Anti-allergic, anti-asthmatic and anti-inflammatory effects of an oxazolidinone hydroxamic acid derivative (PH-251) - A novel dual inhibitor of 5-lipoxygenase and mast cell degranulation.

We have recently reported the discovery of a series of oxazolidinone hydroxamic acid derivatives that are potent inhibitors of 5-lipoxygenase (5-LO) [arachidonate 5-lipoxygenase; EC 1.13.11.

Synthesis and structure-activity relationships of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives as 5-lipoxygenase inhibitors.

Oxazolidinone hydroxamic acid derivatives were synthesised and evaluated for inhibitory activity against leukotriene (LT) biosynthesis in three cell-based test systems and on direct inhibition of recombinant human 5-lipoxygenase (5-LO). Thirteen of the 19 compounds synthesised were considered active ((50% inhibitory concentration (IC) ≤ 10 µM in two or more test systems)). Increasing alkyl chain length on the hydroxamic acid moiety enhanced activity and morpholinyl-containing derivatives were more active than -acetyl-piperizinyl derivatives.

Ang-(1-7)/ MAS1 receptor axis inhibits allergic airway inflammation via blockade of Src-mediated EGFR transactivation in a murine model of asthma.

The angiotensin-(1-7) [Ang-(1-7)]/MAS1 receptor signaling axis is a key endogenous anti-inflammatory signaling pathway. However, the mechanisms by which its mediates the anti-inflammatory effects are not completely understood. Using an allergic murine model of asthma, we investigated whether Ang-1(1-7)/MAS1 receptor axis a): inhibits allergic inflammation via modulation of Src-dependent transactivation of the epidermal growth factor receptor (EGFR) and downstream signaling effectors such as ERK1/2, and b): directly inhibits neutrophil and/or eosinophil chemotaxis ex vivo.

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model.

The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kδ/Akt and NF-κB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IκB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice.

Cyclic Adenosine Monophosphate-Mediated Enhancement of Vascular Endothelial Growth Factor Released by Differentiated Human Monocytic Cells: The Role of Protein Kinase A.

Objective: Our investigation was designed to examine the signaling pathway involved in the enhancement of vascular endothelial growth factor (VEGF) release by β-adrenoceptor agonists.

Materials And Methods: Human U937 cells differentiated into macrophages were primed with lipopolysaccharide (LPS) in the absence or presence of β-adrenoceptor agonists and antagonists. The VEGF released and the intracellular cyclic adenosine monophosphate (cAMP) generated were assayed by ELISA.

Antiallergic and antiasthmatic effects of a novel enhydrazinone ester (CEE-1): inhibition of activation of both mast cells and eosinophils.

Activation of mast cells and eosinophils is a fundamental process in the pathophysiology of allergic diseases. We have previously reported that the novel enhydrazinone ester CEE-1 (ethyl 4-phenylhydrazinocyclohex-3-en-2-oxo-6-phenyl-1-oate) possesses potent anti-inflammatory activity. We have now tested whether the compound also possesses antiallergic and antiasthmatic effects in vitro and in vivo.

Anti-tussive and bronchodilator mechanisms of action for the enaminone E121.

Aims: In this study, we investigated whether the enaminone, E121, has anti-tussive effects in a guinea pig model of cough, and if so, whether this effect is mediated via a central or peripheral site of action. We also assessed whether E121 has bronchodilator effects and the molecular mechanisms underlying any anti-tussive and/or bronchodilator effects.

Main Methods: Whole body plethysmography was used to assess both cough and airway obstruction.

Loss of surface beta-2 adrenoceptors accounts for the insensitivity of cultured human monocytes to beta-2 adrenoceptor agonists.

The short-acting beta-2 adrenoceptor agonists (β(2)-agonists), such as salbutamol, are effective bronchodilators used to treat asthma. They lack significant anti-inflammatory effect in vivo as well as on isolated alveolar macrophages even though they exhibit this effect on freshly isolated monocytes. The purpose of this study was to determine if this observation is related to a change in the expression and/or function of surface β(2)-receptors during the differentiation of these cells to macrophages.

Interactions between theophylline and salbutamol on cytokine release in human monocytes.

The combination of beta(2)-adrenoceptor agonists (beta(2)-agonists) with inhaled steroids has become the standard treatment for mild to moderate asthma. Theophylline has also been combined successfully with inhaled steroids. However, the possible interaction between theophylline and beta(2)-agonists, with regard to their anti-inflammatory effects, has not been clarified.

Low-affinity IgE receptor (FcepsilonRII)-mediated activation of human monocytes by both monomeric IgE and IgE/anti-IgE immune complex.

Monocytes and macrophages of individuals with allergic diseases express increased levels of the low-affinity IgE receptors (FcepsilonRII or CD23) on their surfaces. The cross-linking of CD23-bound IgE antibody by allergen activates the cells to release inflammatory mediators. In mast cells, the binding of IgE to the high-affinity IgE receptors (FcepsilonRI) has recently been shown to activate these cells independent of allergen.

In vitro and in vivo anti-inflammatory effects of andrographolide.

