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PubMed2007

Mechanical strain induces a persistent upregulation of syndecan-1 expression in smooth muscle cells.

Syndecan-1 belongs to a family of transmembrane proteoglycans, acts as a coreceptor for growth factor binding, as well as cell-matrix and cell-cell interactions, and is induced in smooth muscle cells (SMCs) following balloon catheter injury. In this report, we investigated syndecan-1 expression in SMCs in response to several distinct biomechanical force profiles and the related syndecan shedding response. Syndecan-1 mRNA expression increased in response to 5% and 10% cyclic strain (24 h: 206 +/- 40% and 278 +/- 33%, respectively, P < 0.05) when compared to unstrained controls. When subjected to 10% cyclic strain for periods of up to 48 h, syndecan-1 mRNA levels remained elevated at 294 +/- 31%. Notably, the SMC mechanosensor mechanism remained responsive after an initial 24 h "preconditioning" period, as evident by a fivefold increase in syndecan-1 gene expression following a change in cyclic stress from 10% to 20% (48 h: 516 +/- 55%, P < 0.05). Of note, similar behavior was not observed in an analysis of syndecan-2 mRNA levels. Commensurate with mRNA responses, mechanical stress induced an increase in cell-associated syndecan-1 protein levels with an associated increase in protein shedding. Given the varied functions of syndecan-1, stress-induced effects on SMC syndecan-1 expression and shedding may represent an additional component of the pro-inflammatory, growth-stimulating pathways that are activated in response to changes in the mechanical microenvironment of the vascular wall. Syndecan-1 expression is uniquely influenced by changes in the phase and magnitude of the local stress field.

Aorta↗

PubMed2024

Pterostilbene Targets Hallmarks of Aging in the Gene Expression Landscape in Blood of Healthy Rats.

SCOPE: Polyphenols from the phytoestrogen group, including pterostilbene (PTS), are known for their antioxidant, anti-inflammatory, and anti-cancer effects. In recent reports, phytoestrogens attenuate age-related diseases; however, their pro-longevity effects in healthy models in mammals remain unknown. As longevity research demonstrates age-related transcriptomic signatures in human blood, the current study hypothesizes that phytoestrogen-supplemented diet may induce changes in gene expression that ultimately confer pro-longevity benefits. METHODS AND RESULTS: In the present study, RNA sequencing is conducted to determine transcriptome-wide changes in gene expression in whole blood of healthy rats consuming diets supplemented with phytoestrogens. Ortholog cell deconvolution is applied to analyze the omics data. The study discovered that PTS leads to changes in the gene expression landscape and PTS-target genes are associated with functions counteracting hallmarks of aging, including genomic instability, epigenetic alterations, compromised autophagy, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular interaction, and loss of proteostasis. These functions bridge together under anti-inflammatory effects through multiple pathways, including immunometabolism, where changes in cellular metabolism (e.g., ribosome biogenesis) impact the immune system. CONCLUSION: The findings provide a rationale for pre-clinical and clinical longevity studies and encourage investigations on PTS in maintaining cellular homeostasis, decelerating the process of aging, and improving conditions with chronic inflammation.

Animals↗

PubMed2003

Functional proteomics of neurokinin B in the placenta indicates a novel role in regulating cytotrophoblast antioxidant defences.

Neurokinin B (NKB) has recently been demonstrated to be secreted from the placenta in abnormally high amounts in preeclampsia (PE) and to cause hypertension in rats, suggesting it may be a mediator of some pathophysiological features of PE. It is also known that NKB receptors exist in the placenta. To determine the effect of high levels of NKB on the placenta, we have performed proteomics on five separate preparations of cultured purified human term cytotrophoblast cells. The results showed a statistically significant decrease in 20 proteins, of which five were unknown proteins. Proteins important in antioxidant defenses that decreased were thioredoxin, cyclophilin A, cytokeratin 1, and peroxiredoxin 5. Two proteins that inhibit intravascular anticoagulation, cytokeratin 1 and annexin 11 were also decreased. Pathways involving pro-inflammatory cytokine activation of NF-kappa B are opposed by Raf kinase inhibitor protein, which was also decreased. Cofilin 1, a protein involved in defense against bacteria, was also decreased. Among other proteins that were suppressed by NKB were proteasome proteins, desmoplakin, and calgizzarin. Western blots confirmed the decrease in cytokeratin 1 and cyclophilin A protein after NKB exposure. In PE, there is reduced antioxidant activity and increased intravascular coagulation. The findings that high levels of NKB, similar to those observed in PE, can impair these two classes of activity support the hypothesis that high NKB levels may contribute to the pathogenesis of PE.

