u-0126 and Respiratory-Distress-Syndrome

Prostaglandin E(2) (PGE(2)) is a bioactive prostanoid implicated in the inflammatory processes of acute lung injury/acute respiratory distress syndrome. This study investigated whether PGE(2) can induce production of interleukin (IL)-8, the major chemokine for neutrophil activation, from human pulmonary microvascular endothelial cells (HPMVECs). PGE(2) significantly enhanced IL-8 protein production with increases in IL-8 mRNA expression and intracellular cAMP levels. HPMVECs expressed only EP4 receptor mRNA. The PGE(2) effects were mimicked by a selective EP4 receptor agonist, ONO-AE1-329, and inhibited by a selective EP4 receptor antagonist, ONO-AE3-208, or a protein kinase A inhibitor, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylamine salt. The specific agonist for EP1, EP2, or EP3 receptor did not induce IL-8 production. PGE(2)-induced IL-8 production was accompanied by p38 phosphorylation and was significantly inhibited by a p38 inhibitor, SB-203580, but not by an ERK1/2 inhibitor, U-0126, or a JNK inhibitor, SP-600125. Additionally, PGE(2) increased cyclooxygenase-2 expression with no change in constitutive cyclooxygenase-1 expression, suggesting possible involvement of an autocrine or paracrine manner. In conclusion, PGE(2) enhances IL-8 production via EP4 receptor coupled to G(s) protein in HPMVECs. Activation of the cAMP/protein kinase A pathway, followed by p38 activation, is essential for these mechanisms. Because neutrophils play a critical role in the inflammation of acute lung injury/acute respiratory distress syndrome, IL-8 released from the pulmonary microvasculature in response to PGE(2) may contribute to pathophysiology of this disease.

Topics: Acute Lung Injury; Anthracenes; Butadienes; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Endothelial Cells; Humans; Imidazoles; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lung; MAP Kinase Signaling System; Methyl Ethers; Microvessels; Naphthalenes; Neutrophils; Nitriles; p38 Mitogen-Activated Protein Kinases; Phenylbutyrates; Pyridines; Receptors, Prostaglandin E, EP4 Subtype; Respiratory Distress Syndrome; RNA, Messenger; Thionucleotides

To investigate the relationship between aquaporin 4 (AQP4) in alveolar type II (AT-II) cells and MAPK signaling pathway in rats with early-stage oleic acid-induced acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).. Three groups of rats, namely the normal control, ALI and U0126 treatment group were used in this study. After oleic acid-induced ALI in the latter two groups, the rats in the treatment group received 100 micromol/L U0126 treatment at the dose of 10 micro, and dimethyl sulfoxide (DMSO) were given in the normal control and ALI groups. Arterial blood gas and the extravascular lung water (EVLW) content were measured after the treatments, and pathological changes in the lung tissues were observed microscopically. ATII cells were isolated from the lung tissues and identified using tannic acid staining and alkaline phosphatase (APK) staining. The expression of AQP-4 mRNA in the cells was detected with RT-PCR.. Blood gas analysis, HE staining and EVLW content measurement revealed severer injury of the lung tissues in ALI group than in the normal control group, but the severity was comparable between the treatment and ALI groups. RT-PCR demonstrated significantly increased AQP-4 mRNA expression in ALI group as compared with that in the normal control group, and U0126 treatment resulted in obvious reduction in AQP-4 mRNA expression in the U0126 treatment group.. Oleic acid-induced ALI results in the activation of MAPK signaling pathway and up-regulation of AQP-4 mRNA expression in the ATII cells of rats.

Topics: Acute Lung Injury; Animals; Aquaporin 4; Butadienes; Extravascular Lung Water; Gene Expression Regulation; Male; MAP Kinase Signaling System; Nitriles; Oleic Acid; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; RNA, Messenger