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A. Characteristics

  1. Slower onset and more protracted course than in acute inflammation
  2. There is less vascular dilation and exudation of fluids
  3. Chronic inflammation may follow acute phase, but can occur without acute phase also
    1. Autoimmune diseases are characterized by chronic inflammation usually without acute
    2. Chronic inflammation with free radical generation can lead to tissue damage as well
  4. Intracellular organisms are commonly associated with chronic inflammation
    1. M. Tuberculosis, M. Leprae
    2. Schistosomiasis
    3. Treponema pallidum (that is, spirochete)
    4. Certain viruses including Herpes simplex
    5. Fungal Infections
  5. Cell Types Involved
    1. Increased number of macrophages and lymphocyes (mainly Th1 type T cells)
    2. Plasma cells increase after about 1 week
    3. Large numbers of neutrophils are NOT a characteristic of chronic inflammation
    4. However, free radical generation by neutrophils and other cells contributes to damage [8]
    5. Eosinophils are variably present, depending on inciting event and host response
    6. Eventually, in normal response, inflammatory tissue is replaced with granulation tissue
  6. Complement [11]
    1. Complement is activated at sites of tissue injury
    2. Activation occurs through immune complexes and reperfusion injury (lipid release)
    3. Activated complement causes damage through direct injury (membrane attack complex)
    4. Also causes damage by activating lymphocytes bearing complement receptors
    5. This occurs through C4b and C3b complement proteins
    6. In addition, complement amplifies injury through anaphylatoxins C5a and C3a
  7. Fibrous Connective Tissue Deposition
    1. Occurs later in process and can cause tissue hardening
    2. Tissue hardening is called induration
    3. Granulation tissue (reparative) begins replace inflammatory tissue at lesion site
    4. In successful healing, granulation tissue gives way to new parenchymal cells
    5. If fibroconnective tissue induration persists, it is called sclerosis or fibrosis

B. Pathophysiology [1,9]

  1. Principal cells of chronic inflammation are lymphocytes, macrophages, plasma cells
  2. Key part of pathophysiology is migration of cells to site of inflammation [6]
    1. In most cases, cells must leave the blood stream and migrate to site of inflammation
    2. Traversing the endothelium in the blood stream is first event
    3. Leukocytes express cell adhesion molecules (CAM) which allow binding to endothelium
    4. These molecules include integrins, selectins, ICAMs, and other glycoproteins
    5. Chemotactic cytokines (chemokines), mainly ß-family (CC), attract cells to tissue [2]
  3. Macrophages accumulate at site of inflammation at ~24 hours
    1. They predominate over neutrophils after 48 hours
    2. Migration accomplished by integrins (VLA-4 and ß2-integrins), and L-selectin
    3. Express receptors for Ig Fc, Complement C3b, Lipopolysaccharide (CD14)
    4. Also express MIF-R, migration inhibition factor, which keeps macrophages in this area
    5. Macrophages are part of reticuloendothelial system
    6. Include Kupfer, Alveolar, Synovial, Microglia, splenic macrophages, osteoclasts
  4. Migration into tissue is accompanied by blood monocytes conversion to macrophages
    1. Various activation factors involved, including IFNg, Complement (C'), coagulation products
    2. Macrophages also respond to endotoxin (LPS), Glucan, gram positive bacterial products
    3. Macrophage activation accompanied is by production of IL1 and TNFa; PGDF, FGF, CSFs
    4. Involved in stimulating T lymphocyte responses
    5. Functions: Phagocytosis, Secretion, Debris clearance, antigen presentation
    6. Macrophages are attracted to site and stimulated by chemokines as well [2]
    7. These cytokines also stimulate fever (thermogenesis) [4]
  5. Antibacterial Compounds
    1. Various anti-bacterial compounds produced by many cell types
    2. Complement components and coagulation factors (VII, IX, X, V, II, TF, TPA etc)
  6. T Lymphocytes
    1. Helper and cytotoxic, possibly TCRgd+, are involved; helper cells are key
    2. TCRgd+ T cells express gamma-delta T cell receptor and may play unusual roles
    3. NK cells, sIg+ B cells, and other cells involved also, somewhat later in response
    4. Critical events are production of lymphokines by CD4+ T helper Cells (mainly Th1)
    5. Including Interferon (IFN), IL2 help macrophages and B cells and NK Cells
    6. Various other B cell growth / differentiation factors, eg. IL4, IL5, IL6
    7. Also produce TNFß (lymphotoxin), and lymphocyte derived chemotactic factors
    8. Chronic inflammation with fibrosis probably requires Th1 CD4+ T cells
  7. B Lympnhocytes
    1. Require somewhat longer (about 5-7days) to infiltrate tissue
    2. Production of Immunoglobulins is main function (after differentiation to plasma cells)
    3. Activated B cells also present antigens to T cells very efficiently