Annexins↗

PubMed1997

Tetrahydrobiopterin modulates cyclooxygenase-2 expression in human mesangial cells.

Tetrahydrobiopterin (BH4) biosynthetic pathways are stimulated under inflammatory conditions. The newly synthesized BH4 serves as a cofactor for optimal activity of inducible nitric oxide synthase (NOS2). In human mesangial cells (HMC), BH4 is also a limiting factor for NOS2 expression. In this study we show that BH4 availability can also play a modulatory role in the expression of cyclooxygenase 2 (COX-2) in HMC. Supplementing HMC with the BH4 donor sepiapterin potentiated IL-1beta/TNF-alpha-induced COX-2 expression by approximately 2-fold. This effect was abolished by methotrexate. In contrast, the NOS inhibitor L-NAME and the soluble guanylate cyclase inhibitor ODQ did not block sepiapterin amplification of COX-2 expression. Moreover, sepiapterin was found to modulate the tyrosine phosphorylation of several cellular substrates, an early event which occurred well before the induction of NOS2 could be evidenced. These findings suggest a role for BH4 in the modulation of mesangial cell responses to pro-inflammatory stimuli.

Biopterins↗

PubMed1999

Mediating phosphorylation events in the vanadium-induced respiratory burst of alveolar macrophages.

Occupational exposure by inhalation to vanadium-containing particles such as residual oil fly ash results in respiratory tract inflammation. This inflammation, characterized by abundant neutrophilia, appears to be initiated by alveolar macrophages (AMs) encountering particles and the subsequent release of proinflammatory cytokines. Intracellular signaling events in these cells in response to particles or their components are largely unknown. We investigated two immediate responses of AMs to vanadium exposure in vitro, the production of reactive oxygen intermediates (ROI) or respiratory burst (RB), and the tyrosine phosphorylation of cellular proteins. Macrophages exposed in vitro to 100 microM vanadyl chloride/1 microCi 48V incorporated 8.3% of the metal after 30 min. Exposure of AMs to increasing concentrations of sodium metavanadate resulted in a dose-dependent increase in production of ROI as measured by dichlorofluorescin oxidation. The lowest dose yielding a significant response was 50 microM, whereas 1000 microM increased RB activity by 173%. NADPH oxidase inhibitors deoxy-D-glucose (100 mM) and diphenylene iodonium (25 microM) reduced the metavanadate-induced RB by 62 and 71%, respectively, implicating NADPH oxidase as the primary cellular source of ROI. Enhanced cerium chloride oxidation in response to metavanadate localized to the plasma membrane consistent with increased NADPH oxidase activity. Pretreatment of AMs with the epidermal growth factor receptor inhibitor, tryphostin B50 (10 microM), reduced the metavanadate-induced RB, but did not influence overall tyrosine phosphorylation. Metavanadate and H2O2 exposure greatly increased overall tyrosine phosphorylation, yielding a similar but distinguishable pattern of phosphorylation in these cells. These observations demonstrate that in vitro metavanadate exposure regulates two distinct, yet related intracellular signaling pathways important in initiating inflammatory responses in these cells: (1) activation of the NADPH oxidase complex with subsequent increased ROI synthesis, and (2) enhanced tyrosine phosphorylation of cellular proteins.

Animals↗

PubMed1999

Bolus intravenous injection of phosphorothioate oligonucleotides causes hypotension by acting as alpha(1)-adrenergic receptor antagonists.

Bolus intravenous injections of phosphorothioate oligonucleotides (PS-ODN) into primates cause profound hypotension, which has been attributed to complement activation, the biochemical pathway leading to acute inflammatory response. Because the hypotension was not accompanied by peripheral or pulmonary edema and epinephrine was not effective, but administration of 200 ml Ringer's lactate was effective, we examined the possibility that the 15-base PS-ODN interferes with sympathetic tone. We administered doses ranging from 3.3 to 10 mg/kg of a 15-base PS-ODN as a 30-60 s iv bolus into the right atrium of conscious Macaca mulatta. Blood pressure fell to 27 mm Hg following a 5.0 mg/kg dose, but no hypotension was observed after a 3.3 mg/kg dose; 10 mg/kg was lethal. Adrenergic receptor binding was evaluated in radioligand binding assays using rat cerebral cortex membranes with radiolabeled prazosin. The 15-base PS-ODN competes with prazosin for the alpha(1)-adrenergic receptor with an IC50 of 14 microM, which favors binding over serum albumin (K(d) = 37 to 48 microM). Admixing serum albumin with 5.0 mg/kg 15-base PS-ODN prior to injection prevented hypotension, suggesting that unbound PS-ODN interferes with sympathetic tone before binding to plasma proteins. Interactions of the 15-base PS-ODN with the alpha(1)-adrenergic receptor in vivo were confirmed by a decreased response to phenylephrine. Reducing the length from 15 to 9 or 5 bases abolished alpha(1)-adrenergic receptor binding in vitro and bolus infusion of 5.0 mg/kg of 9-base PS-ODN no longer produced hypotension. In conclusion, the 15-base PS-ODN shows cooperative binding to the alpha(1)-adrenergic receptor, which produces cardiovascular effects that are oligomer length, dose, and formulation dependent.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1995

