Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre)adipocytes.

Dipeptidyl peptidase 4 (DPP4) is the target of the gliptins, a recent class of oral antidiabetics. DPP4 (also called CD26) was previously characterized in immune cells but also has important metabolic functions which are not yet fully understood. Thus, we investigated the function of DPP4 in human white preadipocytes and adipocytes.

Non-small cell lung cancer cell survival crucially depends on functional insulin receptors.

Insulin plays an important role as a growth factor and its contribution to tumor proliferation is intensely discussed. It acts via the cognate insulin receptor (IR) but can also activate the IGF1 receptor (IGF1R). Apart from increasing proliferation, insulin might have additional effects in lung cancer.

Dual regulation of β2-adrenoceptor messenger RNA expression in human lung fibroblasts by β2-cAMP signaling; delayed upregulated inhibitors oppose a rapid in onset, direct stimulation of gene expression.

Based on their bronchodilatory effect, β2-adrenoceptor agonists constitute essential elements in the treatment of bronchial asthma and COPD. As treatment with β2-adrenoceptor agonists has been associated with worsening of airway hyper-reactivity, possibly because of loss of β-adrenoceptor function, molecular mechanism of the regulation of β2-adrenoceptor expression were studied. MRC-5 human lung fibroblasts were cultured in absence or presence of test substances followed by β2-adrenoceptor messenger RNA (mRNA) determination by qPCR.

Muscarinic receptor stimulation augments TGF-β1-induced contractile protein expression by airway smooth muscle cells.

Acetylcholine (ACh) is the primary parasympathetic neurotransmitter in the airways. Recently, it was established that ACh, via muscarinic receptors, regulates airway remodeling in animal models of asthma and chronic obstructive pulmonary disease (COPD). The mechanisms involved are not well understood.

β₂-adrenoceptors and muscarinic receptors mediate opposing effects on endothelin-1 expression in human lung fibroblasts.

Human lung fibroblasts are a potential source of endothelin-1 (ET-1), a pro-fibrotic mediator. The present study explored possible muscarinic and β-adrenergic modulations of ET-1 expression in human lung fibroblasts. MRC-5 human lung fibroblasts were cultured.

Endothelin-1 enhances β₂-adrenoceptor gene transcription in human lung fibroblasts.

Aims: The present study aimed to explore possible effects of endothelin-1 (ET-1) on ß(2)-adrenoceptor gene transcription in human lung fibroblasts.

Main Methods: MRC-5 human lung fibroblasts were cultured in absence or presence of test substances, followed by ß(2)-adrenoceptor mRNA determination by quantitative real time PCR.

Key Findings: ET-1 caused a marked and rapid in onset (1 hr) increase in β(2)-adrenoceptor mRNA, an effect additive to that of short time (1 hr) exposure to the β(2)-adrenoceptor agonist olodaterol.

Insulin action on H292 bronchial carcinoma cells as compared to normal bronchial epithelial cells.

Inhaled insulin may contribute to bronchial carcinoma due to IGF-I receptor activation by high local concentrations. Therefore, effects of insulin and IGF-I on human bronchial carcinoma cells (H292) and normal bronchial epithelium cells (HBE) were studied. TGF-β was included since it also influences carcinoma progression.

The β2-subtype of adrenoceptors mediates inhibition of pro-fibrotic events in human lung fibroblasts.

Fibrosis is part of airway remodelling observed in bronchial asthma and COPD. Pro-fibrotic activity of lung fibroblasts may be suppressed by β-adrenoceptor activation. We aimed, first, to characterise the expression pattern of β-adrenoceptor subtypes in human lung fibroblasts and, second, to probe β-adrenoceptor signalling with an emphasis on anti-fibrotic actions.

Inflammatory responses after endothelin B (ETB) receptor activation in human monocytes: new evidence for beneficial anti-inflammatory potency of ETB-receptor antagonism.

Endothelin (ET) stimulates potent ETA/ETB receptors important in the pathogenesis of pulmonary arterial hypertension (PAH) and fibrosis. Though therapy with ET-receptor antagonists is well established uncertainty exists whether selective ETA or dual ETA/ETB-receptor antagonism is superior in PAH. The objective of this study was to further elucidate the pro-inflammatory effects of ET-1 on ETB receptors in cultured human monocytes (10(5)/20 h) compared with non-specific stimulation with LPS in vitro and to define the antagonizing effects of bosentan, a dual ETA/ETB-receptor antagonist, on inflammatory mediator production.

Pulmonary fibroblasts, an emerging target for anti-obstructive drugs.

Fibrotic alterations are part of the airway re-modelling processes observed in asthma and chronic obstructive pulmonary disease. There is increasing evidence that in addition to acute bronchodilatory effects, classical anti-obstructive drugs such as muscarinic antagonists and beta-adrenoceptor agonists may also modulate long-term re-modelling processes. The present review aims to summarise muscarinic and beta-adrenergic effects on pulmonary fibroblasts.

Inhibition of NADPH oxidase by apocynin inhibits lipopolysaccharide (LPS) induced up-regulation of arginase in rat alveolar macrophages.

Reactive oxygen species participate in the pathogenesis of inflammatory airway diseases, in which increased arginase may play a role by interfering with nitric oxide (NO) synthesis and providing substrate for collagen synthesis. Therefore a modulatory role of reactive oxygen species for arginase was explored in alveolar macrophages using the NADPH oxidase inhibitor apocynin. The effects of lipopolysacharides (LPS) and apocynin on nitrite accumulation, arginase activity and mRNA for inducible NO synthase (iNOS), arginase I and II were determined.

