NO信号通路.docVIP

Microorganisms have developed several mechanisms to survive in their hosts environments(寄生环境). These include competition with their hosts for metal acquisition and resistance to host defenses such as NO (Nitric Oxide), a cytotoxic weapon（细胞毒素武器） generated by macrophages（巨噬细胞）. In eukaryotic cells, NO is metabolically produced by NOS (NO Synthase) from L-Arginine, O2 (Molecular Oxygen), and NADPH (Nicotinamide Adenine Dinucleotide, Reduced). In macrophages, an inducible NO synthase (诱导型NO合酶，iNOS or NOS2) is produced after activation by endotoxins or cytokines and generates copious amounts of NO presumably to help kill or inhibit the growth of invading microorganisms or neoplastic（肿瘤） tissue (Ref.1 2). Although iNOS was originally identified and characterized in macrophages, it is present in numerous cell types including endothelial cells（内皮细胞）, fibroblasts, vascular smooth muscle cells（血管平滑肌细胞） and cardiac myocytes（心肌细胞）. Catalytic activity of iNOS is regulated by the availability of the substrate, Calm (Calmodulin，钙调蛋白), L-Arginine, and of the cofactors（辅酶因子）, NADPH and tetrahydrobiopterin. NOS2 utilizes oxygen and electrons from NADPH to oxidize the substrate（底物） L-Arginine into the intermediate OH-L-Arginine, which is then oxidized into NO and L-Citrulline. NO and superoxide (O2-) are radical effectors of the innate immune system that can directly inhibit pathogen replication. Although NOS2 activity is independent of calcium concentrations, a variety of extracellular stimuli can activate distinct signaling pathways that converge to initiate expression of iNOS. Cell wall components of bacteria and fungi trigger the innate immune signaling cascade, leading to expression of iNOS. LPS (内毒素脂多糖，毒性成分为类脂质A，Lipopolysaccharide), a component of the wall of Gram-negative bacteria（革兰氏阴性菌）, binds to LBP (LPS-Binding Protein), which delivers LPS to CD14（内毒素受体抗体）, a high-affinity LPS receptor. TLR4 (Toll-Like Receptor-4) in conjunction with the small extracellular protein MD2 in