Gen Path L11, 12, 14, 15

  1. General Features and Causes of Inflammation
    • 1. Integral physiologic mechanism in elimination of foreign invaders, infectious agents, and damaged tissue.
    • 2. protective response involving host cells, blood vessels, and proteins and other mediators, to eliminate the initial cause of cell injury, the necrotic cells and tissues, and to initiate repair.
    • 3. achieved by diluting, destroying, or otherwise neutralizing harmful agents (e.g., microbes, toxins)
    • 4. eventually heal and repair
    • 5. involves innate immunity
    • 6. steps of inflammatory response (5Rs):
    • (1) recognition of the injurious agent,
    • (2) recruitment of leukocytes,
    • (3) removal of the agent,
    • (4) regulation (control) of the response, and
    • (5) resolution (repair)
    • 7. Outcome of acute inflammation - elimination of noxious stimulus, followed by decline of the reaction and repair of damaged tissue; or persistent injury resulting in chronic inflammation.
  2. Inflammation in organs or tissues
    • Blepharitis - eyelids
    • Cheilitis - lips
    • Sialadenitis – salivary gland
    • Bursitis - bursae (small sacs) of synovial fluid
    • Cystitis - bladder infection
    • Phlebitis – veins (usually in legs)
    • Rhinitis - mucous membrane inside the nose
    • Mastitis - breast tissue
  3. Components of acute and chronic inflammatory responses and their principal functions
    • Plasma proteins
    • - Complement: mediators of inflammation, elimination of microbes
    • - Clotting factors and kininogens: mediators of inflammation
    • Lymphocyte - Immune response
    • Polymorphonuclear leukocyte - Elimination of microbes, dead tissue
    • Endothelium - Source of mediators (NO, cytokines, others)
    • Monocyte -> Macrophage - Elimination of microbes, dead tissue; Source of mediators (cytokines, others); Role in immune response
    • Mast cell - Source of mediators (histamine, others);
    • Fibroblasts, Extracellular matrix proteins and cells - Repair
  4. Leukocyte-Endothelial Interactions and Leukocyte Recruitment into Tissues
    • At sites of infection, macrophages stimed by microbes produce cytokines (eg. TNF and IL-1) that activate the endothelial cells of nearby venules to produce selectins, ligands for integrins, and chemokines.
    • Selectins mediate weak tethering of blood leukocytes on the endothelium, and the shear force of blood flow causes the leukocytes to roll along the endothelial surface.
    • Chemokines produced in the surrounding infected tissues or by the endothelial cells are displayed on
    • the endothelial surface via proteoglycan and bind to receptors on the rolling leukocytes -> activation of the leukocyte integrins to a high-affnity binding state.
    • The activated integrins bind to their Ig superfamily ligands on the endothelial cells -> firm adhesion. The leukocytes then crawl to junctions between endothelial cells and migrate through the venular wall.
    • Chemokines draw in the activated leukocytes into the tissue
  5. Endothelial -> Leukocyte Adhesion Molecules [Major Roles]
    • Selectins and Selectin Ligands
    • P-Selectin -> Silyl-Lewis X modified Prt [Rolling]
    • E-Selectin -> Silyl-Lewis X modified Prt [Rolling & adhesion]
    • GlyCam-1, CD34 -> L-selectin [Rolling of neutrophils, monocytes]
    • Integrins and Integrin ligands
    • ICAM-1 (Ig Family) -> CD11/CD18 (LFA-1, MAC-1) [Firm adhesion, arrest, transmigration]
    • VCAM-1 (Ig Family) -> VLA-4 [Adhesion]
    • Others
    • CD31 -> CD31 (homotypic interaction) [Transmigration of Leukocytes through endothelium]
  6. ___________ receptors are used in phagocytosis of microbes.
    Mannose and scavenger
  7. For killing the microbes in the phagolysosome, ________ and _________ are used.
    • ROS, NO (coming from Arginine+iNOS->citrulline reaction)
    • lysosomal enzymes
  8. Functions of macrophages
    • - Macrophages are activated by microbial products such as LPS (G(-) -> TLR4), cytokines such as NK cell–derived IFN-γ, and complement fragment.
    • - The activation leads to production of inflammatory cytokines ((TNF, IL-1, IL-6, IL-12) which lead to Inflammation and enhanced adaptive immunity.
    • - The activation also leads to activation of Phagocyte oxidase and iNOS, which produce ROS and NO respectively, resulting in killing of microbes.
    • - Complement activation also causes Phagocytosis of microbe into phagosome, and eventually killing the microbe
  9. Acute Inflammation
    • rapidly brings leukocytes and plasma proteins to site of injury
    • clear invaders and digest and remove necrotic tissue
  10. Acute Inflammation - two phases
    • Vascular changes: vasodilation, increased vascular permeability, activation of endothelial cells = increased adhesion & migration of leukocytes
    • Cellular events: Emigration of leukocytes from circulation to site of injury (cellular recruitment); Elimination. Neutrophils (“PMNs”) predominate.
