chronic inflammation

chronic inflammation：general introduction、Causes、Chronic inflammatory cells and mediators……

chronic inflammation

• general introduction
  • • Chronic inflammation is inflammation of prolonged duration (weeks to years) in which continuing inflammation, tissue injury and healing, often by fibrosis, proceed simultaneously
  • Differences between acute and chronic inflammation
    • Acute inflammation is characterised by vascular changes, oedema and a predominantly neutrophilic infiltrate
    • Chronic inflammation is characterised by a different set of reactions
    • Acute inflammation may progress to chronic inflammation if the injurious agent is not removed
  • Reactions in chronic inflammation
    • Infiltration with mononuclear cells, including macrophages, lymphocytes and plasma cells
    • Tissue destruction, induced by inflammatory cells
    • Repair, involving new vessel proliferation (angiogenesis) and fibrosis
  • Granulomatous inflammation is a distinctive pattern of chronic inflammation characterised by aggregates of activated macrophages with scattered lymphocytes
    • 肉芽肿是某些特定病理状态的特征,其识别对诊断很重要
    • settings for granulomas 3
      • when persistent T-cell response to certein microbes(M.tuberculosis), in which T-cell derived cytokines are responsible for chronic macrophage activation
      • may arise in some immune- mediated inflammatory diseases(crohn's disease)
      • may be seen in sarcoidosis肉状瘤病,a disease of unknown aetiology
  • Systemic effects of inflammation:Following an inflammatory stimulus, our body enters the acute-phase reaction, which is induced by cytokines as IL-6 and TNF,released by leukocytes, following that, we experience a series of symptoms(systemic inflammatory response syndrome)系统发炎反应综合征
    • acute-phase response
      • fever,which is induced in response to pyrogens(as bcterial LPS)
      • Elevated plasma levels of actue-phase proteins(C-reactive protein,fibrinogen,serum amyloid A),stimulated by IL-6
      • leukocytosis(increased number of circulating white cells)
• Causes 4
  • Persistent infections by microbes that are difficult to eradicate (i.e. Mycobacterium tuberculosis，certain viruses or parasites)
  • Immune-mediated inflammatory diseases (hypersensitivity diseases), that are caused by excessive and inappropriate activation of the immune system:rheumatoid arthritis
  • Prolonged exposure to potentially toxic agents（nondegradable silica, coal dust, lipid breakdown products in atherosclerosis）
  • Persistent stimuli (gastric ulcer)
• Chronic inflammatory cells and mediators
  • macrophages
    • are the dominant cells of chronic inflammation
    • They derive from circulating blood monocytes When monocytes reach the extravascular tissue, they undergo maturation into macrophages, which are larger and have a greater capacity for phagocytosis
    • Tissue macrophages are activated by diverse stimuli, by two main pathways:
      • In response to most injurious stimuli macrophages are initially activated by the classical pathway, designed to destroy the offending agents and this is followed by alternative activation, which initiates tissue repair
      • classical macrophage activation(M1 population)
        • is induced by microbial products such as endotoxins, T-cell derived signals, IFN-gamma and by foreign substances
        • Classically activated macrophages produce lysosomial enzymes, nitric oxide and ROS, that will enhance their capability to phagocytosis
        • 这一途径在宿主防御against摄入的微生物和许多慢性炎症反应中很重要
      • alternative macrophage activation(M2 population)
        • is induced by cytokines other than IFN-g, such as IL-4 and IL-13
        • Alternatively activated macrophages are not microbicidal, but their principal role is tissue repair
        • They secrete growth factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis
    • Roles
      • ingest and eliminate microbes and dead tissues
      • initiate the process of tissue repair
      • secrete mediators of inflammation
      • display antigens to T-lymphocytes and respond to signals from T-cells
  • lymphocytes
    • B- and T-lymphocytes migrate into inflammatory sites following cytokine stimulation
    • In tissues, B-lymphocytes may develop into plasma cells, and CD4+ T-lymphocytes are activated to secrete cytokines
    • CD4+ t淋巴细胞通过细胞因子的分泌促进炎症，影响炎症反应的性质