C. Types of Chronic Inflammation [3]

  1. Nongranulomatous
    1. Some viruses
    2. Graft rejection
    3. Eosinophilia in helminthic disease
    4. Autoimmune: primary biliary cirrhosis, Crohn's Disease
  2. Granulomatous (CGI)
    1. Caseating ("cheeselike") - with cell necrosis within granuloma
    2. Non-caseating - without cell necrosis
  3. Caseating Granulomas
    1. Mycobacteria: M. tuberculosis, atypical mycobacteria
    2. Fungi: hisoplasmosis, coccidiomycosis
    3. Bacteria: brucellosis, chlamydia, treponemes
    4. Paratoxoplasmosis, leishmania
  4. Non-caseating Granulomas
    1. Sarcoidosis
    2. Berryliosis
    3. Fungal infections such as Aspirgillosis
    4. Hypersensitivity pneumonitis, methotrexate induced pneumonitis
    5. Autoimmune: Wegener's granulomatosis, Churg-Strauss,
    6. Foreign-body reaction with Giant cells

D. Healing and Repair

  1. Process involves potential remodelling
    1. Resolution: unaffected, normal tissue is left
    2. Reconstitution: specialized cells lost during inflammmation replaced by same cells
    3. Regeneration: same cell types, but abnormal architecture
    4. Some processes leave "giant cells", believed to be fused Macrophages, engulfed ?
  2. Granulation Tissue
    1. Refers to new "connective" tissue at site of inflammation
    2. Increased cellularity and vasculature compared to normal connective tissue
    3. First, capillary-like vessels are formed from older vessels
    4. These can actually become quite large before maturing into arterioles and venules
    5. In addition, it is critical that lymphatics grow into the repaired tissue
    6. Can see marked response following Type II Hypersensitivity reactions
  3. Mediators
    1. Growth factors produced by macrophages, platelets, lymphocytes, then fibroblasts
    2. PGDF, TGFß and TGFa (EGF), FGFs, and angiogenin
    3. Angiogensis and collagen deposition are key elements of healing

