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PubMed2006

IL-1beta stimulates rat cardiac fibroblast migration via MAP kinase pathways.

The pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) are elevated following acute myocardial infarction (MI) and have been implicated in the pathophysiology of cardiac disease progression. The cardiac fibroblast represents an important effector cell target for cytokine actions. In particular, cytokine-directed cardiac fibroblast migration is likely to impact both myocardial repair following acute MI and pathological myocardial remodeling in the progression to heart failure. In the present study, we examined the migratory response of neonatal rat cardiac fibroblasts to pro-inflammatory cytokines using modified Boyden chamber assays. On the basis of the knowledge of migration in other cell types, we hypothesized that members of the mitogen-activated protein kinase (MAPK) family may regulate this process. This possibility was addressed with the use of immunoblot detection of active phosphorylated MAPK species and pharmacological inhibitors for individual members of the MAPK cascades. IL-1beta stimulated robust and concentration-dependent increases in migration (maximum, 20-fold over control cells). TNF-alpha had lesser effect (fourfold increase over control). IL-6 did not induce migration. Activation of all three MAPK subfamilies (extracellular signal-regulated kinases, c-Jun NH(2)-terminal kinases, and p38) was shown to occur in response to cytokine stimulation. Fibroblast migration was attenuated by pharmacological inhibition of each MAPK subfamily. Understanding the regulation of cardiac fibroblast migration may provide insights in the search for therapies aimed at enhancing the functional nature of the remodeling process.

Animals↗
PubMed2005

Therapeutic potential of rho-kinase inhibitors in cardiovascular diseases.

Rho-kinase is a signaling molecule that occurs downstream of the small GTPase Rho, which mediates various cellular functions. The Rho/Rho-kinase pathway plays an important role in pathophysiology and progression of various cardiovascular diseases such as hypertension, coronary vasospasm, angina pectoris, and restenosis after percutaneous coronary intervention, all of which are related to arteriosclerosis/atherosclerosis changes of the vasculature. Activation of the Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes of the blood vessels and affects cardiac myocytes. Evidence from in vitro and in vivo studies suggests that Rho-kinase inhibitors have beneficial effects on cardiovascular diseases, particularly arteriosclerosis and coronary vasospasm. Furthermore, activation of the Rho/Rho-kinase pathway contributes to blood pressure regulation via the central sympathetic nervous system. There is evidence to suggest that Rho-kinase is involved in angiotensin II-induced cardiac hypertrophy and endothelial dysfunction, and preliminary data indicate that inhibition of Rho-kinase may be beneficial in vascular disorders such as pulmonary arterial hypertension and erectile dysfunction. Fasudil is currently the only Rho-kinase inhibitor available for clinical use and it is approved in Japan for the prevention of vasospasm in patients with subarachnoid hemorrhage. Emerging clinical data have shown that oral fasudil 80 mg three times daily is effective in preventing myocardial ischemia in patients with stable angina pectoris. Rho-kinase represents a new target for the management of cardiovascular diseases and further studies are needed to define the therapeutic potential of Rho-kinase inhibitors.

Angina Pectoris↗
PubMed1999

Chronic inflammatory ear disease and cholesteatoma: creation of auxiliary attic aeration pathways by microdissection.

HYPOTHESIS: The attic compartments, except for Prussak's space, are aerated through the tympanic isthmus. The aim of this study was to develop aeration pathways that would bypass the isthmus in surgery for chronic inflammatory ear disease and cholesteatoma. BACKGROUND: Microdissection of the epitympanum has shown that the anterior attic and the supratubal recess are separated by the tensor fold, the excision of which creates a large new aeration pathway. METHODS: Earlier surgical experience was reexamined as to the access to the tensor fold. Twenty temporal bones were dissected to create clinically useful new surgical routes for tensor fold removal in the presence of an intact ossicular chain. RESULTS: An endaural atticotomy, extended to the supratubal recess, allows excision of the tensor fold; however, the excision must be performed blindly. Cutting the neck of the malleus to allow lateral lifting of the manubrium exposes the tensor tendon and allows rapid excision of the fold. The elasticity of the tendon assists in approximation of the cut edges. In canal wall up surgery, removal of the lateral attic bone until the root of the zygoma exposes the anterior surface of the head of the malleus and the lateral portion of the transverse crest. Drill-out of the crest leads directly to the posterior side of the tensor fold, allowing its excision under direct vision. Thinning of the attic bone lateral to the body and short process of the incus allows simultaneous removal of the lateral incudomalleal fold. CONCLUSIONS: When the ossicular chain is discontinuous, tensor fold resection can be made under direct vision. With an intact chain, cutting of the neck of the malleus used in tympanic glomus tumors causes no hearing changes, allows complete fold excision, and is adaptable to chronic ear surgery. The frontolateral attic route for removal of tensor fold, together with the lateral incudomalleal fold, can be used in the canal wall up surgery to improve attic aeration.

