The Effect of PPARα and PPARγ Ligands on Inflammation and ABCA1 Expression in Cultured Gallbladder Epithelial Cells

The preservation of gallbladder function by control of inflammation and elimination of cholesterol accumulation in gallbladder epithelial cells (GBEC) could contribute to the prevention of gallstone formation and cholecystitis. Peroxisome proliferator-activated receptors (PPARs) modulate inflammation and lipid metabolism in various cells and GBEC efflux of excessive amounts of absorbed cholesterol through the ATP-binding cassette transporter A1 (ABCA1)-mediated pathway. The aim of this study was to determine whether ligands of PPARα and PPARγ modulate inflammation and have an effect on ABCA1 expression in GBEC. Canine GBEC were cultured on dishes coated with collagen matrix. We performed Western blot analysis for the expression of specific protein and/or RT-PCR for the expression of specific mRNA. PPARα and PPARγ expression was observed and increased in GBEC treated with WY-14643 (PPARα ligand), troglitazone (PPARγ ligand), and lipopolysaccharide (LPS) compared to the no-treatment control and PPARα antagonist (GW-9662) treatment group. WY-14643, troglitazone, and LPS also induced an increase in the expression of ABCA1 protein and mRNA in cultured GBEC. LPS-induced TNFα mRNA expression was suppressed by pre-treatment with WY-14643 and troglitazone preceding LPS treatment in GBEC. PPAR ligands, especially PPARγ, may preserve gallbladder function by suppression of inflammatory reaction and prevention of cholesterol accumulation in GBEC, contributing to the prevention of gallstone formation and progression to cholecystitis.     

Vascular Endothelial Growth Factor (VEGF)—A Possible Mediator of Inflammation and Mucosal Permeability in Patients with Collagenous Colitis

Patients with collagenous colitis have watery diarrhea and histopathologically thickened collagen layer with discrete signs of mucosal inflammation. Vascular endothelial growth factor (VEGF) is a potent angiogenic, mitogenic, permeability, and fibrosis enhancing peptide and it was studied by segmental perfusion and immunohistochemistry in patients and controls. The concentrations of VEGF were significantly increased in perfusates from both the descending colon and the rectum in patients compared to controls but this difference was not found in serum. Immunohistochemical staining showed expression of VEGF within colon epithelial cells, inflammatory cells, and fibroblasts in the lamina propria. The intensity of staining in the surface epithelium was not different between patients and controls but in the lamina propria the intensity was significantly higher among controls. Patients with collagenous colitis have increased colorectal mucosal secretion of VEGF, which may lead to albumin leakage and promote fibrosis with deposition of collagen.     

Activation of NFκB Represents the Central Event in the Neoplastic Progression Associated with Barrett's Esophagus: A Possible Link to the Inflammation and Overexpression of COX-2, PPARγ and Growth Factors

The molecular mechanisms responsible for the progression of malignant transformation in Barrett's esophagus (BE) are still poorly understood. This study was undertaken (1) to investigate the gene and protein expression of cyclooxygenase-2 (COX-2), peroxisome proliferator-activated receptor-gamma (PPARgamma), interleukin-8 (IL-8), hepatocyte growth factor (HGF), gastrin, and its receptor (CCK-2) in the Barrett's epithelium; (2) to analyze the activity of NFkappaB in Barrett's esophagus with low-grade dysplasia; and (3) to assess the effects of PPARgamma ligand (ciglitazone) and gastrin on cell proliferation in the cell line derived from esophageal adenocarcinoma (OE-33). COX-2, PPARgamma, IL-8, HGF, gastrin, and CCK-2 expression levels relative to the control gene encoding GAPDH were analyzed by RT-PCR and Western blot in specimens of BE with low-grade dysplasia (n = 20) and compared with that in the normal squamous esophageal mucosa from the middle portion of the esophagus (n = 20). In vitro experiments included the incubation of cell line OE-33 with ciglitazone (1-15 microM) and gastrin (100 nM). NFkappaB activity in biopsies specimens was measured by highly sensitive ELISA. COX-2, PPARgamma, IL-8, HGF, gastrin, and CCK-2 expressions were significantly increased in BE compared with normal squamous esophageal mucosa. NFkappaB activity was significantly upregulated in BE. Ciglitazone inhibited cell proliferation of OE-33 cells as assessed by BrdU and this effect was attenuated partly by gastrin. (1) COX-2, PPARgamma, HGF, gastrin, and its receptor are significantly upregulated in BE, suggesting a possible role for these factors in Barrett's carcinogenesis; (2) the increased NFkappaB activity is probably linked to increased IL-8 and COX-2 expression; and (3) PPARgamma ligands might be useful as a new therapeutic option in the prevention and treatment of Barrett's carcinoma.     

