Anti-inflammatory actions of bone morphogenetic protein signaling in the stomach

描述(申请人提供)：众所周知，慢性炎症状态的存在会扰乱维持胃粘膜正常形态和功能特征的调节机制，导致胃炎、消化性溃疡和胃癌等疾病的发展。这些疾病的发病机制所涉及的因素仅有部分特征。骨形态发生蛋白S是一种对胃肠道组织的生长和分化起重要作用的调节肽。此外，BMP已被证明在肠道中发挥抗炎作用，这表明它们可能代表了迄今为止尚不明确的胃肠道炎症调节因子。BMPs在胃中的抗炎作用机制目前尚不清楚。在一系列的初步研究中，我们观察到炎症刺激如幽门螺杆菌(HP)和干扰素-3在体内和体外都能诱导BMP-4的表达，支持BMP-4参与胃炎症调节的观点。我们还注意到，BMP抑制物noggin在小鼠胃中的转基因表达，导致了MIP-2、INF-3和TNF-1等细胞因子的表达增加，以及参与促炎机制调节的ERKs和JNKs的激活。观察到转基因小鼠感染幽门螺杆菌，导致比年龄匹配的非转基因小鼠更大的炎性变化，这一观察结果强调了这些发现的相关性。最后，在一系列体外研究中，我们注意到BMP-2、BMP-4和BMP-7对犬的壁细胞和粘液细胞培养上清液中IL-8基因的表达有直接的抑制作用。在这些观察的基础上，我们假设BMP在胃中发挥抗炎作用，缺乏BMP信号会导致更戏剧性和强烈的炎症变化。因此，这项应用的总体目标是通过体内和体外方法研究BMP信号在胃炎症机制调节中的功能和作用机制。在第一个特定目标中，我们将检验假设，如HP，干扰素-3和肿瘤坏死因子-1等炎性刺激在体内调节BMP的表达，这一事件可能代表了一种下调炎症反应强度的自我安全机制。在第二个目的中，我们将通过用炎症刺激攻击noggin转基因小鼠来阐明BMP信号在体内炎症反应调节中的作用。在第三个目标中，我们将重点研究BMP信号在分离的壁细胞和粘液细胞培养中对IL-8表达的作用。通过拟议的研究，我们预计将提供新的见解，这些见解将在临床医学中具有重要意义，因为我们的发现可能有助于更好地了解消化性溃疡和胃癌等疾病的病理生理学。

DESCRIPTION (provided by applicant): The presence of chronic inflammatory states is known to cause perturbations in the regulatory mechanisms that maintain the normal morphological and functional features of the gastric mucosa, leading to the development of diseases such as gastritis, peptic ulcer and gastric cancer. The factors involved in the pathogenesis of these conditions have been only partially characterized. The bone morphogenetic proteins, (BMP) s are regulatory peptides that exert important actions on the growth and differentiation of gastrointestinal tissues. In addition, the BMPs have been shown to exert anti-inflammatory actions in the gut, suggesting that they might represent novel and hitherto poorly characterized regulators of gastrointestinal inflammation. The mechanisms mediating the anti-inflammatory actions of the BMPs in the stomach are currently unknown. In a series of preliminary studies we observed that inflammatory stimuli such as Helicobacter pylori (Hp) and INF-3 induce the expression of BMP-4 both in vivo and in vitro, supporting the notion that BMP-4 is involved in the regulation of gastric inflammation. We also noted that transgenic expression of the BMP inhibitor noggin in the mouse stomach, leads to increased expression of cytokines, such as MIP-2, INF-3 and TNF-1, and to enhanced activation of kinases, such as the ERKs and the JNKs, which are involved in the regulation of pro- inflammatory mechanisms. The relevance of these findings was underscored by the observation that infection of the transgenic mice with Hp, leads to the development of greater inflammatory changes than in non- transgenic, age matched, littermates. Finally, in a series of in vitro studies, we noted that BMP-2, BMP-4 and BMP-7 exert direct, inhibitory actions on both basal and TNF-1-stimulated IL-8 gene expression in cultures of canine parietal and mucus cells. On the basis of these observations we hypothesize that the BMPs exert anti- inflammatory actions in the stomach and that lack of BMP signaling leads to the development of more dramatic and intense inflammatory changes. Accordingly, the overall goal of this application is to investigate the function and the mechanisms of actions of BMP signaling in the regulation of inflammatory mechanisms in the stomach, by using both in vivo and in vitro approaches. In the first specific aim we will test the hypothesis that inflammatory stimuli such as Hp, IFN-3 and TNF-1 regulate BMP expression in vivo and that this event might represent a self-safe mechanism that down-regulates the intensity of the inflammatory response. In the second aim, we will elucidate the role of BMP signaling in the regulation of the inflammatory response in vivo, by challenging the noggin transgenic mice with the inflammatory stimuli. In the third aim, we will focus on the actions of BMP signaling on the expression of IL-8 in cultures of isolated parietal and mucus cells. Through the proposed studies, we expect to shed new insights that will have significant implications in clinical medicine since our discoveries may contribute to a better understanding of the pathophysiology of diseases such as peptic ulcer and gastric cancer.