Cholesteatoma, Middle Ear↗
PubMed2006

Induction of colitis causes inflammatory responses in fat depots: evidence for substance P pathways in human mesenteric preadipocytes.

Intracolonic administration of trinitrobenzene sulfonic acid in mice causes inflammation in the colon that is accompanied by increased expression of proinflammatory cytokines and of the substance P (SP), neurokinin 1 receptor (NK-1R) in the proximal mesenteric fat depot. We also investigated whether human mesenteric preadipocytes contain NK-1R and examined the functional consequences of exposure of these cells to SP as it relates to proinflammatory signaling. We found that human mesenteric preadipocytes express NK-1R both at the mRNA and protein levels. Exposure of human mesenteric preadipocytes to SP increased NK-1R mRNA and protein expression by 3-fold, and stimulated IL-8 mRNA expression and protein secretion. This effect was abolished when these cells were pretreated with the specific NK-1R antagonist CJ 012,255. Moreover, human mesenteric preadipocytes transfected with a luciferase promoter/reporter system containing the IL-8 promoter with a mutated NF-kappaB site lost their ability to respond to SP, indicating that SP-induced IL-8 expression is NF-kappaB-dependent. This report indicates that human mesenteric preadipocytes contain functional SP receptors that are linked to proinflammatory pathways, and that SP can directly increase NK-1R expression. We speculate that mesenteric fat depots may participate in intestinal inflammatory responses via SP-NK-1R-related pathways, as well as other systemic responses to the presence of an ongoing inflammation of the colon.

Abdominal Fat↗
PubMed2005

Modification of environmental toxicity by nutrients: implications in atherosclerosis.

We hypothesize that nutrition can modulate the toxicity of environmental pollutants and thus modulate health and disease outcome associated with chemical insult. There is now increasing evidence that exposure to persistent organic pollutants, such as PCBs, can contribute to the development of inflammatory diseases such as atherosclerosis. Activation, chronic inflammation, and dysfunction of the vascular endothelium are critical events in the initiation and acceleration of atherosclerotic lesion formation. Our studies indicate that an increase in cellular oxidative stress and an imbalance in antioxidant status are critical events in PCB-mediated induction of inflammatory genes and endothelial cell dysfunction. Furthermore, we have found that specific dietary fats can further compromise endothelial dysfunction induced by selected PCBs and that antioxidant nutrients (such as vitamin E and dietary flavonoids) can protect against endothelial cell damage mediated by these persistent organic pollutants. Our recent data suggest that membrane lipid rafts such as caveolae may play a major role in the regulation of PCB-induced inflammatory signaling in endothelial cells. In addition, PCB- and lipid-induced inflammation can be down-regulated by ligands of anti-atherogenic peroxisome proliferator-activated receptors (PPARs). We hypothesize that PCBs contribute to an endothelial inflammatory response in part by down-regulating PPAR signaling. Our data so far support our hypothesis that antioxidant nutrients and related bioactive compounds common in fruits and vegetables protect against environmental toxic insult to the vascular endothelium by down-regulation of signaling pathways involved in inflammatory responses and atherosclerosis. Even though the concept that nutrition may modify or ameliorate the toxicity of environmental chemicals is provocative and warrants further study, the implications for human health could be significant. More research is needed to understand observed interactions of PCB toxicity with nutritional interventions.