Association of Tumor Necrosis Factor-α and Neutrophilic Inflammation in Severe Asthma

BackgroundThere is evidence that neutrophils are increased in the airway of severe disease or acute exacerbations of asthma. The mechanisms by which neutrophils are recruited to the airways and contribute to the pathophysiology of asthma remain to be elucidated. Tumor necrosis factor (TNF-α), which can induce both tissue accumulation and activation of neutrophils and eosinophils, has been shown to be increased in the airways of severe asthma. The objective of this study is to evaluate whether TNF-α is associated with neutrophilic inflammation in asthma.MethodsFollowing an inhalation of hypertonic saline, induced sputum was obtained from 9 healthy controls, 9 mild persistent asthma patients who were treated with low-dose inhaled corticosteroids; and 7 severe persistent asthma patients who were treated with combinations of drugs including high-dose inhaled corticosteroids, oral prednisolone, bronchodilators, and leukotriene receptor antagonist. After 0.1% dithiothreitol (DTT) homog- enization, they were examined for total cell count, cellular differentiation, and the concentrations of TNF-α and myeloperoxidase (MPO).ResultsThe concentration of TNF-α was not correlated with neutrophils in healthy controls or mild asthma patients. In sputum from severe asthma patients, however, the concentration of TNF-α is significantly correlated with both the percentage of neutrophils and the concentration of MPO. The concentration of TNF-α is not correlated with the percentage of eosinophils in healthy controls, mild asthma patients, or severe asthma patients.ConclusionsTNF-α may be a contributing molecule for both accumulation and activation of neutrophils in the airways of severe asthma.     

Interactive Monitoring Service and COPD: Is it Possible to Reduce Nonadherence?

Chronic obstructive pulmonary disease (COPD) represents one of the main causes of death worldwide. It affects hundreds of millions of people and is likely to spread further in the coming years. Despite the chronic nature of the disease and the proven efficacy of current therapies, treatment nonadherence is unfortunately common and too often related to treatment failure, disease exacerbations, hospitalizations, and high healthcare costs. At present, studies aimed to assess and improve patients' adherence in chronic respiratory diseases—and especially in COPD—are limited, but a review of the few data available makes it clear that there is a need for an innovative approach that leverages health technology to encourage patients to adhere to prescribed chronic treatments.     

The Role of Tumor Necrosis Factor-α Receptors in Atherosclerosis

Tumor necrosis factor (TNF-α)-α is a cytokine exhibiting a plethora of activities involved in inflammation, immune regulation, and energy metabolism. TNF is produced by many cell types, including cells found in atherosclerotic lesions, such as activated monocytes or macrophages, T and B lymphocytes, mast cells, and smooth muscle cells. Two receptors mediate the functions of TNF, and both receptors are also present on cells of the artery wall and on cells involved in lesion development. Mice genetically engineered to lack expression of TNF and each of its receptors are now available and are being used to dissect the role of these molecules in protection from or development of atherosclerosis. The role of TNF receptors in atherosclerosis is the primary focus of this review.     

Activation of PPAR α and PPAR β/δ regulates Sertoli cell metabolism

The purpose of this study was to evaluate the existence of a possible simultaneous regulation of fatty acid (FA) metabolism and lactate production by PPAR α and PPAR β/δ activation in Sertoli cells (SC). SC cultures obtained from 20-day-old rats were incubated with WY14643 or GW0742—pharmacological activators of PPAR α and PPAR β/δ respectively. The fatty acid transporter CD36, carnitine palmitoyltransferase 1, long- and medium-chain 3-hydroxyacyl-CoA dehydrogenases mRNA levels were analyzed. An increase in the above-mentioned genes in response to activation of both nuclear receptors was observed. Additionally, PPAR β/δ activation increased lactate production as a consequence of increased pyruvate availability by inhibiting the Pyruvate Dehydrogenase Complex. Altogether, these results suggest that in SC, PPAR α activation participates in the regulation of FA metabolism. On the other hand, PPAR β/δ activation regulates FA metabolism and lactate production ensuring simultaneously the energetic metabolism for SC and germ cells.     