    • 3 subsets of CD4+ helper T-cells secrete different types of cytokines and elicit different types of inflammation:
      • Th1 produce IFN-gamma which activates macrophages via classical pathway(bacterial and viral infection)
      • Th2 cells secrete IL-4,IL-5,IL-13 which recruit and activate eosinphils and alternatively activate macrophages(allergies and parasitic infections, tissue repair)
      • Th17 secrete IL-17 that induces the secretion of chemokines for recruiting neutrophils and monocytes to the site of inflammation(bacterial and viral infection)
  • eosinophils
    • Eosinophils are found in inflammatory sites around parasitic infections and as a part of immune reactions mediated by IgE (allergies)
  • mast cells
    • Mast cells are sentinel cells that can participate in both acute and chronic inflammation肥大细胞是前哨细胞，可以参与急性和慢性炎症
• Tissue repair
  • After an injury, tissue architecture and function must be restored. This process is referred to as repair (healing). It may involve 2 types of reactions:
    • regeneration
      • 这是通过有分裂能力的未受损的残余细胞(皮肤、肠、肝的上皮细胞)的增殖而发生的。
    • scar formation
      • 当损伤太严重或受伤组织无法再生时，通过结缔组织(纤维)沉积发生。纤维化可能是一个后果, as infraction
      • Steps 3
        • angiogenesis新血管的生成
          • is a process of new blood vessel development from existing vessels
          • involves sprouting发芽 of new vessels from existing ones and involves several steps
          • is regulated by growth factors, mainly by the VEGF family of growth factors (Vascular Endothelial Growth Factors)
        • deposition of connective tissue by proliferative fibroblasts(granuloma tissue)
          • 2 steps
            • 1. Migration and proliferation of fibroblasts into the site of injury (driven by growth factors)
            • 2. Deposition of extracellular matrix proteins produced by these cells
        • maturation and reorganisation of the fibrous tissue(remodeling) to produce the fibrous scar
          • 成纤维细胞在伤口愈合早期(第3 - 5天)就开始合成胶原蛋白，并持续数周
          • The granulation tissue (which contains numerous blood vessels) evolves into a scar composed of largely inactive fibroblasts, rich of dense collagen and with only few scattered vascular channels
          • granulation tissue to scar发生了这样的变化
          • After its synthesis and deposition, connective tissue in scar continues to be modified and remodeled，The degradation of collagen and other ECM components depends on matrix metalloproteinases(MMP),基质基质蛋白是由多种类型的细胞产生的，它们的合成受生长因子、细胞因子和其他因子的调控
  • Factors that influence tissue repair 4
    • Tissue repair may be altered by a variety of factors that influence the quality and the adequacy of the reparative process
      • Infections may delay healing感染
      • Nutrition has effects on repair营养
      • Glucocorticoids may weaken scar formation糖皮质激素
      • Mechanical variables, poor perfusion, foreign bodies, the location of the injury and aberration of cell growth may also influence the process机械变量、灌注不良、异物、损伤位置和细胞生长异常
  • Healing of skin wound
    • Depending on the nature and size of the wound, the healing of skin wounds is said to occur by first or second intention
      • Healing by first intention (or primary healing) occurs in uninfected surgical incisions, when the size of injury is small，Epithelial regeneration will lead to the formation of a small scar
      • When the tissue loss is more extensive (such as in large wounds), the repair process is more complex and involves a combination of regeneration and scarring， In second intention healing (healing by secondary union) the inflammatory reaction is more intense and there is development of abundant granulation tissue which will lead to a large scar，Wound contraction will occur, to reduce the skin defects (not seen in primary intention)
• Fibrosis in parenchymal organs
  • Fibrosis refers to the excessive deposition of collagen and other ECM components in a tissue
  • Fibrosis may often be seen in chronic diseases, when in is induced by persistent injurious stimuli, such as infections, immunologic reactions, or after an infarction
  • Fibrosis is often responsible for organ dysfunction and even failure
• Collagen synthesis by fibroblasts is critical to the development of strength in a wound site
• 尽管中性粒细胞的存在是急性炎症的特征，但慢性炎症也可能表现为广泛的中性粒细胞浸润，这是持续微生物或坏死细胞的结果
• Macrophage-lymphocyte interactions
  • bidirectional way,these interactions play an important role in chronic inflammation