MECHANISM(S) OF PERIODONTAL FATTY ACID PMN TOXICITY

中性粒细胞(PMN)是宿主抵抗细菌的第一道防线。 牙周感染。PMN如何以及为什么未能预防这种感染 成人牙周炎目前尚不清楚。很明显，生物 调节PMN反应的介体最初与 受体，继而激活生化反应，最终激活 细胞反应。因此我们推断有毒细菌产品 可以使用类似的机制来改变PMN功能。短链脂肪酸 (SCFA)在这方面特别有趣，因为它们： 牙周病原体的代谢副产物；在牙龈中发现 成人牙周炎患者阴沟液的毫米波浓度； 触发一些次级信使(例如：胞浆钙、pH和肌动蛋白 瞬时)；但是，抑制趋化受体介导的PMN功能。 然而，这一作用的机制尚不清楚。这让我们问了两个问题 相关问题：1)SCFA如何触发第二信使？和2)如何 单链脂肪酸抑制正常趋化受体介导的功能？ 为了回答这些问题，我们将研究阿司匹林的体外和体内效应。 SCFAs+趋化介质在信号转导中的关键步骤 途径和关键的细胞反应。信号转导实验将 检查受体调节、G蛋白激活和胞浆钙， PH和肌动蛋白瞬变。细胞反应实验将检查细胞 极化、肌动蛋白定位和氧代谢。我们将利用 4种显示最高龈沟液的SCFA 牙周病中的浓度(醋酸盐、丙酸、丁酸盐和 乳酸)。先前的工作表明，丙酸和丁酸盐抑制中性粒细胞 功能，而醋酸盐和乳酸盐不起作用。我们还将研究 己酸酯的作用，一种与牙周疾病无关的单链脂肪酸，以及 所有指示的单链脂肪酸的组合。 这些研究之所以意义重大，有两个原因。首先，他们提供 可能同时提供化学和细胞方面的解释 中性粒细胞不能预防牙周感染。第二，他们会 表征简单有机分子对PMN信号的影响 转导和细胞功能。显然，这些信息可以应用于 对其他细胞系统中信号转导和细胞功能的研究 (例如：上皮屏障功能和细胞因子的产生)。最后，这一点 信息可能会提供数据，可用于防止 牙周发病机制。

Neutrophils (PMNs) provide the first line of host defense against bacterial periodontal infections. How and why PMNs fail to prevent this infection in adult periodontitis is currently unknown. It is clear that biological mediators which modulate the PMN response, initially interact with receptors, secondarily activate biochemical responses, and finally activate cellular responses. We therefore reasoned that toxic bacterial products may use similar mechanisms to alter PMN function. Short chain fatty acids (SCFAs) are particularly interesting in this regard because they: are metabolic by-products of periodontal pathogens; are found in gingival crevicular fluid of adult periodontitis patients in mM concentrations; trigger some secondary messengers (e.g.: cytoplasmic calcium, pH, and actin transients); but, inhibit chemotactic receptor mediated PMN functions. However, the mechanism of this action is unknown. This leads us to ask two related questions: 1) How do SCFAs trigger second messengers? and 2) How do SCFAs inhibit normal chemotactic receptor mediated function? To answer these questions we will study the in vitro and in vivo effects of SCFAs + chemotactic mediators on key steps in the signal transduction pathway and key cellular responses. Signal transduction experiments will examine receptor modulation, G-protein activation, and cytoplasmic calcium, pH, and actin transients. Cellular response experiments will examine cell polarization, actin localization, and oxygen metabolism. We will utilize four SCFAs which exhibit the highest gingival crevicular fluid concentration in periodontal disease (acetate, propionate, butyrate, and lactate). Previous work indicates that propionate and butyrate inhibit PMN function, while acetate and lactate do not. We will also examine the effect of caproate, a SCFA not associated with periodontal disease, and combinations of all the indicated SCFAS. These studies are significant for two reasons. First, they offer the potential for providing both a chemical and cellular explanation as to why PMNs fail to prevent periodontal infections. Second, they will characterize the effects of simple organic molecules on PMN signal transduction and cell function. Clearly, this information can be applied to the study of signal transduction and cell function in other cell systems (eg: epithelial barrier function and cytokine production). Finally, this information will potentially provide data which can be used to prevent periodontal pathogenesis.