Laropiprant attenuates EP3 and TP prostanoid receptor-mediated thrombus formation.

The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D(2). Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD(2), which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease.

Endothelial E-type prostanoid 4 receptors promote barrier function and inhibit neutrophil trafficking.

Background: Increased vascular permeability is a fundamental characteristic of inflammation. Substances that are released during inflammation, such as prostaglandin (PG) E(2), can counteract vascular leakage, thereby hampering tissue damage.

Objective: In this study we investigated the role of PGE(2) and its receptors in the barrier function of human pulmonary microvascular endothelial cells and in neutrophil trafficking.

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors.

Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE(2) and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE(2) and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxin-induced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures.

EP4 receptor stimulation down-regulates human eosinophil function.

Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE(2) receptor EP4, ONO AE1-329, potently attenuated the chemotaxis of human peripheral blood eosinophils, upregulation of the adhesion molecule CD11b and the production of reactive oxygen species. These effects were accompanied by the inhibition of cytoskeletal rearrangement and Ca(2+) mobilization.

The prostaglandin E2 receptor EP4 is expressed by human platelets and potently inhibits platelet aggregation and thrombus formation.

Objective: Low concentrations of prostaglandin (PG) E(2) enhance platelet aggregation, whereas high concentrations inhibit it. The effects of PGE(2) are mediated through 4 G protein-coupled receptors, termed E-type prostaglindin (EP) receptor EP1, EP2, EP3, and EP4. The platelet-stimulating effect of PGE(2) has been suggested to involve EP3 receptors.

CRTH2 and D-type prostanoid receptor antagonists as novel therapeutic agents for inflammatory diseases.

Accumulation of type 2 T helper (Th2) lymphocytes and eosinophils is a hallmark of bronchial asthma and other allergic diseases, and it is believed that these cells play a crucial pathogenic role in allergic inflammation. Thus, Th2 cells and eosinophils are currently considered a major therapeutic target in allergic diseases and asthma. However, drugs that selectively target the accumulation and activation of Th2 cells and eosinophils in tissues are unavailable so far.

Endothelium-derived prostaglandin I(2) controls the migration of eosinophils.

Background: Enhanced eosinophil migration from the blood into the tissue is a hallmark of allergic diseases. Prostaglandin (PG) I(2) is the major prostanoid released by endothelial cells. Mice deficient in PGI(2) receptors (IPs) show exaggerated eosinophilic inflammation in response to allergen.

Role of lipoxygenases and lipoxin A(4)/annexin-1 receptor in gastric protection induced by 20% ethanol or sodium salicylate in rats.

The role of cyclooxygenases and prostaglandins in experimental models of gastroprotection is well established. We investigated the effects of the 5-lipoxygenase inhibitor A63162, the 12-lipoxygenase inhibitor baicalein and the 15-lipoxygenase inhibitor PD146176 as well as the nonspecific lipoxin A(4)/annexin-1 antagonist Boc1 on adaptive protection induced by 20% ethanol against 70% ethanol, and on protection induced by sodium salicylate against the mucosal-damage-aggravating effects of celecoxib and dexamethasone during local ischemia-reperfusion in rats. It was found that both types of gastroprotection were antagonized by the lipoxygenase inhibitors and the lipoxin A(4)/annexin-1 antagonist in doses that have no direct damaging effect on gastric mucosa.

Role of lipoxygenases and the lipoxin A(4)/annexin 1 receptor in ischemia-reperfusion-induced gastric mucosal damage in rats.

Rat gastric mucosal damage was induced by ischemia-reperfusion. The 5-lipoxygenase inhibitors MK886 and A63162, the 12-lipoxygenase inhibitor baicalein, the 15-lipoxygenase inhibitor PD146176 and the lipoxin (LX) A(4)/annexin 1 antagonist Boc1 increased mucosal damage in a dose-dependent manner. Low doses of these compounds, which have no effects on mucosal integrity, cause severe damage when combined with low doses of indomethacin, celecoxib or dexamethasone.