  11. Stimuli for Acute Inflammation
    • Infection - bacterial, viral, fungal, parasitic
    • Trauma - blunt & penetrating; physical and chemical agents (e.g. thermal, burn, frost bite, irradiation, chemical)
    • Tissue necrosis - ischemia (e.g. myocardial infarction), chemical injury
    • Foreign bodies – splinters, dirt, suture, crystal deposit
  12. cardinal manifestations of acute inflammation
    • Redness (rubor)
    • Warmth (calor)
    • Swelling, due to edema, when plasma proteins get out (tumor)
    • Pain (dolore)
    • Loss of Function (functio laesa)
  13. TLR and the inflammasome pathways
    • slight difference & overlap
    • TLR pathway can engage the extracellular or the intracellular (cytosol and endosomal) pathway, all of which leads to production of inflammatory cytokines (eg TNF) and adhesion mol.
    • Inflammasome pathway - NLRP3 inflammasome; activation of caspase -1 -> activation and secretion of IL-1 -> acute inflammation
  14. Formation of transudates and exudates
    • Normal - balance between outward hydrostatic and inward osmotic pressures
    • Transudates - increased outward pressure and/or decreased inward pressure. Low in protein, few cells
    • Exudate - increased permeability. High in protein, some cells
  15. Leukocytes activation mechanisms
    • chemokine ligands -> GPCR -> ... -> increased adhesion and transmigration
    • {LPS G- -> MD2/CD14-TLR | cytokines -> receptor} -> {production of mediators -> inflammation is amplified | production of ROS and lysosomal enzyme -> Microbial killing}
    • microbe -> phagocytic receptor -> {production of ROS and lysosomal enzyme | phagocytosis} -> Microbial killing
  16. Leukocyte-Induced Injury
    • Acute & Chronic
    • Asthma - Eosinophils; IgE antibodies
    • Acute
    • Acute respiratory distress syndrome - Neutrophils
    • Acute transplant rejection - Lymphocytes; antibodies and complement
    • Glomerulonephritis - Antibodies and complement; neutrophils, monocytes
    • Septic shock - Cytokines
    • Chronic
    • Rheumatoid arthritis - Lymphocytes, macrophages; antibodies?
    • Atherosclerosis - Macrophages; lymphocytes?
    • Chronic transplant rejection - Lymphocytes, macrophages; cytokines
    • Pulmonary fbrosis - Macrophages; fbroblast
  17. Defects in Leukocyte Functions
    • Acquired
    • Bone marrow suppression: tumors (including leukemias), radiation, and chemotherapy - Production of leukocytes
    • Diabetes, malignancy, sepsis, chronic dialysis - Adhesion and chemotaxis
    • Anemia, sepsis, diabetes, malnutrition - Phagocytosis and microbicidal activity
    • Genetic
    • Leukocyte adhesion defciency 1 - Defective leukocyte adhesion because of mutations in β chain of CD11/CD18 integrins
    • Leukocyte adhesion defciency 2 - Defective leukocyte adhesion because of mutations in fucosyl transferase required for synthesis of sialylated
    • oligosaccharide (receptor for selectins)
    • Chronic granulomatous disease - Decreased oxidative burst
    • X-linked - Phagocyte oxidase (membrane component)
    • Autosomal recessive - Phagocyte oxidase (cytoplasmic components)
    • Myeloperoxidase defciency - Decreased microbial killing because of defective MPO–H2O2 system
    • Chédiak-Higashi syndrome - Decreased leukocyte functions due to mutations in lysosomal membrane traffic
  18. Outcomes of acute inflammation
    resolution, healing by scarring (fibrosis) or chronic inflammation
  19. Morphologic Patterns of Acute Inflammation
    • Serous inflammation
    • Fibrinous inflammation
    • Suppurative (purulent) inflammation and abscess
  20. Serous inflammation:
    • Watery, protein-poor fluid
    • Depending on source- derives either from the plasma or from the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities
    • Burn or viral infection - within or immediately beneath the epidermis of the skin
    • Effusion = Fluid in a serous cavity
  21. Fibrinous inflammation:
    • More severe injuries. Greater vascular permeability - larger molecules (such as fibrinogen) to pass the endothelial barrier.
    • Characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura.
    • Resolution - degraded by fibrinolysis, then removed by macrophages, restoring normal tissue structure
    • Organization - Extensive fibrin-rich exudates not completely removed, are replaced by an ingrowth of fibroblasts and blood vessels
  22. Suppurative (purulent) inflammation and abscess
    • purulent exudate (pus)- neutrophils, necrotic cells, and edema fluid
    • Unique organisms (e.g., staphylococci) are more likely to induce localized suppuration - referred to as pyogenic (pus-forming)
    • Abscesses - focal collections of pus caused by seeding of pyogenic organisms into a tissue or by secondary infections of necrotic foci; may become completely walled off and eventually replaced by connective tissue. Because of the underlying tissue destruction, the usual outcome with abscess formation is scarring.
