflammatory response leading to endothelial dysfunction, accounting, in part, for the vascular complications occurring in sepsis and cardiovascular disease. The responses of endothelial cell activation include induction of the expression of tissue factor (TF), a membrane glycoprotein that promotes thrombosis, and of E-selectin, a cell adhesion molecule that promotes inflammation. In this report, we demonstrate synergistic interactions between the coagulation factor Xa (fXa) and the proinflammatory cytokines TNF, IL-1beta, and CD40L, leading to enhanced expression of TF and E-selectin in endothelial cells. A detailed analysis of the molecular pathways that could account for this activity of fXa showed that fXa inhibited the cytokine-induced expression of dual specificity phosphatases, MAP kinase phosphatase-L, -4, -5, and -7, blocking a negative regulatory effect on c-Jun N-terminal kinase. The synergistic interaction between fXa and TNF was also involved in the inhibition of A20 and IkappaBalpha expression in the IkappaB kinase-NF-kappaB pathway. The data indicate that inhibition of negative regulatory signaling accounts for the amplification of cytokine-induced endothelial cell activation by fXa.

Blood Coagulation↗
PubMed2005

Polyunsaturated fatty acids improve exercise capacity in chronic obstructive pulmonary disease.

BACKGROUND: Muscle wasting and decreased muscle oxidative capacity commonly occur in patients with chronic obstructive pulmonary disease (COPD). Polyunsaturated fatty acids (PUFA) have been shown to mediate several inflammatory and metabolic pathways which may be involved in the pathogenesis of muscle impairment in COPD. The aim of this study was to investigate the effect of PUFA modulation on systemic inflammation, reversal of muscle wasting, and functional status in COPD. METHODS: Eighty patients with COPD (57 men) with forced expiratory volume in 1 second (FEV1) 37.3 (13.8)% predicted received 9 g PUFA or placebo daily in a double blind randomised fashion during an 8 week rehabilitation programme. Body composition (bioelectrical impedance), functional capacity (lung function, incremental cycle ergometry test, submaximal cycle test, isokinetic quadriceps strength) and inflammatory markers (C-reactive protein (CRP), interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha) were assessed at baseline and after 8 weeks. RESULTS: Both groups had similar increases in weight, fat-free mass (FFM), and muscle strength. The peak load of the incremental exercise test increased more in the PUFA group than in the placebo group (difference in increase 9.7 W (95% CI 2.5 to 17.0), p = 0.009) even after adjustment for FFM. The duration of the constant work rate test also increased more in patients receiving PUFA (difference in increase 4.3 min (95% CI 0.6 to 7.9), p = 0.023). The positive effects of PUFA could not be attributed to a decrease in systemic levels of CRP, IL-6 and TNF-alpha. CONCLUSIONS: This is the first study to show beneficial effects of PUFA on exercise capacity in patients with COPD.

C-Reactive Protein↗
PubMed2005

Chemokine production and E-selectin expression in activated endothelial cells are inhibited by p38 MAPK (mitogen activated protein kinase) inhibitor RWJ 67657.

Endothelial cells play an important role in inflammatory diseases like rheumatoid arthritis by recruitment of inflammatory cells. The cytokines TNF-alpha and IL-1beta are major inducers of endothelial cell activation and are stimulators of inflammatory signal transduction pathway involving p38 MAPK (mitogen-activated protein kinase). The present study investigated the effects of p38 MAPK inhibition on cell adhesion molecule (CAM) expression and chemokine production by endothelial cells both on mRNA and protein level. Pre-treatment of endothelial cells with the pharmacologically relevant concentration of 1 microM of the p38 MAPK inhibitor RWJ 67657 reduced TNF-alpha and IL-1beta induced mRNA and membrane expression of E-selectin. Moderate inhibitory effects on ICAM-1 and VCAM-1 expression were found. Significant reduction of mRNA expression and protein production of the inflammatory cytokine IL-6 and the chemokines IL-8 and MCP-1 was demonstrated. Treatment with RWJ 67657 could lead to reduced leukocyte infiltration by the reduction of E-selectin expression and chemokine production.