Prostaglandin E2 inhibits eosinophil trafficking through E-prostanoid 2 receptors.

The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Prostaglandin (PG) E(2) exerts anti-inflammatory and bronchoprotective mechanisms in asthma, but the underlying mechanisms have remained unclear. In this study we show that PGE(2) potently inhibits the chemotaxis of purified human eosinophils toward eotaxin, PGD(2), and C5a.

Prostaglandin H2 induces the migration of human eosinophils through the chemoattractant receptor homologous molecule of Th2 cells, CRTH2.

The major mast cell product PGD2 is released during the allergic response and stimulates the chemotaxis of eosinophils, basophils, and Th2-type T lymphocytes. The chemoattractant receptor homologous molecule of Th2 cells (CRTH2) has been shown to mediate the chemotactic effect of PGD2. PGH2 is the common precursor of all PGs and is produced by several cells that express cyclooxygenases.

Kallikrein inhibitors limit kinin B(2) antagonist-induced progression of oedematous to haemorrhagic pancreatitis in rats.

Background And Purpose: Exocrine hyperstimulation with caerulein is an established model for oedematous acute pancreatitis. Prevention of oedema formation by bradykinin B(2) receptor antagonists induces a progression to a haemorrhagic course in this model. We have investigated whether increased kallikrein activity in the pancreas is responsible for vascular damage and whether this could be prevented by selective kallikrein inhibitors.

CRTH2 is not involved in the anti-enteropooling effect of PGD2 in the small intestine.

The majority of prostaglandins (PGs) are known to induce intestinal fluid secretion (enteropooling). In contrast, PGD(2) has been demonstrated to inhibit fluid secretion induced by other PGs. This study was aimed to investigate, by the use of selective agonists/antagonists, which type of PGD(2) receptor mediates this inhibitory effect.

Anti-inflammatory actions of perfluorooctanoic acid and peroxisome proliferator-activated receptors (PPAR) alpha and gamma in experimental acute pancreatitis.

Perfluorooctanoic acid (PFOA) and agonists of peroxisome proliferator-activated receptors (PPAR) alpha and gamma were investigated for potential anti-inflammatory effects in cerulein-induced acute pancreatitis in rats. PFOA significantly reduced both leukocyte accumulation and prostanoid synthesis. The PPAR-alpha agonist clofibrate had no effect on leukocyte activation but significantly inhibited prostanoid synthesis whereas the PPAR-gamma agonist rosiglitazone significantly reduced leukocyte activation but did not affect synthesis of prostaglandins in the pancreas.

Effect of endotoxin treatment on the expression and localization of spinal cyclooxygenase, prostaglandin synthases, and PGD2 receptors.

Systemic inflammation leads to increased expression of spinal cyclooxygenase (COX)-2 and to a subsequent increase of prostaglandin (PG) biosynthesis, which contribute to the development of hyperalgesia and allodynia. In this study, endotoxin caused a sequential induction of membrane bound prostaglandin E synthase-1 and lipocalin-type PGD synthase (L-PGDS) in the mouse spinal cord. L-PGDS expression was detected in the leptomeninges, oligodendrocytes, and interestingly, in discrete perivascular cells.

The role of the prostaglandin D2 receptor, DP, in eosinophil trafficking.

Prostaglandin (PG) D2 is a major mast cell product that acts via two receptors, the D-type prostanoid (DP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role of DP has remained unclear. We report in this study that, in addition to CRTH2, the DP receptor plays an important role in eosinophil trafficking.

A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst.

Background: Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been revealed to be a novel receptor for prostaglandin (PG) D(2), which is a major mast cell product released during the allergic response. The aim of this study was to analyze the effects of a newly developed small molecule antagonist of CRTH2, Cay10471, on eosinophil function with respect to recruitment, respiratory burst and degranulation.

Methods: Chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils were determined using microBoyden chambers.