Animals↗
PubMed2005

Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia.

Ischemic stroke is one of the main causes of death and disability. We investigated whether melanocortin peptides, which have protective effects in severe hypoxic conditions, also produce neuroprotection in a gerbil model of ischemic stroke. A 10-min period of global cerebral ischemia, induced by occluding both common carotid arteries, caused impairment in spatial learning and memory that was associated with activation of inflammatory and apoptotic pathways, including severe DNA damage and delayed neuronal death, in the hippocampus. Treatment with nanomolar doses of the melanocortin analog [Nle4, D-Phe7] alpha-MSH [which activates the melanocortin receptor subtypes (MC) mainly expressed in central nervous system, namely MC3 and MC4] modulated the inflammatory and apoptotic cascades and reduced hippocampus injuries even when delayed up to 9 h after ischemia, with consequent dose-dependent improvement in subsequent functional recovery. The selective MC3 receptor agonist gamma2-MSH had no protective effects. Pharmacological blockade of MC4 receptors prevented the neuroprotective effects of [Nle4, D-Phe7] alpha-MSH and worsened some ischemia outcomes. Together, our findings suggest that MC4 receptor-stimulating melanocortins might provide potential to develop a class of drugs with a broad treatment window for a novel approach to neuroprotection in ischemic stroke.

Animals↗
PubMed2006

Novel signal transduction pathways: analysis of STAT-3 and Rac-1 signaling in inflammatory bowel disease.

Although the precise etiology of inflammatory bowel disease still remains unclear, considerable progress has been made in the identification of novel signal transduction pathways that elucidate the immunopathogenesis involved in the perpetuation of the inflammatory process. Augmented T cell resistance against apoptosis is regarded as a pivotal factor in the pathogenesis, as it impairs mucosal homeostasis and leads to unrestrained accumulation of activated T cells, which subsequently lead to the amplification of the inflammatory response. Therefore novel therapeutic strategies aim at restoring mucosal T cell susceptibility to apoptosis through targeting of signal transduction pathways that are elemental for augmented resistance of T lymphocytes against apoptosis. For example, a newly developed humanized anti-IL-6R monoclonal antibody that induces intestinal T cell apoptosis showed clinical efficacy in patients with active Crohn;s disease. Moreover, recent data that relate the immunosuppressive effects of azathioprine in inflammatory bowel disease to its apoptosis-inducing potential, have important implications for the design of a more specific therapeutic approach. The examination of these novel signal transduction pathways has elucidated the pathogenetic mechanisms involved in inflammatory bowel disease and gives hope for the development of new strategies that may result in a more effective and less toxic therapeutic procedure.

Apoptosis↗
PubMed2004

Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface.

PURPOSE: To evaluate whether experimentally induced dry eye in mice activates mitogen-activated protein kinase (MAPK) signaling pathways, c-Jun N-terminal kinases (JNK), extracellular-regulated kinases (ERK), and p38 and stimulates ocular surface inflammation. METHODS: 129SvEv/CD-1 mixed mice aged 6 to 8 weeks were treated with systemic scopolamine and exposure to an air draft for different lengths of time, from 4 hours to 10 days. Untreated mice were used as the control. The concentrations of IL-1beta and TNF-alpha in tear fluid washings and in corneal and conjunctival epithelia were measured by ELISA. MMP-9 in tear washings was evaluated by zymography, and gelatinase activity in the cornea and conjunctiva was determined by in situ zymography. Corneal and conjunctival epithelia were lysed in RIPA buffer for Western blot with MAPK antibodies, or they were lysed in 4 M guanidium thiocyanate solution for extraction of total RNA, which was used to determine gene expression by semiquantitative RT-PCR, real-time PCR, and gene array. RESULTS: Compared with those in age-matched control subjects, the concentrations of IL-1beta and MMP-9 in tear fluid washings and the concentrations of IL-1beta and TNF-alpha and gelatinolytic activity in the corneal and conjunctival epithelia were significantly increased in mice receiving treatments to induce dry eye after 5 or 10 days. The expression of IL-1beta, TNF-alpha, and MMP-9 mRNA by the corneal and conjunctival epithelia was also stimulated in mice treated for 5 or 10 days. The levels of phosphorylated JNK1/2, ERK1/2, and p38 MAPKs in the corneal and conjunctival epithelia were markedly increased as early as 4 hours after treatment, and they remained elevated up to 5 days. CONCLUSIONS: Experimental dry eye stimulates expression and production of IL-1beta, TNF-alpha, and MMP-9 and activates MAPK signaling pathways on the ocular surface. MAPKs are known to stimulate the production of inflammatory cytokines and MMPs, and they could play an important role in the induction of these factors that have been implicated in the pathogenesis of dry eye disease.