Cells, Cultured↗
PubMed2006

Protein kinase Czeta is up-regulated in osteoarthritic cartilage and is required for activation of NF-kappaB by tumor necrosis factor and interleukin-1 in articular chondrocytes.

Protein kinase Czeta (PKCzeta) is an intracellular serine/threonine protein kinase that has been implicated in the signaling pathways for certain inflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), in some cell types. A study of gene expression in articular chondrocytes from osteoarthritis (OA) patients revealed that PKCzeta is transcriptionally up-regulated in human OA articular cartilage clinical samples. This finding led to the hypothesis that PKCzeta may be an important signaling component of cytokine-mediated cartilage matrix destruction in articular chondrocytes, believed to be an underlying factor in the pathophysiology of OA. IL-1 treatment of chondrocytes in culture resulted in rapidly increased phosphorylation of PKCzeta, implicating PKCzeta activation in the signaling pathway. Chondrocyte cell-based assays were used to evaluate the contribution of PKCzeta activity in NF-kappaB activation and extracellular matrix degradation mediated by IL-1, TNF, or sphingomyelinase. In primary chondrocytes, IL-1 and TNF-alpha caused an increase in NF-kappaB activity resulting in induction of aggrecanase-1 and aggrecanase-2 expression, with consequent increased proteoglycan degradation. This effect was blocked by the pan-specific PKC inhibitors RO 31-8220 and bisindolylmaleimide I, partially blocked by Gö 6976, and was unaffected by the PKCzeta-sparing inhibitor calphostin C. A cell-permeable PKCzeta pseudosubstrate peptide inhibitor was capable of blocking TNFand IL-1-mediated NF-kappaB activation and proteoglycan degradation in chondrocyte pellet cultures. In addition, overexpression of a dominant negative PKCzeta protein effectively prevented cytokine-mediated NF-kappaB activation in primary chondrocytes. These data implicate PKCzeta as a necessary component of the IL-1 and TNF signaling pathways in chondrocytes that result in catabolic destruction of extracellular matrix proteins in osteoarthritic cartilage.

ADAM Proteins↗
PubMed2001

Methamphetamine induces AP-1 and NF-kappaB binding and transactivation in human brain endothelial cells.

Cellular and molecular mechanisms of methamphetamine (METH)-induced neurotoxicity may involve alterations of cellular redox status and induction of inflammatory genes in endothelial cells. To study these hypotheses, molecular signaling pathways of METH-induced inflammatory responses via activation of redox-sensitive transcription factors were investigated in human brain microvascular endothelial cells (HBMEC). A dose-dependent depletion of total glutathione levels was detected in HBMEC exposed to METH. In addition, electrophoretic mobility shift assay (EMSA) showed significant increases in DNA binding activities of redox-responsive transcription factors, AP-1 and NF-kappaB, in HBMEC treated with METH. METH-mediated AP-1 or NF-kappaB activation was accompanied by induction of transactivation of AP-1 or NF-kappaB, as measured by dual luciferase assay using specific reporter plasmids. Because NF-kappaB and AP-1 are known to regulate expression of inflammatory genes, expression of the gene encoding for tumor necrosis factor-alpha (TNF-alpha) was also studied in METH-treated HBMEC. A dose-dependent overexpression of the TNF-alpha gene was observed in HBMEC treated with METH. The importance of AP-1 and NF-kappaB in METH-induced TNF-alpha gene was confirmed in functional promoter studies using constructs of the TNF-alpha promoter with mutated AP-1 or NF-kappaB sites. These results indicate that METH-induced disturbances in cellular redox status and activation of AP-1 and NF-kappaB can play critical roles in the signaling pathways leading to upregulation of inflammatory genes in human brain endothelial cells.

Amphetamine-Related Disorders↗
PubMed2005

Changes of 5-lipoxygenase pathway and proinflammatory mediators in cerebral cortex and lung tissue of sensitized rats.

