p38MAPK信号通路及其在全身炎症反应中的作用

分裂原激活的蛋白激酶（ＭＡＰＫ）级联是细胞内主要的信号转导系统。细胞运用这一系统将细胞外信号传递细胞核，介导细胞产生反应。近年来发现一类新的ＭＡＰＫ通路——ｐ３８ＭＡＰＫ信号通路，对其结构和功能以及在全身炎症反应中的作用机制已有所了解，在信号通路水平阻断和调控ｐ３８ＭＡＰＫ的表达和活性、治疗过度炎症反应性疾病可能成为急性炎症反应新的治疗途径。     

p38 MAPK与内毒素性肺损伤

MAPK是信号由细胞表面转导到细胞内部的重要传递者,参与了LPS激活效应细胞产生活性物质的细胞内信号转导过程.p38 MAPK通过磷酸化转录因子引起多种相关基因转录,调控活性物质的表达,参与炎症反应过程.在信号通路水平阻断和调控p38 MAPK的表达将成为治疗急性肺损伤的新途径.     

核因子-κB在糖尿病肾组织中的表达及干预治疗

核因子(NF)-κB是细胞中一种重要的核转录因子，它参与细胞内的信号转导、免疫反应、炎症反应以及细胞生长发育等多种生物过程，在细胞因子诱导的基因表达中起关键性的调控作用。活化的NF-κB可能通过调控许多炎症因子的转录过程在糖尿病肾病（DN）的发生发展过程中起重要作用。抑制NF-κB的激活和IκB的降解等干预治疗可能是防治DN的手段之一。     

TOLL样受体家族与LPS信号转导

细菌脂多糖 (LPS)可激活巨噬细胞、内皮细胞等引起一些炎症介质的释放 ,最终可导致机体的损伤甚至休克死亡。在这一过程中LPS如何被机体细胞识别并启动细胞反应已引起高度重视。十几年来研究已明确LBP CD14、CD11 CD18可使LPS解聚并被运送和结合到细胞表面 ,但是这些分子缺乏信号转导的功能。近二三年发现了一种功能性的LPS跨膜受体———Toll样受体家族。Toll样受体被认为是其它LPS受体的协同受体或接头受体 (adaptorreceptor) ,正是这种受体直接将LPS的刺激信号向细胞内传递 ,其胞浆区具有与IL 1受体同源的结构 ,其作用涉及炎症因子主要是细胞因子级联反应中的基因激活及反应基因的调节     

055 TOLL样受体家族与LPS信号转导

细菌脂多糖(LPS)可激活巨噬细胞、内皮细胞等引起一些炎症介质的释放,最终可导致机体的损伤甚至休克死亡.在这一过程中LPS如何被机体细胞识别并启动细胞反应已引起高度重视.十几年来研究已明确LBP/CD14、CD11/CD18可使LPS解聚并被运送和结合到细胞表面,但是这些分子缺乏信号转导的功能.近二三年发现了一种功能性的LPS跨膜受体--Toll样受体家族.Toll样受体被认为是其它LPS受体的协同受体或接头受体(adaptor receptor),正是这种受体直接将LPS的刺激信号向细胞内传递,其胞浆区具有与IL-1受体同源的结构,其作用涉及炎症因子主要是细胞因子级联反应中的基因激活及反应基因的调节.     

破骨细胞的RANK信号转导系统研究进展

信号转导系统(signal transduction system)是由接收信号的特定受体、受体后信号转导通路、转录因子和作用终端组成,信号通过受体激活细胞内的信号转导通路,引发离子通道开放、蛋白质可逆磷酸化反应及基因表达改变等变化,导致一系列生物学效应,调节细胞的增殖、分化、代谢、适应、防御和凋亡等.信号转导系统的过程可概括为:细胞外信号与受体结合→受体将胞外信号转换为胞内信号→启动细胞内信号转导通路→激活转录因子→启动基因的表达→细胞生物学效应.     