Animals↗
PubMed2005

Tubular expression of angiotensin II receptors and their regulation in IgA nephropathy.

Enhanced renal expression for the renin-angiotensin system (RAS) is detected in IgA nephropathy (IgAN). Previous data showed an altered glomerular expression of angiotensin II type 1 receptor (AT1R), suggesting a regulatory response to high intrarenal angiotensin II (Ang II) concentration in IgAN. In this study, the expression and regulation of Ang II receptors were examined in human proximal tubular epithelial cells (PTEC) in IgAN. Tubular expression of AT1R and Ang II type 2 receptor (AT2R) was increased in IgAN. In vitro culture experiment showed that the upregulation of Ang II receptors was not due to the direct effect of IgA but the indirect effect after IgA deposition on human mesangial cell. When PTEC were cultured with conditioned culture medium from human mesangial cells activated with IgA, Ang II production was upregulated, leading to inflammation and apoptosis via the AT1R and AT2R, respectively. Sequential expression of Ang II receptors determined the injury of PTEC induced by mediators in the conditioned medium. The initial interaction between Ang II and AT1R activated both protein kinase C and mitogen-activated protein kinase pathways, leading to inflammatory responses. This early AT1R-dependent event was followed by upregulation of AT2R expression and continued Ang II release. The interaction between Ang II and AT2R subsequently led to expression of cleaved poly[ADP-ribose] polymerase through downregulation of the mitogen-activated protein kinase pathway. The data suggest that appropriate control of Ang II receptor activities in PTEC may ameliorate tubulointerstitial injury in IgAN.

Angiotensin II↗
PubMed2001

Osteoclastogenesis and osteoclast activation in dialysis-related amyloid osteopathy.

Dialysis-related amyloid osteopathy (DRAO) is characterized by local osteoarticular lytic lesions, which sometimes cause a pathological fracture and reduce the quality of life in affected patients. In DRAO, active osteoclastic bone resorption is found at the bone surface facing the invaded synovial tissue and/or intervertebral disc, whereas reactive bone formation is absent. The eroded bone surface is covered with osteoclasts, suggesting the local promotion of osteoclastogenesis and osteoclast activation around DRAO. Inflammatory cells infiltrating the synovial tissue are likely to promote inflammatory osteolysis. Three possible pathways can be considered for the osteoclastogenesis and/or osteoclast activation in inflammatory osteolysis in DRAO: (1) indirect action of the inflammatory cytokines through the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin ligand (RANKL/OPGL) expression in osteoblasts, (2) direct action of inflammatory cytokines, and (3) RANKL/OPGL expression in inflammatory cells. To apply antiosteoclastic agents as another therapy for DRAO, we have to clarify the roles of those pathways in local osteoclastogenesis and/or osteoclast activation.

Amyloidosis↗
PubMed2004

The treatment of psoriasis and psoriatic arthritis with etanercept: practical considerations on monotherapy, combination therapy, and safety.

It is quite evident the pathogenesis of psoriasis is modulated by immune-mediated mechanisms that invoke activated T cells and inflammatory cytokines, such as tumor necrosis factor-alpha. Current immunosuppressive systemic treatments may be effective in controlling psoriasis to a certain degree but have significant drawbacks, such as toxicity and relapse of the disease on discontinuation. The advantages of biologic agents are their greater selectivity in targeting specific pathways in the inflammatory cascade of psoriasis with a much higher safety profile. With specific antagonism directed against tumor necrosis factor-alpha, etanercept has demonstrated remarkable efficacy in the treatment of psoriasis and psoriatic arthritis.

