cicaprost and Inflammation

To investigate the therapeutic potential of a prostacyclin (IP) receptor agonist for ocular inflammation and the effect on immune cells.. The anti-inflammatory activities of cicaprost were determined in primary human monocyte-derived macrophages and human monocyte-derived dendritic cells (MoDC), as well as a lipopolysaccharides (LPS)-induced rat uveitis model. Multiple cytokine release was measured by utilizing Luminex Technology. Prostacyclin (IP) Receptor expression was detected by reverse transcription-polymerase chain receptor. Leukocyte infiltration and protein exudation in the rat uveitis model were measured using a hemocytometer and protein concentration by a NanoDrop instrument.. Cicapost, an IP receptor agonist, potently inhibits proinflammatory chemokines/cytokine production not only from LPS- or TNFα (tumor necrosis factor-alpha)-induced primary human monocyte-derived macrophages, but also from LPS-stimulated MoDC. While constitutively expressed in macrophages, the IP receptor was inducible by LPS stimulation in MoDCs. In a LPS-induced rat uveitis model, cicaprost efficaciously prevents ocular inflammatory cell and protein leakage, as well as inflammatory cytokine release.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Dendritic Cells; Disease Models, Animal; Epoprostenol; Humans; Inflammation; Lipopolysaccharides; Macrophages; Male; Rats, Inbred Lew; Receptors, Epoprostenol; Tumor Necrosis Factor-alpha; Uveitis

Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration-approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.

Topics: Allergens; Animals; Antihypertensive Agents; Asthma; CD4-Positive T-Lymphocytes; Cell Proliferation; Chemokines; Epoprostenol; Hypersensitivity; Indomethacin; Inflammation; Interleukin-13; Interleukin-5; Lung; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Knockout; Ovalbumin; Receptors, Epoprostenol; Signal Transduction; STAT6 Transcription Factor; Th2 Cells

Prostacyclin (PGI2) is well known to play crucial roles in induction of edema and pain behavior in the periphery. In the present study, we investigated the central role of PGI2 in inflammatory pain. Intraplantar injection of carrageenan markedly induced the expression of prostacyclin receptor (IP receptor) mRNA with the maximum at 6 h, coincidently induction of the inducible form of cyclooxygenase (COX-2), although IP receptor mRNA was weakly expressed in the spinal cord of naive mice. Intrathecal administration of the IP agonist cicaprost induced mechanical hyperalgesia 6 h after carrageenan injection. These results suggest that PGI2 is involved in pain transmission at the spinal cord following expression of IP receptor mRNA induced by peripheral inflammation.

Topics: Animals; Brain; Carrageenan; Epoprostenol; Hindlimb; Hyperalgesia; Inflammation; Male; Mice; Nociceptors; Pain Threshold; Physical Stimulation; Receptors, Epoprostenol; Receptors, Prostaglandin; Reference Values; RNA, Messenger; Time Factors

Prostanoids are a group of bioactive lipids working as local mediators and include D, E, F and I types of prostaglandins (PGs) and thromboxanes. Prostacyclin (PGI2) acts on platelets and blood vessels to inhibit platelet aggregation and to cause vasodilatation, and is thought to be important for vascular homeostasis. Aspirin-like drugs, including indomethacin, which inhibit prostanoid biosynthesis, suppress fever, inflammatory swelling and pain, and interfere with female reproduction, suggesting that prostanoids are involved in these processes, although it is not clear which prostanoid is the endogenous mediator of a particular process. Prostanoids act on seven-transmembrane-domain receptors which are selective for each type. Here we disrupt the gene for the prostacyclin receptor in mice by using homologous recombination. The receptor-deficient mice are viable, reproductive and normotensive. However, their susceptibility to thrombosis is increased, and their inflammatory and pain responses are reduced to the levels observed in indomethacin-treated wild-type mice. Our results establish that prostacyclin is an antithrombotic agent in vivo and provide evidence for its role as a mediator of inflammation and pain.

Topics: Animals; Antithrombins; Blood Pressure; Dinoprostone; Epoprostenol; Gene Targeting; Inflammation; Mice; Mice, Inbred C57BL; Mutagenesis; Pain; Platelet Aggregation; Receptors, Epoprostenol; Receptors, Prostaglandin; Restriction Mapping; Thrombosis