(A2011389), and the Administration of Traditional Chinese Medicine of Guangdong MG-132 Province,China (20111238, 2010187). C.The contribution of each author to the manuscript: Xue-dong Li and Zhao-yong Liu have completed the preparation of the manuscript; Xue-dong Li, Bo Chang, Bin Chen, Dong-xin Liu,Yun-guo Wang,and Chun Guo have completed the experiment of the manuscript; Jian-kun Xu and Dong-yang Huang have completed the statistics of the manuscript; Xue-dong Li and Shi-xin Du as the principal applicant for the funding.inary result, the cell-permeable NF- B inhibitor SN50 did not inhibit PGE2-induced IL-8 production or mRNA expression in HPMVECs (data not shown). Consistent with this finding, our laboratory previously reported that IL-8 production by mechanical cyclic stretch was regulated by p38 activation, but not by the NF- B-pathway in Cilostazol HPMVECs (26).

Thus it is likely that NF- B activation is not involved in p38-mediated IL-8 production in HPMVECs. The MAP kinase-dependent, NF- B-independent IL-8 production was also Elvitegravir 697761-98-1 reported in human colonic epithelial cells (2). We consider that there are cell type-specific differences in NF- B-dependent IL-8 synthesis. It is possible that PGs, including PGE2, act in autocrine and paracrine fashions (31). Importantly, both mRNA and proteins of COX-2, an inducible COX isoform, were increased by PGE2 in HPMVECs. In contrast, COX-1 expression was constitutively observed, but not affected, by PGE2. The MAP kinase signaling cascade, including p38 activation, is linked to induction of COX-2 expression (42). It was reported that COX-2 induction leads to endogenous PGE2 production by activating p38 in human umbilical vein ECs (44).

In the present study, the mRNA expression for COX-2, but not for COX-1, mRNA was purchase Hesperidin significantly reduced by the p38 inhibitor SB- 203580, demonstrating that p38 activation is also essential for COX-2 induction by PGE2 in HPMVECs. Thus an autocrine or paracrine mechanism via induction of COX-2 may be involved in the PGE2-induced IL-8 production in HPMVECs. Nevertheless, COX-2 as well as COX-1 mediates synthesis of varieties of prostanoids derived from arachidonic acid. Thus further studies would be necessary to elucidate downstream pathways of COX-2. In the present study, we investigated a dose-dependent effect of PGE2 (1 nM–1  M) and found that PGE2 at a concentration of 10 nM significantly increased the IL-8 concentrations in HPMVECs . Moreover, high concentrations (0.1 and 1  M) of PGE2 used in our experimental study were based on previous works by different laboratories in ECs and other cell types (16, 28, 47).

The PGE2 concentrations in plasma are nanomolar levels in human normal volunteers Clinical perfusion (41). It has been demonstrated that PGE2 levels in the lung are increased in inflammatory lung diseases (3, 39, 46). Thus pulmonary microvasculature may be exposed to higher concentrations of PGE2 in severe inflammation, specifically ALI/ARDS and sepsis. PGE2 not only acts as a proinflammatory mediator, but also has protective effects on the lung and airways (19, 51). PGE2 also has potential as a barrier protector in the regulation of pulmonary endothelial permeability (6, 11, 12). It promotes migration of pulmonary microvascular ECs and angiogenesis via the EP4 receptor in mice  .