Slomiany Bronislaw L, Slomiany Amalia
Research Center, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA.
Int J Biomed Sci. 2010 Mar;6(1):37-44.
Recent advances in identifying the salivary constituents of significance to the maintenance of soft oral tissue integrity have brought to focus the importance of a 28-amino acid peptide hormone, ghrelin. Here, we report on the role of ghrelin in countering the disturbances in salivary mucin synthesis caused by ethanol cytotoxicity in rat sublingual gland acinar cells. We show that the countering effect of ghrelin on mucin synthesis was associated with the increase in NO and PGE2 production, and the enhancement in cytosolic phospholipase A2 (cPLA2) activity. The ghrelin-induced up-regulation in mucin synthesis, like that of cPLA2 activity, was subject to suppression by Src inhibitor, PP2, ERK inhibitor, PD98059, as well as Akt inhibitor, SH-5 and ascorbate. Moreover, the loss in countering effect of ghrelin on the ethanol cytotoxicity and mucin synthesis was attained with cNOS inhibitor, L-NAME as well as COX-1 inhibitor, SC-560. Furthermore, while the effect of L-NAME was also reflected in the inhibition of the acinar cell capacity for NO and PGE2 generation, and cPLA2 S-nitrosylation, the COX-1 inhibitor caused the inhibition in PGE2 only. Our findings demonstrate that ghrelin protection of the acinar cells against ethanol cytotoxicity and the impairment in salivary mucin synthesis involves Src kinase activation of the Akt/cNOS pathway that leads to up-regulation in cNOS activity. We also show that cNOS-derived NO induction of the cPLA2 activation through S-nitrosylation, for the increase in PGE2 generation, is an essential element of the protective mechanism of ghrelin action.
在确定对维持口腔软组织完整性具有重要意义的唾液成分方面，最近的进展使一种由28个氨基酸组成的肽激素——胃饥饿素的重要性受到关注。在此，我们报告胃饥饿素在对抗乙醇细胞毒性对大鼠舌下腺腺泡细胞唾液黏蛋白合成造成的干扰中所起的作用。我们发现，胃饥饿素对黏蛋白合成的对抗作用与一氧化氮（NO）和前列腺素E2（PGE2）生成增加以及胞质磷脂酶A2（cPLA2）活性增强有关。胃饥饿素诱导的黏蛋白合成上调，与cPLA2活性上调一样，受到Src抑制剂PP2、细胞外信号调节激酶（ERK）抑制剂PD98059以及Akt抑制剂SH-5和抗坏血酸的抑制。此外，使用一氧化氮合酶（cNOS）抑制剂L-NAME以及环氧化酶-1（COX-1）抑制剂SC-560可导致胃饥饿素对乙醇细胞毒性和黏蛋白合成的对抗作用丧失。此外，虽然L-NAME的作用还体现在抑制腺泡细胞产生NO和PGE2的能力以及cPLA2的S-亚硝基化，但COX-1抑制剂仅导致PGE2生成受到抑制。我们的研究结果表明，胃饥饿素对腺泡细胞的保护作用，使其免受乙醇细胞毒性和唾液黏蛋白合成受损的影响，涉及Src激酶激活Akt/cNOS途径，从而导致cNOS活性上调。我们还表明，cNOS衍生的NO通过S-亚硝基化诱导cPLA2激活，以增加PGE2生成，是胃饥饿素作用保护机制的一个关键要素。
