Kapoor Sabrina, Fitzpatrick Martin, Clay Elizabeth, Bayley Rachel, Wallace Graham R., Young Stephen P.
Rheumatology Research Group, School of Immunity & Infection, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
Inflammation is a normal and extraordinarily important component of responses to infection and injury. The cardinal features of swelling, redness, stiffness and increasing temperature are strong indicators of the significant changes in tissue metabolism and the ingress of immune cells into the tissues. The increase in blood flow which underlies many of these changes may result in changes to the supply of nutrients and in particular the level of oxygen in the tissues. Inward migration of immune cells, which is also enabled by the increased blood flow, will put further stress on the metabolic environment of the tissues. The activity of macrophages and neutrophils in clearing infection and repairing tissue damage also have significant metabolic consequences particularly because of the production of cytokines and cytotoxic molecules such as reactive oxygen species and reactive nitrogen species, which are required to kill invading organisms. Production of these molecules will consume considerable quantities of oxygen, ATP and NADPH. These antimicrobial agents put considerable stress on host cells in the surrounding and distal tissues and can lead to significant loss of protective metabolites such as glutathione. Most infections and traumatic injuries are cleared or repaired relatively rapidly and metabolic homoeostasis is soon restored. However, there is a broad range of inflammatory diseases which involve chronic activation of the immune system and, as a result, chronic persistent inflammation. We have been studying the metabolic consequences of chronic inflammatory diseases with the aim of identifying metabolic fingerprints which may provide clues about why the localised tissue disease persists. For example, why in rheumatoid arthritis does persistent inflammation lead to widespread cartilage and joint destruction? However, the metabolic consequences of chronic inflammation are much more widespread than the localised disease and can lead on to important comorbidities such as accelerated atherosclerosis and cardiovascular disease. Metabolomic analysis may be able to distinguish between localised and systemic metabolic consequences of inflammation and provide novel targets for therapeutic intervention in these important human diseases.
炎症是对感染和损伤作出反应时正常且极其重要的组成部分。肿胀、发红、僵硬和温度升高这些主要特征有力地表明了组织代谢的显著变化以及免疫细胞侵入组织。许多这些变化背后的血流量增加可能会导致营养物质供应的改变，尤其是组织中氧气水平的改变。同样由血流量增加促成的免疫细胞向内迁移，将给组织的代谢环境带来进一步压力。巨噬细胞和中性粒细胞在清除感染和修复组织损伤方面的活动也具有重大的代谢后果，特别是因为细胞因子以及活性氧和活性氮等细胞毒性分子的产生，而这些是杀死入侵生物体所必需的。这些分子的产生将消耗大量的氧气、三磷酸腺苷（ATP）和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）。这些抗菌剂给周围和远端组织中的宿主细胞带来相当大的压力，并可能导致谷胱甘肽等保护性代谢物的大量损失。大多数感染和创伤性损伤会相对迅速地得到清除或修复，代谢稳态很快得以恢复。然而，有广泛的炎症性疾病涉及免疫系统的慢性激活，因此导致慢性持续性炎症。我们一直在研究慢性炎症性疾病的代谢后果，目的是识别代谢指纹，这些指纹可能为局部组织疾病持续存在的原因提供线索。例如，为什么在类风湿性关节炎中，持续性炎症会导致广泛的软骨和关节破坏？然而，慢性炎症的代谢后果比局部疾病更为广泛，并且可能导致重要的合并症，如加速动脉粥样硬化和心血管疾病。代谢组学分析或许能够区分炎症的局部和全身代谢后果，并为这些重要人类疾病的治疗干预提供新的靶点。