AIM: To explore the change of 5-lipoxygenase (5-LO) pathway expression and proinflammatory mediators level of lung tissue and cerebral cortex, and the possible regulatory mechanism through central nervous 5-LO pathways to pulmonary inflammatory status in antigen repeated challenged rats. METHODS: Four groups of rats were treated as control, asthma model, asthma model treatment with dexamethasone (DXM, 0.5 mg/kg, i.p.) and ketotifen (5 mg/kg, i.g.). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, interferon (IFN)-gamma, and nitric oxide (NO) were detected by ELISA kits. The mRNA expression of 5-LO and LTA4-hydrolase (LTA4-H) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), and the protein content of 5-LO was measured by Western blot. RESULTS: Increase of TNF-alpha, IL-4, NO level, and decrease of IFN-gamma level in bronchoalveolar lavage fluid (BALF) and cerebral cortex in sensitized rats were shown after repeated antigen challenge. The expression of 5-LO and LTA4-H mRNA, and 5-LO protein levels were increased in lung tissue and cerebral cortex in asthma rats. In comparison with the asthma model, DXM significantly inhibited the increase of cytokine levels and the expression of 5-LO pathway enzyme (P<0.05). Ketotifen also inhibited the increase of TNF-alpha level and 5-LO pathway enzyme expression in lung and cerebral cortex, but had no effect on the level of NO, IL-4, and IFN-gamma. CONCLUSION: The correlative increase of 5-LO pathway enzyme expression and proinflammatory mediators of brain may have a regulatory effect on pulmonary inflammation in asthma.

Animals↗
PubMed2026

Transcriptomic changes in the gut mucosa of fasting northern elephant seal pups reveal immune modulation during early microbiome establishment.

Fasting is an integral component of the life-history of many species. Following abrupt weaning, northern elephant seal pups (Mirounga angustirostris) undergo an extended post-weaning fast of approximately 60&#xa0;days. During this period, enteric bacterial diversity increases, suggesting that host immune regulation may facilitate the establishment of microbial communities. However, the molecular processes occurring within the intestinal mucosa during this transition remain poorly understood. To investigate these mechanisms, we characterized transcriptional changes in the enteric mucosa of male and female northern elephant seal pups sampled at weaning and after one month of fasting. Total RNA isolated from rectal swabs was sequenced and aligned to the Mirounga angustirostris reference genome. Differential gene expression and gene set enrichment analyses were used to identify genes and pathways associated with fasting and sex-specific responses. Fasting was accompanied primarily by transcriptional downregulation, including genes involved in antimicrobial defense, inflammation, protein turnover, and epithelial remodeling. In contrast, several genes associated with B-cell activity and immune recognition were upregulated. Gene Set Enrichment Analysis revealed coordinated activation of immune-regulatory pathways indicating dynamic modulation of intestinal immunity rather than generalized immune suppression. Pronounced sex-specific differences were also observed. Male pups exhibited transcriptional patterns consistent with enhanced immune tolerance, whereas females showed broader immune-pathway activation, including enrichment of pro-inflammatory and stress-response pathways. Several non-coding RNAs also displayed sex-specific changes in expression. Together, these findings suggest that fasting induces transcriptional remodeling of the gut and may contribute to immune regulation during a critical period of microbiome establishment in northern elephant seal pups.

Animals↗
PubMed2005

The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer's disease: therapeutic implications.