Andrographolide - the major active principle isolated from the plant Andrographis paniculata, has been shown to possess a strong anti-inflammatory activity. The possibility that the drug may affect asthmatic inflammation, through inhibition of the relevant inflammatory cytokines, has not been explored. The purpose of this study was, firstly, to investigate the ability of andrographolide to inhibit the release of inflammatory cytokines in vitro in a model of non-specific inflammation and subsequently to determine whether such effect can also be exerted in vivo in allergic lung inflammation.

The role of adenosine A(2) receptors in the regulation of TNF-alpha production and PGE(2) release in mouse peritoneal macrophages.

The adenosine A(2) receptors are known to mediate most of the anti-inflammatory activities of adenosine. In lipopolysaccharides (LPS)-stimulated macrophages adenosine strongly inhibits TNF-alpha release, but may also enhance PGE(2) generation. The aims of this study were to determine the relative contributions of the A(2A) and A(2B) receptor subclasses in these two effects and to determine whether the enhanced release of PGE(2) contributes to the inhibition of TNF-alpha release.

Reactive oxygen species mediate phorbol ester-stimulated cAMP response in human eosinophils.

Recently, we showed that phorbol 12-myristate 13-acetate (PMA) can cause a direct, PKC-dependent, stimulation of intracellular cAMP in human eosinophils. Since PMA also stimulates the release of reactive oxygen species in these cells, we have investigated whether reactive oxygen species are involved in the cAMP response. Provided eosinophils were incubated for <20 min at 37 degrees C before stimulation, PMA potently stimulated cAMP generation that surpassed that of histamine.

Therapy of bronchial asthma with adenosine receptor agonists or antagonists.

Adenosine is an endogenous nucleoside that is released under pathological conditions and interacts with four G-protein-coupled receptor subtypes. These receptors are widely distributed throughout the body. They are involved in many central and peripheral processes, including immunological and inflammatory responses.

Positive coupling of atypical adenosine A3 receptors on human eosinophils to adenylyl cyclase.

Adenosine A(3) receptors are reported to couple negatively to adenylyl cyclase (AC) but their mediation of anti-inflammatory effects in human eosinophils prompted us to investigate their coupling to AC. The A(3)-selective agonists IB-MECA and Cl-IB-MECA evoked a concentration-dependent generation of cAMP (EC(50), 3.2 and 1.

Characteristics of asthmatic children in Kuwait.

This article summarizes clinical characteristics and identifies sensitizing allergens in 135 asthmatic children under 13 years of age in Kuwait, a desert environment with scant vegetation and weather conditions least associated with asthma. There were 84 males (M:F 1.65:1).

Effect of wortmannin on human eosinophil responses in vitro and on bronchial inflammation and airway hyperresponsiveness in Guinea pigs in vivo.

Many mediators activate eosinophils via transduction pathways involving the enzyme phosphatidylinositol 3-kinase. The initial investigation of wortmannin, a specific inhibitor of PI3-kinase, was of its effect on human and guinea pig eosinophil superoxide (O(2)(-)) release and degranulation in vitro. Subsequently, the effect on allergen- and Sephadex-induced bronchial inflammation and airway hyperresponsiveness (AHR) in vivo in guinea pigs was investigated.

Involvement of A(3) receptors in the potentiation by adenosine of the inhibitory effect of theophylline on human eosinophil degranulation: possible novel mechanism of the anti-inflammatory action of theophylline.

The current use of theophylline in asthma is based on both the bronchodilatory and the anti-inflammatory effects. The exact mechanism of these actions is still controversial and may include the inhibition of adenosine 3',5'-monophosphate phosphodiesterase enzyme (PDE) and antagonism of adenosine receptors. In this study, the mechanism of the anti-inflammatory action was investigated by studying the inhibition by theophylline of complement C5a (C5a)-induced degranulation of human eosinophils and its interaction with adenosine.

Requirement of additional adenylate cyclase activation for the inhibition of human eosinophil degranulation by phosphodiesterase IV inhibitors.

Human eosinophils contain predominantly phosphodiesterase type IV, but selective inhibitors of this isoenzyme fail to inhibit certain eosinophil responses such as degranulation. In this study, the effect of activation of adenylate cyclase on the ability of several highly selective PDE IV inhibitors to inhibit complement C5a-induced O2- release and degranulation of human eosinophils in vitro was investigated. All four selective PDE IV inhibitors, N-(3,5-dichloropyrid-4-yl)-3-cyclopentyl-oxy-4-methoxybenzamide (RP 73401), rolipram, N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylacidamide (AWD 12-281) and c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexane carboxylic acid) (SB 207499) potently inhibited C5a-induced O2- generation (IC50 = 0.

Histamine H(2) receptors mediate the inhibitory effect of histamine on human eosinophil degranulation.

The effect of histamine on human eosinophil degranulation and the receptor mediating such effect were studied in vitro using the complement C5a-mediated eosinophil peroxidase (EPO) release model. Following pre-treatment with 5 microg ml(-1) cytochalasin B(CB), C5a induced a concentration-dependent release of EPO from eosinophils isolated from healthy donors. Histamine (0.