Cytotoxic T lymphocytes and HIV-1 related neurologic disorders.

In summary, one can conclude that infected persons exhibit an extremely vigorous, virus-specific CTL response, and in at least some individuals this response is broadly directed at multiple epitopes. These cells are present at the time or initial control of viremia and can also be detected after more than a decade of asymptomatic infection. These cells can also be found in the central nervous system in persons with ADC, and one can envision pathways in which the inflammatory cytokines released by these cells upon activation could contribute to the neurologic sequelae of infection. However, the precise role of these cells as a protective host defense and the possible contribution of these cells, or products released by these cells, to tissue damage at sites such as the lung and brain remain to be determined. Further delineation of the role played by CTLs in the pathogenesis of disease should be extremely useful in helping to understand the disease itself and to guide intervention strategies.

AIDS Dementia Complex↗

PubMed2026

From Gene Function to Precision Intervention: CRISPR/Cas9 and Stem Cell-Based Strategies as Emerging Disease-Modifying Approaches in PMOS.

Polyendocrine metabolic ovarian syndrome (PMOS) is a complex endocrine-metabolic disorder affecting up to 18% of women worldwide and remains the leading cause of anovulatory infertility. Despite extensive research, current treatments primarily target symptoms, including menstrual irregularities, hyperandrogenism, and metabolic dysfunction, without addressing the underlying molecular and tissue-level disturbances. Advances in multi‑omic profiling have identified disruptions across neuroendocrine, metabolic, inflammatory, and extracellular matrix pathways, alongside genetic susceptibility at loci such as DENND1A, CYP17A1, LHCGR, FSHR, IRS1, and PPARG. However, the functional roles of many variants remain unresolved. CRISPR/Cas9 gene editing enables precise interrogation of these pathways, while stem cell-based platforms, including mesenchymal stem cells (MSCs), exosomes, and gene-edited induced pluripotent stem cells (iPSCs), may serve as complementary platforms for regeneration and disease modeling. Preclinical studies demonstrate that MSCs and their derivatives modulate inflammation, restore ovarian structure, and improve metabolic parameters, while iPSC-based models enable patient-specific investigation of steroidogenic and metabolic abnormalities. Translational challenges remain, including targeted delivery, off-target effects, phenotypic heterogeneity, and regulatory considerations. Integrating CRISPR‑based functional genomics with stem cell research may shift PMOS management from symptom‑focused care to targeted, mechanism‑driven interventions that could modify the course of PMOS (Graphical Abstract).

Humans↗

PubMed1992

Leukotriene B4 in the immune system.

Leukotriene (LT) B4 is a biologically active molecule derived from arachidonic acid via the 5-lipoxygenase pathway. It mediates certain inflammatory and immunological reactions. The role of LTB4 in the immune system has been questioned since lymphocytes have been regarded to lack the enzymes involved in LTB4 formation. This review focuses on the recently described biosynthesis of LTB4 in B-lymphocytes and the effects of this compound on lymphocyte functions.

Adjuvants, Immunologic↗

PubMed1994

Interleukin 1 activity in haemolymph from strains of the snail Biomphalaria glabrata varying in susceptibility to the human blood fluke, Schistosoma mansoni: presence, differential expression, and biological function.

