Anti-inflammatory effects of PGE2 in the lung: role of the EP4 receptor subtype.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway. Current treatment options (long acting ß-adrenoceptor agonists and glucocorticosteroids) are not optimal as they are only effective in certain patient groups and safety concerns exist regarding both compound classes. Therefore, novel bronchodilator and anti-inflammatory strategies are being pursued. Prostaglandin E2 (PGE2) is an arachidonic acid-derived eicosanoid produced by the lung which acts on four different G-protein coupled receptors (EP1-4) to cause an array of beneficial and deleterious effects. The aim of this study was to identify the EP receptor mediating the anti-inflammatory actions of PGE2 in the lung using a range of cell-based assays and in vivo models. METHODS AND RESULTS: It was demonstrated in three distinct model systems (innate stimulus, lipopolysaccharide (LPS); allergic response, ovalbumin (OVA); inhaled pollutant, cigarette smoke) that mice missing functional EP4 (Ptger4(-/-)) receptors had higher levels of airway inflammation, suggesting that endogenous PGE2 was suppressing inflammation via EP4 receptor activation. Cell-based assay systems (murine and human monocytes/alveolar macrophages) demonstrated that PGE2 inhibited cytokine release from LPS-stimulated cells and that this was mimicked by an EP4 (but not EP1-3) receptor agonist and inhibited by an EP4 receptor antagonist. The anti-inflammatory effect occurred at the transcriptional level and was via the adenylyl cyclase/cAMP/ cAMP-dependent protein kinase (PKA) axis. CONCLUSION: This study demonstrates that EP4 receptor activation is responsible for the anti-inflammatory activity of PGE2 in a range of disease relevant models and, as such, could represent a novel therapeutic target for chronic airway inflammatory conditions.

[Development of anti-inflammatory drugs targeted against prostaglandin-related molecules].

Prostaglandin E2 (PGE2) is a proinflammatory mediator that is synthesized by cyclooxygenases (COX-1 and COX-2) and prostaglandin E synthases (cPGES-1 and mPGES-1); PGE2 exerts its biological effects by binding to specific receptors. Although non-steroidal anti-inflammatory drugs(NSAIDs), which are non-selective COX inhibitors, have been very often used as painkillers, their side effects such as gastrointestinal hemorrhage remain a serious problem. Therefore, the selective COX-2 inhibitors were developed; the use of these inhibitors exerted anti-inflammatory effects without the increased risk of gastrointestinal events. Unfortunately, however, several clinical studies demonstrated that the inhibition of COX-2 was associated with the increased risk of cardiovascular events. Consequently, mPGES-1 and PGE2 receptors are currently expected to be attractive targets for anti-inflammatory drug development in order to reduce the side effects.

EP4 agonist alleviates indomethacin-induced gastric lesions and promotes chronic gastric ulcer healing.

AIM: To investigate EP4-selective agonist effect on indomethacin-induced gastric lesions and on the spontaneous healing of chronic gastric ulcers. METHODS: In a mouse model of gastric bleeding with high dose of indomethacin (20 mg/kg), an EP4-selective agonist was administered orally. Stomach lesions and gastric mucous regeneration were monitored. In a mouse model of chronic gastric ulcer induced by acetic acid, EP4 agonist effect on the healing of chronic gastric ulcer was evaluated in the presence or absence of low dose indomethacin (3 mg/kg). In cultured human gastric mucous cells, EP4 agonist effect on indomethacin-induced apoptosis was assessed by flow cytometry. RESULTS: The EP4-selective agonist reduced high dose indomethacin-induced acute hemorrhagic damage and promoted mucous epithelial regeneration. Low-dose indomethacin aggravated ulcer bleeding and inflammation, and delayed the healing of the established chronic gastric ulcer. The EP4 agonist, when applied locally, not only offset indomethacin-induced gastric bleeding and inflammation, but also accelerated ulcer healing. In the absence of indomethacin, the EP4 agonist even accelerated chronic gastric ulcer healing and suppressed inflammatory cell infiltration in the granulation tissue. In vitro, the EP4 agonist protected human gastric mucous cells from indomethacin-induced apoptosis. CONCLUSION: EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells.

Valor predictivo del ecodoppler color peneano con inyección de droga vasoactiva en pacientes con disfunción eréctil / Penile color Doppler US predictive value after vasoactive drug injection in patients with erectile disfunction

A fin de demostrar la utilidad del eco Doppler con drogas vasoactivas para definir la terapéutica en pacientes con disfunción eréctil se estudiaron 54 pacientes con tumescencia nocturna insuficiente, a quienes se les realizó ecografía peneana y Doppler color de las materias cavernosas en condiciones basales y con inyección intracavernosa de 1 cm3 de Trimix, registrándose las velocidades sistólicas basales y postinyección temprana, tardía y postestímulo y evaluando las velocidades sistólicas, distólicas y los índices de resistencia. Los estudios permitieron clasificar a los pacientes en 5 grupos de acuerdo a la etiología de la disfunción y de ese modo brindarles la terapéutica adecuada

Valor predictivo del ecodoppler color peneano con inyección de droga vasoactiva en pacientes con disfunción eréctil / Penile color Doppler US predictive value after vasoactive drug injection in patients with erectile disfunction

A fin de demostrar la utilidad del eco Doppler con drogas vasoactivas para definir la terapéutica en pacientes con disfunción eréctil se estudiaron 54 pacientes con tumescencia nocturna insuficiente, a quienes se les realizó ecografía peneana y Doppler color de las materias cavernosas en condiciones basales y con inyección intracavernosa de 1 cm3 de Trimix, registrándose las velocidades sistólicas basales y postinyección temprana, tardía y postestímulo y evaluando las velocidades sistólicas, distólicas y los índices de resistencia. Los estudios permitieron clasificar a los pacientes en 5 grupos de acuerdo a la etiología de la disfunción y de ese modo brindarles la terapéutica adecuada (AU)