The amyloid plaques in Alzheimer's disease (AD) brains are co-localised with a broad variety of inflammation-related proteins (complement proteins, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the Abeta depositions in the neuroparenchyma are closely associated with a locally-induced, non-immune-mediated chronic inflammatory response. Clinicopathological and neuroradiological data show that activation of microglia are a relatively early pathogenic event that precedes the process of severe neuropil destruction in patients. Recent gene findings (cDNA microarray) confirm the immunohistochemical findings of an early involvement of inflammatory and regenerative pathways in AD pathogenesis. Abeta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mice models harbouring the pathological AD mutations, while "later" neurodegenerative characteristics are not seen in these models. Next to the plaques, Abeta amyloid deposition is frequently found in the walls of cerebral vessels (cerebral amyloid angiopathy). Most common is the type of amyloid deposition in the walls of meningeal and medium-sized cortical arteries, and more rarely, microcapillary amyloid angiopathy (dyshoric angiopathy). Immunohistochemical studies show that in AD patients, the majority of the amyloid deposits in the walls of the larger vessels is not associated with a chronic inflammatory response in contrast to micro-capillary amyloid angiopathy. In this contribution, we will give an overview of the similarities and differences between the involvement of inflammatory mechanisms in vascular and plaque amyloid in AD and transgenic models. The implications of the reviewed studies for an inflammation-based therapeutical approach in AD will be discussed.

Alzheimer Disease↗
PubMed1993

Nimesulide as a downregulator of the activity of the neutrophil myeloperoxidase pathway. Focus on the histoprotective potential of the drug during inflammatory processes.

Neutrophils, recruited to tissue sites of inflammation, release a variety of oxidants and enzymes, which are responsible for tissue damage. Among the oxidants released are potent chlorinated compounds, such as hypochlorous acid and chloramines, which induce tissue cell damage and inactivate protease inhibitors, particularly alpha 1-antitrypsin, the specific inhibitor of neutrophil elastase. In studying a rational approach to the pharmacological control of neutrophil-mediated tissue injury, we investigated the activity of the anti-inflammatory drug nimesulide. This agent reduced the function of the myeloperoxidase pathway (which generates hypochlorous acid), by exerting a cell-directed inhibitory activity, as shown by measurement of superoxide anion and hydrogen peroxide production. Nimesulide also inactivated hypochlorous acid directly and protected alpha 1-antitrypsin from the neutrophil-mediated oxidation. Thus, neutrophil elastolytic activity may be attenuated by nimesulide-spared alpha 1-antitrypsin. The prevention of oxidative inactivation of alpha 1-antitrypsin by nimesulide strictly correlates with the drug's ability to suppress the extracellular availability of hypochlorous acid. Taken together, these data suggest that nimesulide may prevent tissue injury at sites of inflammation by maintaining natural host protective systems.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Nociceptor sensitization by extracellular signal-regulated kinases.

Inflammatory pain, characterized by a decrease in mechanical nociceptive threshold (hyperalgesia), arises through actions of inflammatory mediators, many of which sensitize primary afferent nociceptors via G-protein-coupled receptors. Two signaling pathways, one involving protein kinase A (PKA) and one involving the epsilon isozyme of protein kinase C (PKCepsilon), have been implicated in primary afferent nociceptor sensitization. Here we describe a third, independent pathway that involves activation of extracellular signal-regulated kinases (ERKs) 1 and 2. Epinephrine, which induces hyperalgesia by direct action at beta(2)-adrenergic receptors on primary afferent nociceptors, stimulated phosphorylation of ERK1/2 in cultured rat dorsal root ganglion cells. This was inhibited by a beta(2)-adrenergic receptor blocker and by an inhibitor of mitogen and extracellular signal-regulated kinase kinase (MEK), which phosphorylates and activates ERK1/2. Inhibitors of G(i/o)-proteins, Ras farnesyltransferases, and MEK decreased epinephrine-induced hyper-algesia. In a similar manner, phosphorylation of ERK1/2 was also decreased by these inhibitors. Local injection of dominant active MEK produced hyperalgesia that was unaffected by PKA or PKCepsilon inhibitors. Conversely, hyperalgesia produced by agents that activate PKA or PKCepsilon was unaffected by MEK inhibitors. We conclude that a Ras-MEK-ERK1/2 cascade acts independent of PKA or PKCepsilon as a novel signaling pathway for the production of inflammatory pain. This pathway may present a target for a new class of analgesic agents.