破骨细胞的RANK信号转导系统研究进展

信号转导系统(Signal transduCtion system)是由接收信号的特定受体、受体后信号转导通路、转录因子和作用终端组成，信号通过受体激活细胞内的信号转导通路，引发离子通道开放、蛋白质可逆磷酸化反应及基因表达改变等变化，导致一系列生物学效应，调节细胞的增殖、分化、代谢、适应、防御和凋亡等。信号转导系统的过程可概括为：     

TOLL样受体家族与LPS信号转导

细菌脂多糖（LPS）可激活巨噬细胞、内皮细胞等引起一些炎症介质的释放,最终可导致机体的损伤甚至休克死亡。在这一过程中LPS如何机体细胞识别并启动细胞反应已引起高度重视。十几年来研究已明确LBP／CD14、CD11／CD18可使LPS解聚并被运送和结合到细胞表面,但是这些分子缺乏信号转导的功能。近二三年发现了一种功能性的LPS跨膜受体－－Toll样受体家族。Toll样受体被认为是其它LPS受体的协同受体或接头受体（adaptor receptor）,正是这种受体直接将LPS的刺激信号向细胞内传递,其胞浆区具有与IL－1受体同源的结构,其作用涉及炎症因子主要是细胞因子级联反应中的基因激活及反应基因的调节。     

核因子-кB在糖尿病肾组织中的表达及干预治疗

核因子(NF)-кB是细胞中一种重要的核转录因子,它参与细胞内的信号转导、免疫反应、炎症反应以及细胞生长发育等多种生物过程,在细胞因子诱导的基因表达中起关键性的调控作用.活化的NF-кB可能通过调控许多炎症因子的转录过程在糖尿病肾病(DN)的发生发展过程中起重要作用.抑制NF-кB的激活和IкB的降解等干预治疗可能是防治DN的手段之一.     

LPS受体及其信号传导通路

细菌脂多糖(lipopolysaccharide,LPS)可激活单核细胞、臣噬细胞及内皮细胞,引起细胞因子合成和释放,导致全身性炎症反应发生.而LPS跨膜信号转导是引起细胞效应的关键.本文主要综述与LPS的跨膜信号转导有关Toll样受体一TLR2(Toll-like receptor 2)和(TLR4Toll-like receptor4)的结构特点、配体范围、基因表达调节以及信号转导机制.正是Toll样受体直接将LPS刺激信号传入细胞内,激活NF-κB信号途径,导致效应基因的表达.     

Extracellular matrix and lung inflammation

Lung injury triggers an acute inflammatory response characterized by increased expression and deposition of extracellular matrix (ECM) components such as fibronectin and collagen. Although the function of newly deposited matrices in injured lungs is unknown, their ability to affect the migration, proliferation, differentiation, and activation state of cells in vitro suggests an important role in the initiation and maintenance of the inflammatory response in vivo. Interactions between immune and nonimmune cells with the lung ECM are mediated via cell surface receptors of the integrin family which link the ECM with intracellular molecules involved in signal transduction. Activation of integrin-mediated intracellular signals may promote inflammation by facilitating leukocyte recruitment and cytokine expression. *** DIRECT SUPPORT *** A02GS030 00009     

内毒素诱导p38MAPK信号转导作用的研究进展

The diseases caused by endotoxin have seriously affected human health. Previous studies have shown that p38 MAPK pathway is involved in the intracellular signal transduction induced by lipopolysaccharide (LPS), which plays an important role in the activation of inflammation-related cells to release inflammation mediator. Recently there have been some progresses in the isoforms distribution, substrate, molecular mechanism of regulating the release of inflammatory mediators, cellular specific activation and levels of p38 MAPK.     

Src protein tyrosine kinase family and acute lung injury]

Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as sepsis and acute lung injury. Inflammatory mediators released from a variety of cells in response to acute inflammations can interact with immune cells, microvascular endothelial cells and other tissue cells, to elicit a series of intracellular signaling reactions where activation of Src protein tyrosine kinase (PTK) family members is involved. Using cellular and molecular approaches and transgenic animals, Src PTK family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils and other immune cells. Src PTK family members also play a critical role in the regulation of vascular permeability and inflammatory responses in tissue cells. Importantly, animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuated acute lung injury. Further investigation may lead to the clinical application of these inhibitors as drugs for acute lung injury.     