Adolescent↗
PubMed2026

Serum Proteomic Profiling Implicates a Dysregulated Neurohormonal-Inflammatory Axis in Post-Fontan Sinus Tachycardia.

BACKGROUND: Postoperative sinus tachycardia is a poorly understood complication following the Fontan procedure. The molecular signaling cascades triggering acute tachycardia remain uncharacterized, limiting therapeutic innovation. Here, we present a retrospective study leveraging serum proteomics and machine learning to identify the molecular drivers of postoperative Fontan sinus tachycardia. METHODS: We integrated a clinically relevant ovine Fontan model with continuous telemetric heart rate monitoring and human patient data. Serum proteomics coupled with least absolute shrinkage and selection operator and Boruta machine learning algorithms were used to identify protein panels predictive of postoperative sinus tachycardia. Cross-species validation was performed by comparing proteomic signatures from sheep and pediatric patients undergoing Glenn or Fontan surgery. RESULTS: Ovine Fontan animals demonstrated significant heart rate elevation beginning on postoperative day 1, peaking at postoperative day 3 (159.4±11.7 bpm versus preoperative, 105.3±10.5 bpm; P=0.0002), before trending toward baseline by postoperative day 10. This pattern was mirrored in human patients with a more modest magnitude. Surgical controls did not exhibit tachycardia. The principal component most correlated with heart rate (principal component 1: r=0.78, P=2.2×10-4) was enriched for inflammatory and neural pathways. The Boruta algorithm identified an 11-protein panel with strong predictive power (area under the receiver operating characteristic curve, 0.963). Cross-species comparison demonstrated that angiotensinogen, angiotensin-converting enzyme, and pentraxin 3 were similarly dysregulated in both species postoperatively. CONCLUSIONS: This study provides molecular evidence implicating a dysregulated neurohormonal-inflammatory axis in acute postoperative Fontan sinus tachycardia and establishes a foundation for developing targeted diagnostics and therapeutics for this complication.

Animals↗
PubMed2000

Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase. Mediation through different signaling pathways.

The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is considered to be a result of their inhibitory effect on cyclooxygenase (COX) activity. Here, we report that flufenamic acid shows two opposing effects on COX-2 expression; it induces COX-2 expression in the colon cancer cell line (HT-29) and macrophage cell line (RAW 264.7); conversely, it inhibits tumor necrosis factor alpha (TNFalpha)- or lipopolysaccharide (LPS)-induced COX-2 expression. This inhibition correlates with the suppression of TNFalpha- or LPS-induced NFkappaB activation by flufenamic acid. The inhibitor of extracellular signal-regulated protein kinase, p38, or NFkappaB does not affect the NSAID-induced COX-2 expression. These results suggest that the NSAID-induced COX-2 expression is not mediated through activation of NFkappaB and mitogen-activated protein kinases. An activator of peroxisome proliferator-activated receptor gamma, 15-deoxy-Delta(12,14)-prostaglandin J(2), also induces COX-2 expression and inhibits TNFalpha-induced NFkappaB activation and COX-2 expression. Flufenamic acid and 15-deoxy-Delta(12,14)-prostaglandin J(2) also inhibit LPS-induced expression of inducible form of nitric-oxide synthase and interleukin-1alpha in RAW 264.7 cells. Together, these results indicate that the NSAIDs inhibit mitogen-induced COX-2 expression while they induce COX-2 expression. Furthermore, the results suggest that the anti-inflammatory effects of flufenamic acid and some other NSAIDs are due to their inhibitory action on the mitogen-induced expression of COX-2 and downstream markers of inflammation in addition to their inhibitory effect on COX enzyme activity.

Adenocarcinoma↗
PubMed1998

Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development.