PGD2 metabolism in plasma: kinetics and relationship with bioactivity on DP1 and CRTH2 receptors.

Prostaglandin (PG)D(2), an important mediator in allergic diseases, is rapidly transformed in plasma to active metabolites that bind and activate two distinct receptors, DP1 and CRTH2. Since the rate of PGD(2) degradation and the bioactivity of the resulting metabolites are still unclear, the aim of our study was to analyze the kinetics and biological effects of PGD(2) metabolites formed in plasma. Eosinophil shape change was taken as a parameter of chemotactic activation mediated by CRTH2 whereas inhibition of platelet aggregation served as a measure of DP1 activity.

Hierarchy of eosinophil chemoattractants: role of p38 mitogen-activated protein kinase.

Several chemoattractants can regulate the recruitment of eosinophils to sites of inflammation, but the hierarchy among them is unknown. We observed here that eosinophil chemotaxis towards eotaxin or 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) was amplified up to sixfold in the presence of prostaglandin (PG) D2. This effect was only seen in eosinophils, and not in neutrophils or basophils.

Dexamethasone impairs the gastric mucosal integrity in rats treated with a cyclooxygenase-1 but not with a cyclooxygenase-2 inhibitor.

In rats, neither the cyclooxygenase-1 inhibitor SC-560 nor the cyclooxygenase-2 inhibitor rofecoxib damages the gastric mucosa. Coadministration of dexamethasone induced injury in SC-560- but not in rofecoxib-treated rats. High levels of cyclooxygenase-1 protein occurred in the gastric mucosa of control rats, with no change after administration of SC-560.

Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice.

Traditional NSAIDs, selective cyclooxygenase (COX)-2 inhibitors, and inhibitors of nitric oxide synthase (NOS) impair the healing of preexisting gastric ulcers. However, the role of COX-1 (with or without impairment of COX-2) and the interaction between COX and NOS isoforms during healing are less clear. Thus we investigated healing and regulation of COX and NOS isoforms during ulcer healing in COX-1 and COX-2 deficiency and inhibition mouse models.

Selective increase of dark phase water intake in neuropeptide-Y Y2 and Y4 receptor knockout mice.

Neuropeptide-Y (NPY) is involved in the regulation of ingestive behaviour and energy homeostasis. Since deletion of the NPY Y2 and Y4 receptor gene increases and decreases food intake, respectively, we examined whether water intake during the light and dark phases is altered in Y2 and Y4 receptor knockout mice. The water consumption of mice staying in their home cages was measured by weighing the water bottles at the beginning and end of the light phase during 4 consecutive days.

5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent chemoattractant for human basophils.

Background: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a chemoattractant for eosinophils and neutrophils, and the messenger RNA for its receptor, the oxo-eicosatetraenoic acid receptor (OXE), has been detected in several tissues.

Objectives: This study aimed at clarifying the role of 5-oxo-ETE in the regulation of basophil function.

Methods: Basophil responses were determined in assays of flow-cytometric shape change, Ca(2+) flux, chemotaxis, and histamine release.

Role of cyclooxygenase isoforms in gastric mucosal defense and ulcer healing.

The rationale for the development of selective inhibitors of cyclooxygenase-2 (COX-2) was the proposal that this enzyme plays an important role in inflammation but does not contribute to the resistance of the gastrointestinal mucosa against injury. However, studies from several groups have established that both COX-1 and COX-2 have important functions in the maintenance of gastrointestinal mucosal integrity. Thus, in the normal rat stomach lesions only develop when both COX-1 and COX-2 are inhibited.

Stem cell factor stimulates the chemotaxis, integrin upregulation, and survival of human basophils.

Background: Little is known about the mechanisms that regulate the selective recruitment of basophils to sites of allergic inflammation.

Objective: Here we examine the role of stem cell factor (SCF) in the regulation of basophil function.

Methods: Human basophils were isolated from peripheral blood, and their migration was investigated in chemotaxis assays.