The role of PTEN in allergic inflammation

Bronchial asthma is a chronic inflammatory disease of the airways, characterized by airway eosinophilia, goblet cell hyperplasia with mucus hyper-secretion, and hyper-responsiveness to inhaled allergens and to non-specific stimuli. Eosinophil accumulation and subsequent activation in bronchial tissues play critical roles in the pathophysiology of bronchial asthma. Many inflammatory mediators attract and activate eosinophils via signal transduction pathways involving an enzyme phosphatidylinositol 3-kinase (PI3-kinase). Studies using wortmannin, a specific inhibitor of PI3-kinase, have revealed the involvement of PI3-kinase in the biochemical transduction of activation signals generated by many inflammatory mediators in eosinophils. Wortmannin prevents the development of airway inflammation, either by inhibiting the eosinophil infiltration of bronchial tissues or their activation on arrival. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is part of a complex signaling system that affects a variety of important cell functions. PTEN opposes the action of PI3-kinase by dephosphorylating the signaling lipid phosphatidylinositol 3,4,5-triphosphate. Recently we have demonstrated that PTEN expression is diminished in airway epithelial cells of antigen-sensitized and -challenged mice. Administration of PI3-kinase inhibitors or adenoviruses carrying PTEN complementary DNA remarkably reduces eosinophil levels and inflammation. One likely mechanism for this reduction is PTEN-mediated eosinophil degranulation and suppression of interleukin (IL)-4 and IL-5.These findings indicate that use of PTEN may be a good therapeutic strategy for the management of allergic inflammation.     

Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants

The endothelium is immunoregulatory in that inhibiting the function of vascular adhesion molecules blocks leukocyte recruitment and thus tissue inflammation. The function of endothelial cells during leukocyte recruitment is regulated by reactive oxygen species (ROS) and antioxidants. In inflammatory sites and lymph nodes, the endothelium is stimulated to express adhesion molecules that mediate leukocyte binding. Upon leukocyte binding, these adhesion molecules activate endothelial cell signal transduction that then alters endothelial cell shape for the opening of passageways through which leukocytes can migrate. If the stimulation of this opening is blocked, inflammation is blocked. In this review, we focus on the endothelial cell adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1). Expression of VCAM-1 is induced on endothelial cells during inflammatory diseases by several mediators, including ROS. Then, VCAM-1 on the endothelium functions as both a scaffold for leukocyte migration and a trigger of endothelial signaling through NADPH oxidase-generated ROS. These ROS induce signals for the opening of intercellular passageways through which leukocytes migrate. In several inflammatory diseases, inflammation is blocked by inhibition of leukocyte binding to VCAM-1 or by inhibition of VCAM-1 signal transduction. VCAM-1 signal transduction and VCAM-1-dependent inflammation are blocked by antioxidants. Thus, VCAM-1 signaling is a target for intervention by pharmacological agents and by antioxidants during inflammatory diseases. This review discusses ROS and antioxidant functions during activation of VCAM-1 expression and VCAM-1 signaling in inflammatory diseases.     

The PI3K/Akt pathway is required for LPS activation of microglial cells

Upregulation of inflammatory responses in the brain is associated with a number of neurodegenerative diseases. Microglia are activated in neurodegenerative diseases, producing pro-inflammatory mediators. Critically, lipopolysaccharide (LPS)-induced microglial activation causes dopaminergic neurodegeneration in vitro and in vivo. The signaling mechanisms triggered by LPS to stimulate the release of pro-inflammatory mediators in microglial cells are still incompletely understood. To further explore the mechanisms of LPS-mediated inflammatory response of microglial cells, we studied the role of phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathways known to be activated by toll-like receptor-4 signaling through LPS. In the current study, we report that the activation profile of LPS-induced pAkt activation preceded those of LPS-induced NF-κB activation, suggesting a role for PI3K/Akt in the pathway activation of NF-κB-dependent inflammatory responses of activated microglia. These results, providing the first evidence that PI3K dependent signaling is involved in the inflammatory responses of microglial cells following LPS stimulation, may be useful in preventing inflammatory based neurodegenerative processes.     

A BASH/SLP-76-related adaptor protein MIST/Clnk involved in IgE receptor-mediated mast cell degranulation

Cross-linking of the high-affinity IgE receptor (FcepsilonRI) on mast cells by IgE-antigen complex triggers signal transduction cascades leading to the release of inflammatory mediators and production of cytokines, which are critical for the development of allergic reactions. We have identified a novel member of the BASH/SLP-76 immunoreceptor-coupled adaptor family expressed in mast cells, termed MIST (for mast cell immunoreceptor signal transducer), which has later been found to be identical to a recently reported cytokine-dependent hemopoietic cell linker, Clnk. Upon FcepsilonRI cross-linking, MIST/Clnk is tyrosine phosphorylated and associates with signaling proteins, phospholipase Cgamma, Vav, Grb2 and linker for activation of T cells (LAT). Overexpression of a mutant form of MIST/Clnk inhibited FcepsilonRI-mediated degranulation, increase in intracellular Ca(2+), NF-AT activation and phosphorylation of LAT. As a crucial signaling component for FcepsilonRI-induced mast cell degranulation, MIST/Clnk might serve as a target for anti-allergic therapy.     