The c-Jun amino-terminal kinase (JNK) group of MAP kinases has been identified in mammals and insects. JNK is activated by exposure of cells to cytokines or environmental stress, indicating that this signaling pathway may contribute to inflammatory responses. Genetic and biochemical studies demonstrate that this signaling pathway also regulates cellular proliferation, apoptosis, and tissue morphogenesis. A functional role for JNK is therefore established in both the cellular response to stress and in many normal physiological processes.

Animals↗
PubMed2001

Intracellular signaling pathways as a target for the treatment of rheumatoid arthritis.

Recent advances in our understanding of cellular and molecular mechanisms of rheumatoid arthritis have highlighted a critical role for interleukin-1 and tumor necrosis factor alpha. The quest for chemically amenable targets has recently led to the identification and characterization of the intracellular signaling pathways associated with these inflammatory cytokines. In particular the mitogen-activated protein kinase pathway, the nuclear factor kappaB pathway and the cross-talk between these offer several potential therapeutic opportunities for rheumatoid arthritis.

Animals↗
PubMed2006

Short communication: differences between macrophages and dendritic cells in the cyclic AMP-dependent regulation of lipopolysaccharide-induced cytokine and chemokine synthesis.

Cyclic adenosine monophosphate (cAMP) is an intracellular signaling molecule responsible for directing cellular responses to extracellular signals. Once believed to signal exclusively through its ability to bind protein kinase A (PKA), recent research has revealed alternative cAMP-binding targets involved in PKA-independent processes. In this study we addressed the hypothesis that the guanine nucleotide exchange protein directly activated by cAMP (Epac-1) and PKA differentially regulate inflammatory mediator production in distinct phagocytic cell types. To accomplish this, we compared the release of cAMP-regulated polypeptide inflammatory mediators in both macrophages (obtained from the lung and peritoneum) and bone marrow-derived dendritic cells (DCs) stimulated with bacterial endotoxin. Using the highly selective Epac-1 and PKA activating cAMP analogs 8-pCPT-2 -O-Me-cAMP and 6-Bnz-cAMP, respectively, we found that macrophages differ from DCs in the involvement of these distinct cAMP pathways in modulating inflammatory mediator release in response to endotoxin. Whereas the regulation of cytokine and chemokine production in macrophages by cAMP was solely dependent on PKA, we found that both Epac-1 and PKA activation could regulate mediator production in DCs. This finding may be important in the pharmacologic regulation of immune responses through manipulation of cAMP signaling cascades and contributes to our understanding of the differences between these cell types.

Animals↗
PubMed2006

Microglial integrity is maintained by erythropoietin through integration of Akt and its substrates of glycogen synthase kinase-3beta, beta-catenin, and nuclear factor-kappaB.

Recognized as a robust cytoprotectant for multiple tissues of the hematopoietic, vascular, cardiac, and nervous systems, erythropoietin (EPO) also is considered to be an attractive therapeutic candidate to modulate inflammatory cell function and survival during neurodegenerative disorders. To this end, microglia of the central nervous system serve a complex function not only to dispense of foreign organisms and injured cells of the brain, but also to foster tissue repair and reorganization during neuronal and vascular cell insults. We therefore examined the ability of EPO to modulate microglial cell survival and the underlying signal transduction pathways that govern microglial integrity during oxygen-glucose deprivation (OGD)--induced oxidative stress. We demonstrate in the microglial cell line EOC 2 that EPO provides direct microglial protection against early and late apoptotic programs of membrane phosphatidylserine exposure and genomic DNA degradation. Furthermore, expression and activation of Akt1 is vital to the cytoprotective capacity of EPO, since pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression eliminates the ability of EPO to protect microglial cells. Through Akt1 dependent mechanisms that can be abrogated through the gene silencing of Akt1, maintenance of microglial cell integrity during OGD by EPO is closely integrated with the phosphorylation and inhibition of glycogen synthase kinase-3beta activity as well as the intracellular trafficking of beta-catenin and nuclear factor-kappaB. Further work that continues to elucidate the ability of EPO to target the intricate pathways that determine inflammatory cell function and integrity may lay the ground work for new therapeutic avenues for neurodegenerative disease.

Animals↗