Fish Oil Blunted Nicotine-Induced Vascular Endothelial Abnormalities Possibly via Activation of PPARγ-eNOS-NO Signals

Nicotine exposure is associated with an induction of vascular endothelial dysfunction (VED), a hallmark of various cardiovascular disorders. The present study investigated the effect of fish oil in nicotine-induced experimental VED. VED was assessed by employing isolated aortic ring preparation, estimating aortic and serum nitrite/nitrate, aortic superoxide anion generation, and serum TBARS, and carrying out electron microscopic and histological studies of thoracic aorta. Nicotine (2 mg/kg/day, i.p., 4 weeks) administration produced VED in rats by attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentration, impairing endothelial integrity, and inducing vascular oxidative stress. Treatment with fish oil (2 mL/kg/day p.o., 4 weeks) markedly prevented nicotine-induced endothelial functional and structural abnormalities and oxidative stress. However, administration of GW9662, a selective inhibitor of PPARγ, to a significant degree attenuated fish oil-associated anti-oxidant action and vascular endothelial functional and structural improvements. Intriguingly, in vitro incubation of L-NAME (100 μM), an inhibitor of nitric oxide synthase (NOS), markedly attenuated fish oil-induced improvement in endothelium-dependent relaxation in the aorta of nicotine-administered rats. Nicotine administration altered the lipid profile by increasing serum total cholesterol, which was significantly prevented by fish oil treatment. The vascular protective potential of fish oil in preventing nicotine-induced VED may pertain to its additional properties (besides its lipid-lowering effect) such as activation of PPARγ and subsequent possible activation of endothelial NOS and generation of nitric oxide, and consequent reduction in oxidative stress.     

Mesenchymal Stem Cells Reduce Cigarette Smoke-Induced Inflammation and Airflow Obstruction in Rats via TGF-β1 Signaling

Cigarette smoke has been shown to cause chronic inflammation of the lungs, eventually leading to chronic obstructive pulmonary disease (COPD). Additionally, recent studies have suggested that mesenchymal stem cells (MSCs) can mediate local inflammatory responses in the lungs. Thus, the aim of the present study was to test the effects of rat MSCs (rMSCs) on inflammation of the lungs and destructive pulmonary function induced by cigarette smoke in rats. Rats were exposed to cigarette smoke for 7 weeks. rMSCs were cultured in vitro and infused intratracheally into cigarette smoke-exposed rats. The total and differential cell counts in the bronchoalveolar lavage fluid (BALF), histological changes, pro-inflammatory cytokines, transforming growth factor-β1 (TGF-β1) expression, and pulmonary function were evaluated. Additionally, human peripheral blood mononuclear cells and human MSCs were cocultured in vitro to detect cytokines and TGF-β1 levels. We found that rMSC administration resulted in downregulation of pro-inflammatory cytokines in the lungs while increasing TGF-β1 expression, reducing total inflammatory cell numbers in the BALF, and improving pulmonary histopathology and airflow obstruction. Coculture revealed that human MSCs mediated an anti-inflammatory effect partly via upregulation of TGF-β1. These findings suggested that MSCs may have therapeutic potential in cigarette smoke-induced inflammation and airflow obstruction, partly via upregulation of TGF-β1.     

Moving Beyond JUPITER: Will Inhibiting Inflammation Reduce Vascular Event Rates?

People with schizophrenia have higher rates of medical illness and mortality than the general population. Cardiovascular disease is a major contributor to premature death in patients with schizophrenia. There has been an increase literature discussing the high prevalence of dyslipidemia, which is one of risk factors for cardiovascular disease, induced by second generation antipsychotic agents. Depression is associated with increased risks of diabetes, hypertension, cardiovascular disease. However, those may not be secondary to the use of antidepressant agents. In order to reduce the risk of cardiovascular disease in patients with schizophrenia receiving antipsychotic agents, obtaining fasting lipid measurements at regular intervals is needed. Further investigations are needed to evaluate the effects of antidepressive agents on lipid profiles.     