Deletion of apoptosis signal-regulating kinase-1 prevents ventilator-induced lung injury in mice

Both hyperoxia and mechanical ventilation can independently cause lung injury. In combination, these insults produce accelerated and severe lung injury. We recently reported that pre-exposure to hyperoxia for 12 hours, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone. We also reported that such injury and apoptosis are inhibited by antioxidant treatment. In this study, we hypothesized that apoptosis signal-regulating kinase-1 (ASK-1), a redox-sensitive, mitogen-activated protein kinase kinase kinase, plays a role in lung injury and apoptosis in this model. To determine the role of ASK-1 in lung injury, the release of inflammatory mediators and apoptosis, attributable to 12 hours of hyperoxia, were followed by large tidal volume mechanical ventilation with hyperoxia. Wild-type and ASK-1 knockout mice were subjected to hyperoxia (Fi(O(2)) = 0.9) for 12 hours before 4 hours of large tidal mechanical ventilation (tidal volume = 25 μl/g) with hyperoxia, and were compared with nonventilated control mice. Lung injury, apoptosis, and cytokine release were measured. The deletion of ASK-1 significantly inhibited lung injury and apoptosis, but did not affect the release of inflammatory mediators, compared with the wild-type mice. ASK-1 is an important regulator of lung injury and apoptosis in this model. Further study is needed to determine the mechanism of lung injury and apoptosis by ASK-1 and its downstream mediators in the lung.     

Nonphagocytic oxidase 1 causes death in lung epithelial cells via a TNF-RI-JNK signaling axis

Airway epithelial cells are simultaneously exposed to and produce cytokines and reactive oxygen species (ROS) in inflammatory settings. The signaling events and the physiologic outcomes of exposure to these inflammatory mediators remain to be elucidated. Previously we demonstrated that in cultured mouse lung epithelial cells exposed to bolus administration of H(2)O(2), TNF-alpha-induced NF-kappaB activity was inhibited, whereas c-Jun-N-terminal kinase (JNK) activation was enhanced via a mechanism involving TNF receptor-1 (TNF-RI). In this study we used the nonphagocytic NADPH oxidase (Nox1) to study the effects of endogenously produced ROS on a line of mouse alveolar type II epithelial cells. Nox1 expression and activation inhibited TNF-alpha-induced inhibitor of kappaB kinase (IKK), and NF-kappaB while promoting JNK activation and cell death. Nox1-induced JNK activation and cell death were attenuated through expression of a dominant-negative TNF-RI construct, implicating a role for TNF-RI in Nox1 signaling. Furthermore, Nox1 used the TNF-RI adaptor protein TNF-receptor-associated factor-2 (TRAF2), and the redox-regulated JNK MAP3K, apoptosis signal kinase-1 (ASK1), to activate JNK. In addition, ASK1 siRNA attenuated both Nox1-induced JNK activity and cell death. Collectively, these studies suggest a mechanism by which ROS produced in lung epithelial cells activate JNK and cause cell death using TNF-RI and the TRAF2-ASK1 signaling axis.     

The PI3K/Akt pathway is required for LPS activation of microglial cells

Upregulation of inflammatory responses in the brain is associated with a number of neurodegenerative diseases. Microglia are activated in neurodegenerative diseases, producing pro-inflammatory mediators. Critically, lipopolysaccharide (LPS)-induced microglial activation causes dopaminergic neurodegeneration in vitro and in vivo. The signaling mechanisms triggered by LPS to stimulate the release of pro-inflammatory mediators in microglial cells are still incompletely understood. To further explore the mechanisms of LPS-mediated inflammatory response of microglial cells, we studied the role of phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathways known to be activated by toll-like receptor-4 signaling through LPS. In the current study, we report that the activation profile of LPS-induced pAkt activation preceded those of LPS-induced NF-κB activation, suggesting a role for PI3K/Akt in the pathway activation of NF-κB-dependent inflammatory responses of activated microglia. These results, providing the first evidence that PI3K dependent signaling is involved in the inflammatory responses of microglial cells following LPS stimulation, may be useful in preventing inflammatory based neurodegenerative processes.