Cytokines control many of the steps in the complex pathways of immune and inflammatory responses in mammals. Recent reports also indicate that some invertebrates may produce cytokines such as interleukin 1 (IL-1). Certain strains of the snail, Biomphalaria glabrata (intermediate host for the human blood fluke, Schistosoma mansoni), possess a soluble plasma factor that stimulates the haemocyte-mediated killing of larval schistosomes, making them resistant to infection. In this study, we have sought to determine whether these snails possessed IL-1 in their plasma, and whether this cytokine was associated with resistance of B. glabrata to S. mansoni. Plasma from susceptible (M-line) and resistant (10-R2, 13-16-R1) strains of B. glabrata that had been unexposed or exposed to S. mansoni were tested for the presence of IL-1-like activity. Experiments employing both a bioassay and an immunoassay indicated that an IL-1-like molecule was present, in varying quantities, among the snail strains. Further, plasma IL-1 levels were significantly affected by exposure to S. mansoni, with levels dropping in M-line and 10-R2 snails, but increasing in the 13-16-R1 strain. However, both resistant strains maintained significantly higher IL-1 levels than M-line snails. Recombinant, human IL-1 (rhIL-1) was shown to prime haemocytes from both resistant snail strains for superoxide production, but had no effect on haemocytes from susceptible B. glabrata. Moreover, the addition of an IL-1 receptor antagonist protein (IRAP) eliminated this priming effect. Priming with rhIL-1 and/or IRAP had no effect on phagocytosis rates in any of the snail strains tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Dynamic expression of the membrane attack complex (MAC) of the complement system in failing human myocardium.

Inflammatory cytokine-mediated pathways are activated in heart failure and participate in the pathogenesis and progression of the disease. Another major response to inflammation is mediated through the complement system with the production of the membrane attack complex (MAC), a protein known to cause cell lysis and mediate apoptosis. It was postulated that the complement system is activated in patients with heart failure, and this study investigated whether hemodynamic conditions regulate this pathway. The expression of the MAC was assessed in myocardial biopsy samples of normal and failing hearts by immunohistochemistry and Western blot analysis. Myocardial samples from failing hearts were obtained before and after left ventricular assist device implantation. Immunohistochemical staining and Western blot analysis identified increased MAC expression in failing but not normal myocardium. After hemodynamic unloading with left ventricular assist device support, MAC expression returned to levels found in normal controls. In failing hearts, MAC expression did not differ between ischemic and nonischemic causes of heart failure. In conclusion, increased MAC expression in failing human hearts indicates that the complement system is activated in the heart failure milieu. Its removal after hemodynamic normalization is evidence of dynamic regulation, suggesting a pathogenic role for the MAC. These findings identify the complement system as part of a novel pathophysiologic path in heart failure that can potentially be targeted by future therapy.

Apoptosis↗

PubMed2005

Nordihydroguaiaretic acid inhibits IFN-gamma-induced STAT tyrosine phosphorylation in rat brain astrocytes.

The Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signal cascades are major pathways that mediate the inflammatory functions of interferon-gamma (IFN-gamma), an important pro-inflammatory cytokine. Therefore, regulation of JAK/STAT signaling should modulate IFN-gamma-mediated inflammation. In this study, we found that nordihydroguaiaretic acid (NDGA), a well-known lipoxygenase (LO) inhibitor, suppressed IFN-gamma-induced inflammatory responses in brain astrocytes. In the presence of NDGA, interferon regulatory factor-1 expression was significantly reduced. Expression of monocyte chemotactic protein-1 and interferon-gamma inducible protein-10 mRNA in response to IFN-gamma was significantly suppressed in the presence of NDGA, as was tyrosine-phosphorylation of JAK and STAT. However, the 5-LO products, leukotriene B(4) (LTB(4)) and leukotriene C(4), were not detected in cells treated with IFN-gamma, indicating that the effect of NDGA seemed to be independent of 5-LO inhibition. In addition, two other 5-LO inhibitors (Rev5901 and AA861) did not mimic the effect of NDGA, and the 5-LO metabolites, 5-hydroxyeicosatetraenoic acid and LTB(4), were unable to reverse NDGA-driven suppression of STAT activation or affect basal STAT phosphorylation. Taken together, these results suggest that NDGA regulates IFN-gamma-mediated inflammation through mechanisms unrelated to the inhibition of 5-LO.

Animals↗

PubMedDate not supplied

Adipositas cordis, fatty infiltration of the right ventricle, and arrhythmogenic right ventricular cardiomyopathy. Just a matter of fat?