Ultrasound Biomicroscopic Imaging for Interleukin-1 Receptor Antagonist–Inhibiting Atherosclerosis and Markers of Inflammation in Atherosclerotic Development in Apolipoprotein-E Knockout Mice

We sought to validate the hypothesis that the development of atherosclerosis can be suppressed by the interleukin-1 receptor antagonist (IL-1Ra) in murine models of atherosclerosis in vivo, noninvasively seen by means of high-resolution ultrasound biomicroscopy, and we studied changes in inflammatory markers such as IL-1 and C-reactive protein (CRP) plasma levels in these models of atherosclerosis.We divided IL-1Ra^+/−/apolipoprotein-E (apoE)^−/− and IL-1Ra^+/+/apoE^−/− mice into 2 age groups, used as atherosclerotic models. The control groups were age-matched IL-1Ra^+/+/apoE^+/+ mice. Plaque thickness was measured in the ascending aorta in short-axis images by means of ultrasound and histology. Plasma levels of IL-1 and CRP were quantified in the 3 murine groups.At 16 weeks, plaque thickness in the ascending aortas of the IL-1Ra^+/−/apoE^−/− mice was significantly greater than that in the IL-1Ra^+/+/apoE^−/− mice, on ultrasound and histology (P <0.01). In contrast, at 32 weeks, the differences between these 2 genotypes were not statistically significant. Serum IL-1 levels were lower in the IL-1Ra^+/−/apoE^−/− mice than in the IL-1Ra^+/+/apoE^−/− mice at 16 and 32 weeks (P <0.05). At 16 weeks, serum CRP levels in the IL-1Ra^+/−/apoE^−/− mice were higher than in the IL-1Ra^+/+/apoE^−/− mice (P <0.01).Our results suggest that ultrasound biomicroscopy enables evaluation of atherosclerotic lesions in vivo, noninvasively and in real-time, in apoE^−/− mice. Partial IL-1Ra deficiencies might promote early plaque development in 16-week-old apoE^−/− mice. The balance of IL-1 and IL-1Ra might influence atherosclerotic development. Finally, CRP might affect the initiation of atherosclerosis, rather than its progression.     

Inflammation, TNFα and endothelial dysfunction link lenalidomide to venous thrombosis in chronic lymphocytic leukemia

Patients receiving lenalidomide are at an increased risk for deep venous thrombosis (DVT). Here, we prospectively investigated the DVT risk in patients with relapsed chronic lymphocytic leukemia (CLL) treated with lenalidomide (n = 32). Five patients developed six incidents of DVT over 1 year for an annual incidence of 16%. Three of these were considered drug-related. Median time to DVT was 105 days (range 56-259 days). No pulmonary embolism was detected. Hypercoagulability screen before study entry was negative in all patients who subsequently developed DVTs. Compared to normal volunteers CLL patients had increased baseline levels of D-dimer, thrombin-antithrombin, soluble vascular endothelial adhesion molecule 1 (sVCAM-1), and thrombomodulin (p < 0.001). After 1 week on lenalidomide D-dimer, thrombomodulin, sVCAM-1, factor VIII, TNFα, and C-reactive protein were significantly increased while protein C was decreased (p < 0.001). In patients with lenalidomide-related DVTs, TNFα, and sVCAM-1 were more strongly upregulated than in all other patients (p < 0.05) and TNFα and sVCAM-1 levels were significantly correlated (r = 0.65, p < 0.001). These data link lenalidomide associated DVTs with TNFα upregulation and endothelial cell dysfunction and suggest that aspirin may have a role for DVT prophylaxis in these patients.     

Increased nitric oxide production and gender-dependent changes in PPARα expression and signaling in the fetal lung from diabetic rats

The fetal lung is affected by maternal diabetes. Nuclear receptor PPARα regulates nitric oxide (NO) overproduction in different tissues. We aimed to determine whether fetal lung PPARα expression is altered by maternal diabetes, and if there are gender-dependent changes in PPARα regulation of NO production in the fetal lung. Fetal lungs from control and diabetic rats were explanted on day 21 of gestation and evaluated for PPARα expression and NO production. Fetuses were injected with the PPARα ligand LTB(4) on days 19, 20 and 21, and the fetal lung explanted on day 21 to evaluate PPARα and the inducible isoform of NO synthase (iNOS). Besides, pregnant rats were fed with olive oil- and safflower oil-supplemented diets, enriched in PPAR ligands, for evaluation of fetal lung NO production and PPARα expression. We found reduced PPARα concentrations only in the lung from male fetuses from the diabetic group when compared to controls, although maternal diabetes led to NO overproduction in both male and female fetal lungs. Fetal activation of PPARα led to changes in lung PPARα expression only in female fetuses, although this treatment increased iNOS expression in both male and female fetuses in the diabetic group. Diets supplemented with olive oil and not with safflower oil led to a reduction in NO production in male and female fetal lungs. In conclusion, there are gender-dependent changes in PPARα expression and signaling in the fetal lung from diabetic rats, although PPARα activation prevents maternal diabetes-induced lung NO overproduction in both male and female fetuses.