Adrenergic beta-2 Receptor Antagonists↗
PubMed2005

Future treatment of osteoarthritis.

Osteoarthritis represents an advanced stage of disease progression caused in part by injury, loss of cartilage structure and function, and an imbalance in inflammatory and noninflammatory pathways. The burden of this disease will increase in direct proportion to the increase in the older adult population. Research on current and experimental treatment protocols are reviewed, including the effect of hyaluronic acid in both in vitro and in vivo studies, autologous chondrocyte and osteochondral plug implantation, and gene therapy. Disease-modifying osteoarthritis drugs and in vivo studies of glucosamine and chondroitin sulfate are reviewed.

Adjuvants, Immunologic↗
PubMed2006

Pancreatic regeneration in chronic pancreatitis requires activation of the notch signaling pathway.

Chronic pancreatitis as an inflammatory process characterized by morphological changes, pancreatic dysfunction, and pain. During pancreatic injury and repair the Notch signaling pathway is reinstated. The current study analyzed this pathway in chronic pancreatitis and characterized its influence on fibrogenesis. Real-time quantitative PCR and immunohistochemistry were used for expression studies. Notch activation was determined by a specific luciferase-HES-1-reporter gene constructs. Cells were stimulated with alcohol, glucose, bile acids, and steroids. Notch-2, -3, and -4 mRNA, were overexpressed in chronic pancreatitis specimens. The ligands Jagged-1, -2, and Delta-1 were highly overexpressed. Jagged-1 and Notch receptors were observed in nerves, regenerating exocrine cells, and endocrine cells. Delta staining was present in ductal but not in acinus cells and not in nerves. Activation of Notch signaling was detectable upon cell stimulation with glucose, steroids, and bile acids. High glucose levels were further associated with increased collagen-I production. The Notch pathway is reactivated during chronic pancreatitis. Among the stimuli activating the Notch pathway are steroids, high glucose levels, and bile acids. These findings suggest a possible role of the Notch pathway during pancreatic regeneration since Jagged-1 inhibits inducible collagen-1 production, suggesting a new mechanism of tissue repair in this disease.

Animals↗
PubMed1987

Lipoxygenase pathway inhibition impairs the allograft response.

The inflammatory response may play a critical role in determining the ultimate fate of the allograft. Certain inflammatory mediators derived from the arachidonic acid lipoxygenase pathway (e.g., leukotriene B4), stimulate T cell function in vitro, but their role in allograft rejection is unknown. Nordihydroguaiaretic acid (NDGA) inhibits both the lipoxygenase (LO) pathway and T cell function in vitro. In this study, we investigated the effects of systemic LO inhibition with NDGA on the in vivo generation of allospecific and natural killer (NK) effector cells and arachidonic acid metabolites from sponge matrix allografts in mice. In control animals, generation of both allospecific cytolytic and NK cells increased progressively up to 12 days after grafting. Sponge cell synthesis of both leukotriene B4 (LTB4) and the cyclooxygenase product prostaglandin E2 (PGE2) could also be detected over this period. Recipient NDGA treatment (50 mg/kg/day) impaired both the accumulation and the specific cytotoxic potential of lymphocytes in allograft. Compared with control animals (1196 +/- 30 pg/10(6) cells), cells from recipients of NDGA produced significantly less LTB4 (55 +/- 10 pg/10(6) cells, p less than 0.01) but produced normal amounts of PGE2 (340 +/- /255 +/- 22 pg/10(6) cells, p = NS), thus proving the specificity of the NDGA treatment on LO pathway function. We conclude that cells capable of metabolizing arachidonic acid by both pathways accumulate in sponge allografts, but LO activity is specifically suppressed by systemic NDGA. Furthermore, systemic LO inhibition reduces the nonspecific inflammatory component, as well as allospecific cytolytic and NK generation, without compromising animal survival. These studies suggest that suppression of specific components of the inflammatory response associated with allograft rejection by LO inhibition may be a useful approach to selective immunosuppression.

Animals↗