Whether fatty infiltration of the right ventricle has to be considered "per se" a sufficient morphologic hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still a source of controversy; ARVC should be kept distinct from both fatty infiltration of the right ventricle and adipositas cordis. In fact, it is well known that a certain amount of intramyocardial fat is present in the right ventricular antero-lateral and apical regions even in the normal heart and that the epicardial fat increases with increasing body weight. However, both the fibro-fatty and fatty variants of ARVC show, besides fatty replacement of the right ventricular myocardium, degenerative changes of the myocytes and interstitial fibrosis, with or without extensive replacement-type fibrosis. The need to adopt strict diagnostic criteria is warranted not only in the clinical setting but also in the forensic and general pathology arena. When dealing with a case of sudden death, in which the only morphologic finding consists of an increased amount of epicardial or intramyocardial fat, a more convincing arrhythmogenic source such as myocardial inflammatory infiltrates, fibrosis, anomalous pathways, and ion channel disease should always be searched for, in order to avoid an over-diagnosis of ARVC cases.

Adipose Tissue↗

PubMed2004

Complement C1q expression induced by Abeta in rat hippocampal organotypic slice cultures.

Amyloid beta peptide (Abeta) is a major component of senile plaques, one of the principle pathological features in Alzheimer's disease (AD) brains. Fibrillar Abeta has been shown to bind C1 via C1q, the recognition component of the classical complement pathway, resulting in the activation of the complement pathway, thereby initiating an inflammatory cascade in the brain. C1q has also been shown to enhance phagocytic activities of microglia, which could benefit in clearance of apoptotic cells or cellular debris. To begin to define the role of C1q in tissue injury mediated by Abeta, we assessed the appearance of C1q in hippocampal slice cultures treated with freshly solubilized or fibrillar Abeta 1-42. Here we demonstrate a dose- and time-dependent uptake of exogenously applied Abeta by pyramidal neurons in organotypic slice cultures from rat hippocampus. Importantly, when slices were immunostained with antibody against rat C1q, a distinct reactivity for C1q in cells within the neuronal cell layer of cornu ammonis (CA) of hippocampus, primarily the CA1/CA2, was observed in the Abeta-treated slices. No such immunoreactivity was detected in untreated cultures or upon addition of control peptides. ELISA assays also showed an increase in C1q in tissue extracts from slices of the treated group. Similarly, the mRNA level of C1q in slices was increased within 24 h after Abeta treatment. These data demonstrate that upon exposure to Abeta, C1q is expressed in neurons in this organotypic system. The induction of C1q may be an early, perhaps beneficial, tissue or cellular response to injury triggered by particular pathogenic stimuli.

Amyloid beta-Peptides↗

PubMed2006

Persistent activation of nuclear factor kappa-B signaling pathway in patients with unstable angina and elevated levels of C-reactive protein evidence for a direct proinflammatory effect of azide and lipopolysaccharide-free C-reactive protein on human monocytes via nuclear factor kappa-B activation.

OBJECTIVES: Our study investigated: 1) the contribution of nuclear factor kappa-B (NF-kappaB) signaling pathway to the enhanced inflammatory response observed in unstable angina (UA) patients with elevated levels of C-reactive protein (CRP); and 2) whether CRP may have direct proinflammatory effects via NF-kappaB activation. BACKGROUND: Unstable angina patients with elevated CRP have enhanced inflammatory response and increased risk of persistent instability, myocardial infarction, and death. METHODS: We studied 28 patients with history of UA and persistently elevated CRP (>3 mg/l) followed for 24 months and free of symptoms for at least 6 months (group 1), 14 patients with history of UA and low CRP (group 2), and 24 patients with chronic stable angina and low CRP (group 3). Peripheral blood monocytes were analyzed for spontaneous NF-kappaB activation and interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha production. To assess the direct proinflammatory effects of CRP, monocytes from 8 healthy subjects were stimulated in vitro with increasing doses of CRP (5 to 10 to 25 microg/ml), lipopolysaccharide (LPS) (1 to 10 ng/ml), or both. RESULTS: Spontaneous NF-kappaB activation in vivo was demonstrated in 82% of group 1 versus 14% of group 2 and 21% of group 3 patients (p < 0.001). Interleukin-6 and TNF-alpha production was significantly correlated with the NF-kappaB activation status (r = 0.55, p < 0.001 and r = 0.53, p = 0.006, respectively). Patients with NF-kappaB activation had recurrence of acute coronary events (60% vs. 28%; p = 0.017). C-reactive protein induced a significant but modest in vitro NF-kappaB activation in human monocytes (p = 0.002). Coincubation with LPS produced a greater-than-additive response (p < 0.01 vs. CRP and LPS alone). CONCLUSIONS: Nuclear factor kappa-B activation might represent a mechanism by which CRP amplifies and perpetuates the inflammatory component of acute coronary syndromes and influences the clinical outcome.