MAPK pathway mediates muscarinic receptor-induced human lung fibroblast proliferation.

Airway remodelling is a pathological feature of chronic inflammatory and obstructive airway diseases like asthma and COPD wherein fibroblasts contribute to structural alteration processes. We recently reported expression of multiple muscarinic receptors in human lung fibroblasts and demonstrated muscarinic receptor-induced, G(i)-mediated proliferation in these cells. We now explore the underlying intracellular signalling pathways.

New evidence of H1-receptor independent COX-2 inhibition by fexofenadine HCl in vitro.

Background/aims: Fexofenadine HCl (FEX) has previously been shown to have anti-inflammatory properties in relieving nasal congestion in allergic rhinitis. The objective of this study was to further elucidate the mechanism of action behind the anti-inflammatory properties of FEX in addition to its H(1)-receptor antagonism.

Methods: The effects of two antihistamines, FEX and loratadine (LOR), were investigated on cyclooxygenase (COX)-1 and -2 enzymes in vitro.

Muscarinic receptors mediate stimulation of human lung fibroblast proliferation.

Airway remodeling is a structural alteration associated with chronic inflammatory and obstructive airway diseases, wherein fibroblasts are crucially involved. The present study investigates whether lung fibroblast proliferation is influenced by muscarinic mechanisms. For this purpose, expression of muscarinic receptors in MRC-5 human lung fibroblasts was characterized by semiquantitative RT-PCR, and the effects of muscarinic agonists and antagonists on ((3)H)-thymidine incorporation as a measure of proliferative activity were studied under different culture conditions.

Decreased systemic bioavailability of L-arginine in patients with cystic fibrosis.

Background: L-arginine is the common substrate for nitric oxide synthases and arginases. Increased arginase levels in the blood of patients with cystic fibrosis may result in L-arginine deficiency and thereby contribute to low airway nitric oxide formation and impaired pulmonary function.

Methods: Plasma amino acid and arginase levels were studied in ten patients with cystic fibrosis before and after 14 days of antibiotic treatment for pulmonary exacerbation.

Control by cholinergic mechanisms.

In the respiratory tract acetylcholine is neurotransmitter in ganglia and postganglionic parasympathetic nerves, but in addition is paracrine mediator released from various non-neuronal cells. Almost every cell type present in the respiratory tract expresses nicotinic and muscarinic receptors and therefore appears to be a target for acetylcholine. The present review describes the mechanisms of synthesis and release of acetylcholine from neuronal and non-neuronal cells and the differential control mechanisms.

Differential effects of fexofenadine on arachidonic acid metabolism in cultured human monocytes.

The relief of nasal congestion with the antihistamine fexofenadine in seasonal allergic rhinitis is thought to be due to its additional anti-inflammatory properties. The objective of this study was to evaluate the in vitro effects of fexofenadine on stimulated arachidonic acid metabolism. Human monocytes, isolated from blood and donated by 5 healthy volunteers, were either incubated for 20 h with 10 microg/ml lipopolysaccharide, with and without fexofenadine (10(-8)-10(-3) mol/l, n = 8-19), or were incubated for 20 h, with and without fexofenadine, and then stimulated with 0.

Increased arginase activity in cystic fibrosis airways.

Rationale: Airway nitric oxide concentrations are reduced in cystic fibrosis (CF). Arginases compete for L-arginine, the substrate of nitric oxide synthesis.

Objectives: We hypothesized that increased arginase activity may be one factor contributing to nitric oxide deficiency in CF.

Inhibitory activity of 1,8-cineol (eucalyptol) on cytokine production in cultured human lymphocytes and monocytes.

Background: The therapeutic value of secretolytic agents in COPD and asthma is still disputed. For this reason, in a preclinical study we aimed to test the potential anti-inflammatory efficacy of 1,8-cineol (eucalyptol) in inhibiting polyclonal stimulated cytokine production by human unselected lymphocytes and LPS-stimulated monocytes.

Methods: Cytokine production was determined following 20 h of incubation cells with 1,8-cineol simultaneously with the stimuli in culture supernatants by enzyme immunoassay.

Glucocorticoid inhibition of interleukin-4 (IL-4) and interleukin-13 (IL-13) induced up-regulation of arginase in rat airway fibroblasts.

Arginase appears to play a significant role in the pathogenesis of inflammatory and obstructive airway diseases by interfering with NO synthesis (hyperreactivity) and by providing substrate for collagen synthesis (remodelling). IL-4 and IL-13 are key proinflammatory cytokines in asthma, and their effects on arginase in rat primary airway fibroblasts in culture were studied. Airway fibroblasts showed significant arginase activity, which was higher when the culture medium contained 10% fetal calf serum (FCS) (20 mU/mg protein) compared to 5% FCS (6 mU/mg protein).

Effects of phosphodiesterase inhibitors on L-arginine pathways in rat alveolar macrophages.

Effects of phosphodiesterase inhibitors on L-arginine-dependent pathways in rat alveolar macrophages, inducible nitric oxide (NO) synthase (iNOS) and arginase, were studied. Culture of rat alveolar macrophages in the presence of lipopolysaccharides (20 h) caused an increase of arginase activity (by 135%) and nitrite concentration (fourfold). The nonselective phosphodiesterase inhibitor IBMX (2-isobutyl-1-methylxanthine) enhanced arginase activity by 35% and nitrite accumulation by 130%.