E. Systemic Effects of Inflammation

  1. Fever
    1. Mediated by endogenous pyrogens, IL1, IL6, TNFa
    2. Mainly produced by neutrophils, macrophages, and endothelium
    3. Activation of these cell types by lymphocytes is required in some situations
  2. Leukocytosis
    1. Activated T cells produce many cytokines including Colony Stimulating Factors (CSF)
    2. Utilization of neutrophils leads to reduced blood levels, increased marrow production
    3. Strain on marrow for production causes release of immature neutrophils
    4. These blood myelocytes (bands or "band forms") are described by a "left shift"
    5. Left Shift - immature neutrophils (usually shown on left side of generation diagrams)
  3. Hypotension
    1. Believed to be due to arteriolar dilation, loss of fluid to nonvascular space
    2. Nitric oxide appears be the major mediator, formerly called "EDRF"
    3. Also mediated by prostaglandins, histamine, others
  4. Anemia of Chronic Disease [7]
    1. IL1 and TNFa directly suppress erythropoietin production from the kidney
    2. This is independent of tissue oxygenation levels
    3. IL1 and TNFa also block differentiation of erythrocytes from precursor cells
    4. Reversal of inflammation leads to normalization of blood counts
  5. Cytokines such as IL1, IL6 and IFNg induce or repress various proteins
  6. The following Acute Phase Proteins (ARP) levels increase with inflammation [4]:
    1. C-Reactive Protein (CRP)
    2. Serum Amyloid A - chronically high levels cause amyloidosis
    3. Haptoglobin
    4. Alpha-Acid Glycoprotein
    5. Alpha1-Protease Inhibitor
    6. Fibrinogen
    7. Ceruloplasmin
    8. Complement Proteins C3 and C4
    9. C1 Esterase Inhibitor
    10. C4b Binding Protein
    11. Alpha2-Macroglobulin
    12. Ferritin
    13. Phospholipase A2
    14. Plasminogen activator inhibitor 1 (PAI-1)
    15. Fibronectin
    16. Hemopexin (less than haptoglobin)
    17. Pancreatic secretory trypsin inhibitor
    18. Inter-alpha protease inhibitor
    19. Mannose binding protein
  7. The following ARP levels decrease with inflammation [4]:
    1. Albumin
    2. Transthyretin (Prealbumin)
    3. Transferrin
    4. Alpha2-HS Glycoprotein
  8. Elevated IL-6 and C-reactive protein (CRP) Levels
    1. Associated with mortality [5], frailty and functional decline [12] in elderly
    2. Highest and lowest quartiles of IL-6 and CRP compared in elderly
    3. High IL-6 associated with 1.9X risk of death, 1.5X risk of functional decline
    4. High CRP associated with 1.6X risk of death overall [5]
    5. Elevated CRP associated with cardiovascular death but not noncardiovascular death in women [13]
    6. High IL-6 and CRP associated with 2.6X risk of death
    7. High IL-6 and elevated D-Dimer levels associated with 2.0X risk of functional decline [12]

F. Chronic Inflammation and Cancer [10]

  1. Chronic inflammation may cause DNA instability
  2. Various cytokines are expressed in chronically inflamed tissue
  3. A variety of malignancies have been linked to inflammation and/or infection
    1. Bladder Cancer - Schistosomiasis
    2. Cervical Cancer - papillomavirus
    3. Ovarian Cancer - talc inflammation, pelvic inflammatory disease, tissue remodelling
    4. Gastric Cancer and MALT Lymphoma - Helicobacter pylori
    5. Esophageal Cancer - Barrett's Metaplasia
    6. Colorectal Cancer - inflammatory bowel disease
    7. Pancreatic Cancer - chronic pancreatitis
    8. Hepatocellular Cancer - chronic active hepatitis
    9. Bronchial Carcinoma - silica, asbestos, cigarette smoke
    10. Mesothelioma - asbestos
    11. Kaposi's Sarcoma - human herpesvirus 8 (HHV-8)
  4. Unclear exactly which cytokines are involved in tumor promotion

Resources

calcAbsolute Neutrophil Count

References

  1. Luscinskas FW and Gimbrone MA Jr. 1996. Annu Rev Med. 47:413 abstract
  2. Adams DH and Lloyd AR. 1997. Lancet. 349:490 abstract
  3. Newman LS, Rose CS, Maier LA. 1997. NEJM. 336(17):1224 abstract
  4. Mackowiak PA. 1998. Arch Intern Med. 158(17):1870 abstract
  5. Harris TB, Ferrucci L, Tracy RP, et al. 1999. Am J Med. 106(5):506 abstract
  6. Molitoris BA and Marrs J. 1999. Am J Med. 106(5):583 abstract
  7. Spivak JL. 2000. Lancet. 355(9216):1707 abstract
  8. McCord JM. 2000. Am J Med. 108(8):652 abstract
  9. Delves PJ and Roitt IM. 2000. NEJM. 343(1):37 abstract
  10. Balkwill F and Mantovani A. 2001. Lancet. 357(9255):539 abstract
  11. Walport MJ. 2001. NEJM. 344(15):1140 abstract
  12. Cohen HJ, Harris T, Pieper CF. 2003. Am J Med. 114(3):180 abstract
  13. Tice JA, Browner W, Tracy RP, Cummings SR. 2003. Am J Med. 114(3):199 abstract