Adult↗

PubMed2004

Expression of cyclooxygenase-2 in corneal cells after photorefractive keratectomy and laser in situ keratomileusis in rabbits.

PURPOSE: To compare the expression pattern of cyclooxygenase-2 (COX-2) in rabbit corneal cells after photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) with the same refractive correction. SETTING: Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan. METHODS: Thirty adult albino rabbits were used in the study. Photorefractive keratectomy or LASIK was performed in 1 eye of each animal for the same refractive correction. Each animal was killed after healing intervals up to 6 months. Paraffin sections of the cornea were processed for immunohistochemistry for COX-2 and NFkappaB (p65). RESULTS: After PRK, the central and peripheral corneal epithelia up-regulated COX-2 at 3 days; the central epithelium was positive at 4 weeks. Central and peripheral epithelia returned to negative 3 months later. After LASIK, the central epithelium on the corneal flap up-regulated COX-2 at 1 and 2 weeks; it returned to negative at 4 weeks. The peripheral epithelium was labeled with the antibody. Keratocytes around the stromal incision between the flap and the stromal bed up-regulated COX-2 and returned to negative at 3 months. COX-1 was not detected immunohistochemically in corneal tissue during the healing intervals after both procedures. Nuclear factor kappaB was detected in the cytoplasm and nuclei of migrating corneal epithelial cells 1 day after PRK, was positive in the cytoplasm at 3 days and negative in cytoplasm and nuclei at week and later. CONCLUSIONS: Migrating injured epithelium expressed COX-2 until week 4 during post-PRK healing. Central uninjured epithelium as well as stromal keratocytes expressed COX-2 from 3 days to 2 weeks after LASIK. Uninjured peripheral epithelium also expressed COX-2 at 4 weeks. Activation of stromal keratocytes may induce expression of COX-2 in overlying uninjured epithelium via the inflammatory cytokine(s)/NFkappaB pathway.

Animals↗

PubMed2003

A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4.

Preterm birth is a leading cause of neonatal morbidity and mortality. Despite a growing body of evidence correlating inflammation with preterm birth, the signal transduction pathways responsible for the emptying of the uterus in the setting of intrauterine inflammation has not been elucidated. We now report a unique, reproducible mouse model of localized intrauterine inflammation. This model results in 100% preterm delivery with no maternal mortality. Using our model, we also show that platelet-activating factor is a crucial mediator of both inflammation-induced preterm birth and fetal demise. Using C3H/HeJ mice, we demonstrate that toll-like receptor-4 (TLR-4) plays a role in lipopolysaccharide-induced preterm birth but not in inflammation-induced fetal death. Immunohistochemistry studies demonstrate the presence of the platelet-activating factor receptor in both endometrial glands and smooth muscle in uterine tissues. Molecular studies demonstrate the differential expression of platelet-activating factor receptor and TLR-4 in uterine and cervical tissue throughout gestation. Quantitative polymerase chain reaction revealed an up-regulation of TLR-4 in the fundal region of the uterus in response to intrauterine inflammation. The use of this model will increase our understanding of the significant clinical problem of inflammation-induced preterm birth and will elucidate signal transduction pathways involved in an inflammatory state.

Animals↗

PubMed2001

Clinical and cellular effects of cytochrome P-450 modulators.

Stress stimulates the hypothalamic-pituitary-adrenal axis and leads to elevated glucocorticoid hormones (GCs). GCs reduce inflammation and suppress responses mediated by cytokines, including fever and pulmonary inflammation. Besides cyclooxygenases and lipoxygenases, cytochrome P-450 enzymes (CYP), referred to as epoxygenases, are also involved in the metabolism of arachidonic acid, implicating epoxygenases in regulating inflammation and the generation of fever. Intraperitoneal injection of lipopolysaccharide (LPS) triggers fever in rats and mice, and administration of compounds known to induce CYP reduces LPS-induced fever, while inhibitors of CYP suppress fever. Consistent with these findings, inhibitors of CYP augment the elevation of LPS-induced prostaglandin E2 levels, an endogenous pyrogen, and administration of epoxygenase metabolites results in antipyresis. CYP inducers also reduce lung inflammation, the resulting mucous cell metaplasia, and the percentage of Bcl-2-positive mucous cells in rat airways after intratracheal instillation of LPS. Together, these observations indicate that CYP modulators may have therapeutic anti-inflammatory effects, and this pathway may be involved in stress-induced reduction of inflammation.

Animals↗