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  • It has been reported that

    2019-08-01

    It has been reported that cAMP also acts via Epac and Epac to attenuate CREB. However, in human monocytes ONO-AE1-329 (the EP4 receptor agonist used in this study) worked entirely through the cAMP-PKA pathway and not vis Epac [12]. Our data suggests that the cAMP-PKA-CREB pathway predominates for MUC5AC secretion in these cultured human airway epithelial cells. EP2 receptor activation at the apical side increased MUC5AC mRNA in ciliated-enriched cells. This is consistent with reports that the EP2 receptor is mainly expressed at the apical surface of epithelial cells and EP2 receptor activation increased intracellular cAMP [7], [22]. Although it is possible that EP2 increases secreted mucin, this is probably clinically irrelevant as we found decreased EP2 receptor expression on IL-13 transformed goblet cells and no significant effect on mucin in those cultures. We previously reported that sPLA2 increases secreted mucin from goblet cells through both the cyclooxygenase and the lipoxygenase pathways [17]. It is also reported that IL-1β induced PGE2 production in airway epithelial cells and increased MUC5AC production [14]. Although Trudeau and colleagues reported that IL-13 attenuates PGE2 synthesis and PGE2 secretion in airway cells from normal and ITE subjects [23], both the data presented in these experiments and our previous studies showed that 14 days exposure to IL-13 increases PGE2 secretion, which is consistent with clinical reports that PGE2 in asthma sputa is greatly increased [8], [17]. PGE2 most likely increases secreted mucin in asthma through the EP4 receptor. Differing from our results, an in vivo study showed that subcutaneous injection of the EP2, EP3, and EP4 receptor agonists blocked mucus hypersecretion induced by ovalbumin challenge in the rat nose [24], whilst we show that EP4 receptor activation increased MUC5AC production. It may be that in the animal study, the systemic administration of the EP4 receptor agonist activated circulating macrophages or monocytes inhibiting inflammatory cytokine release including IL-13 [7], [12]. It is also possible that activation of the receptors has a different effect in the rat than in cultured human airway cells. Clinically, inhibition of cyclooxygenase (the pathway necessary for prostaglandin synthesis), can profoundly worsen asthma in so-called triad asthmatics who are sensitive to acetyl silicic acid. Although the pathogenic mechanism of this type of asthma is not fully understood, it is likely to be due in part, to imbalance in eicosanoid metabolism with increased production of cysteinyl leukotrienes and reduced synthesis of PGE2 [25].
    Conflicts of interest
    Author contributions
    Acknowledgements
    This research was funded by CHF research grant (Children\'s Hospital of Richmond at VCU) and in part by a grant from the Denny Hamlin Foundation (to TA).
    Introduction During tumor progression, cancer cells develop the ability to degrade the extracellular matrix that allows them to move through the surrounding tissue and to breach blood vessel walls ITE (Martin et al., 2000). This results in intravasation, the process of cancer cells entry into the blood vessels. Cancer cells further spread to secondary organs, where they can form metastases that are the main cause of patient mortality in most solid cancers. Invadopodia, protrusions rich in F-actin and capable of degrading a number of proteins in extracellular matrix (ECM), have been hypothesized to facilitate the breach of the basement membrane necessary for several steps in metastasis (Beaty and Condeelis, 2014). Recent studies revealed that invadopodia assembly is directly molecularly linked with metastasis in mouse models and humans (Eckert et al., 2011, Gligorijevic et al., 2012). Further, real-time imaging in mice provided evidence that invadopodia are essential for both intravasation and extravasation of cancer cells into/from the blood vessels (Gligorijevic et al., 2014, Leong et al., 2014).