Chronic Inflammation I (Foundations Exam 1)

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chronic inflammation

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inflammation of prolonged duration (often weeks to months), in which active inflammation, tissue destruction and repair are occurring simultaneously
- may follow acute inflammation or an injury elicits it from the beginning

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major causes of chronic inflammation

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1. persistent infections (viruses, fungi, parasites, and mycobacteria)
2. autoimmune response - develops against a patient's own tissues (rheumatoid arthritis, systemic lupus erythematosus)
3. prolonged exposure to toxic agents - exposure to asbestos or coal; alcohol abuse

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morphologic features of chronic inflammation

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1. infiltration with mononuclear cells (macrophages, lymphocytes, and plasma cells)
--> organized lymphoid tissue with germinal centers may form
2. tissue destruction --> due to persistence of injury
3. healing by connective tissue replacement --> fibrosis and angiogenesis (proliferation of blood vessels)

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macrophage functions in chronic inflammation

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- dominant cell
- in tissues, monocytes differentiate into macrophages
- substances secreted may result in tissue injury and fibrosis
- some of the toxic products released: ROS, proteases
- active proliferation at site and immobilization

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lymphocytes (chronic inflammation)

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- recruited by macrophages
- interact closely with macrophages during response

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plasma cells (chronic inflammation)

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- derived from B lymphocytes
- produce antibodies against persistent antigens

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eosinophils (chronic inflammation)

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- involving IgE (usually allergic reactions) and in parasitic infections
- major basic protein --> main contents of cytoplasmic granules --> toxic to parasites

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mast cells (chronic inflammation)

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- display a cell surface receptor for IgE
- produce cytokines that either promote or limit inflammation

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neutrophils (chronic inflammation)

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- recruited by active macrophages and T lymphocytes

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regeneration

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- growth of cells and tissues to replace lost structures
-most common: skin, epithelia that line GI tract, and hematopoetic cells
- requires: intact CT scaffold and viable stem cells
- ECM is critical
- compensatory growth in liver and kidney after partial hepatectomy or nephrectomy

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healing with scar formation

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- common response to wound or chronic inflammation
- extracellular matrix is damaged
- insufficient numbers of viable stem cells
- original tissue cannot fully be reconstituted
- fibroblasts are activated to lay down collagen

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stem cells

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undifferentiated cells which are characterized by their prolonged capacity for self renewal and asymmetric replication

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asymmetric replication

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some will remain undifferentiated and continue to self replicate, while others will mature and differentiate into a non dividing, specialized cell

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embryonic stem cells

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- pluripotent (multiple potential) cells
- differentiate into all the specialized tissues of the human body

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adult stem cells

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- specific sites within multiple organs
- more limited capacity for differentiation
- reconstitute the organ in which they reside

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epidermal growth factor (EGF)

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- stimulates growth of a variety of epithelial tissues, hepatocytes, fibroblasts
- produced by keratinocytes in the skin, macrophages, and other inflammatory cells

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hepatocyte growth factor (HGF)

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- stimulates growth in various epithelial cells, including hepatocytes and bile duct cells
- promotes cell migration in development
- produced mainly by fibroblasts and endothelial cells
- many tumors express receptors for HGF

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vascular endothelial growth factor (VEGF)

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- induces formation of blood vessels (vasculogenesis and angiogenesis)
- setting of chronic inflammation, wound healing, and tumor growth

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platelet-derived growth factor (PDGF)

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- proliferation and migration of fibroblasts, smooth muscle cells, and monocytes
- produced by platelets, activated macrophages, and endothelial cells

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fibroblast growth factor (FGF)

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- produced by a variety of cells
- important for migration of macrophages, endothelial cells and fibroblasts into damaged tissues for wound repair
- stimulates growth of keratinocytes in skin, promotes angiogenesis, hematopoesis and development

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transforming growth factor beta (TGF-beta)

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- potent stimulator of fibrosis
- proliferation of fibroblasts and smooth muscle
- activates fibroblasts
- enhances the production of collagen and other components
- produced by macrophages, endothelial cells and platelets

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granulation tissue

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- specialized type of tissue reaction to injury
- consists of new small blood vessels and proliferating, activated fibroblasts
- often leaky --> edematous or reddened appearance due to leakage of proteins and RBCs
- may start early scar formation (collagen)

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angiogenesis

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- formation of new blood vessels in adults
- critical factor in the growth of tumors and the re-vascularization of tissue with inadequate blood supply
mechanisms:
1. growth from endothelial precursor cells
2. growth from pre-existing vessels
--> VEGF (important), also PDGF and TGF-beta

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fibroblast migration and proliferation

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- migration and proliferation of fibroblasts is stimulated by growth factors (TGF-beta, PDGF, EGF)
- secreted by macrophages at site of injury

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deposition of the ECM

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- most of the growth factors that promote fibroblast proliferation also stimulate the synthesis of collagen
- collagen type III--> one of the first collagens to be laid down
- loose and "young"
- as repair progresses, angiogenesis ceases, number of endothelial cells and fibroblasts decreases --> avascular pale scar

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tissue remodeling

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- change in components of ECM
--> transition from collagen type III to denser and more mature collagen type I
- remodeled and shaped to a density and size that is optimal for the anatomic site and tissue type
- degradation of unnecessary collagen and proteins by metalloproteinases (MMPs)

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scar formation

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1. fibroblast migration and proliferation
2. deposition of the ECM
3. tissue remodeling

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cutaneous wound healing

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- single injurious event (wound or cut to the skin) that is over quickly and the body is then allowed to heal without ongoing injury
1. inflammation --> blood clot formation --> inflammation
2. proliferation --> granulation tissue formation and re-epithelialization of skin
3. maturation --> ECM deposition, scar maturation, wound contraction, recovery of tensile strength

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first intention

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"primary union"
- tissue edges are closely approximated, as in surgical incision)

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second intention

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- filling in of a large defect with separated edges, usually due to significant tissue loss

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factors that impact wound healing

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systemic factors
1. nutritional status
2. circulatory status
3. diseases such as diabetes
4. use of anti-inflammatory medications such as glucocorticoids

local factors:
1. infection (most important)
2. mechanical factors
3. size, location, and type of wound

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complications in wound healing

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1. deficient scar formation --> wound separation or ulceration
2. excessive tissue formation
3. formation of contractures --> distortion of the scar or adjacent structures (severe burns)

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fibrosis associated with chronic inflammation

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often involve continuous tissue injury and active inflammation, due to persistence of initial stimulus