  23. Vasodilation - chemical mediators (e.g. histamine): erythema and stasis of blood flow.
  24. Increased vascular permeability is induced by
    histamine, kinins, and other mediators- produce gaps between endothelial cells; by direct or leukocyte-induced endothelial injury; and by increased passage of fluids through the endothelium
  25. Sources of biochemical mediators
    • Endogenous:
    • i. Cell-derived:
    • - Some preformed; stored in intracellular granules (e.g in platelets, macrophages, neutrophils and mast cells).
    • - Others are produced de novo in response to inflammatory stimuli
    • ii. Plasma derived: Circulate in inactive, precursor form; require activation.
    • Exogenous:
    • E.g. bacterial endotoxin, cobra venom
  26. Mediators of inflammation
    • Cell-derived -
    • Preformed:
    • Histamine - Mast cells, basophils, platelets
    • Serotonin - Platelets
    • Newly synthesized:
    • Prostaglandins - All leukocytes, mast cells
    • Leukotrienes - All leukocytes, mast cells
    • Platelet-activating factor - All leukocytes, EC
    • Reactive oxygen species - All leukocytes
    • Nitric oxide - Macrophages, EC
    • Cytokines - Macrophages, lymphocytes, EC, mast cells
    • Neuropeptides - Leukocytes, nerve fibers
    • Plasma derived -
    • Complement activation:
    • C3a, C5a - anaphylatoxins
    • C3b
    • C5b-9 - membrane attack complex
    • Factor XII (Hageman factor) activation -
    • Kinin system (bradykinin)
    • Coagulation / fibrinolysis system
  27. Histamine from _____ cells involved with ______; Serotonin comes from _______, _______.
    • mast
    • vasodilation
    • platelets
    • vasoconstriction
  28. Cell-Derived
    • Histamine <- Mast cells, basophils, platelets [Vasodilation, increased vascular permeability, endothelial activation]
    • Serotonin <- Platelets [Vasoconstriction]
    • Prostaglandins <- Mast cells, leukocytes [Vasodilation, pain, fever]
    • Leukotrienes <- Mast cells, leukocytes [Increased vascular permeability, chemotaxis, leukocyte adhesion and activation]
    • Platelet-activating factor <- Leukocytes, mast cells [Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst]
    • Reactive oxygen species <- Leukocytes [Killing of microbes, tissue damage]
    • Nitric oxide <- Endothelium, macrophages [Vascular smooth muscle relaxation; killing of microbes]
    • Cytokines (TNF, IL-1, IL-6) <- Macrophages, endothelial cells, mast cells [Local: endothelial activation (expression of adhesion molecules). Systemic: fever, metabolic abnormalities, hypotension (shock)]
    • Chemokines - Leukocytes, activated macrophages [Chemotaxis, leukocyte activation]
  29. Regulation of actions of mediators
    • Mostly tightly regulated & short-lived (quick decay)
    • i. Arachidonic acid metabolites - Inactivated by enzymes; e.g. kininase inactivates bradykinin
    • ii. Antioxidants scavenge toxic oxygen metabolites
    • iii. Complement regulatory proteins block complement activation
  30. Principal Inflammatory Actions of Arachidonic Acid Metabolites
    • Vasodilation - Prostaglandins PGI2 (prostacyclin),
    • PGE1, PGE2, PGD2
    • Vasoconstriction - Thromboxane A2, leukotrienes C4,
    • D4, E4
    • Increased vascular permeability <- Leukotrienes C4, D4, E4
    • Chemotaxis, leukocyte adhesion <- Leukotriene B4, HETE
  31. ROS: Roles include
    microbial killing and tissue injury.
  32. NO:
    Effects are vasodilation and microbial killing.
  33. Lysosomal enzymes: Roles include
    microbial killing and tissue injury.
  34. IL-1 TNF roles
    fever; chemotaxis
  35. vasodilation can be induced by
    histamine, NO, prostaglandins
  36. Mediators - Increased vascular permeability
    • Histamine and serotonin
    • C3a and C5a (by liberating vasoactive amines from mast cells, other cells)
    • Bradykinin
    • Leukotrienes C4, D4, E4
    • PAF
    • Substance P
  37. Mediators - Chemotaxis, leukocyte recruitment and activation
    • TNF, IL-1
    • Chemokines
    • C3a, C5a
    • Leukotriene B4
    • Bacterial products (e.g., N-formyl methyl peptides)
  38. Interrelationships among the four plasma mediator systems triggered by activation of factor XII (Hageman factor)
    • Hageman factor is not very active until it encounters the basement membrane of collagen to activate platelets
    • Produces Factor XIIa, which can take four distinct pathways
    • Kinin cascade - leads to production of bradykinin, which is very important in pain
    • fibrinolytic system - involves plasmin
    • clotting cascade - thrombin production
    • Complement cascade
  39. Chronic- characterized by a set of reactions:
    • Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells
    • Tissue destruction, largely induced by the products of the inflammatory cells
    • Repair, involving new vessel proliferation (angiogenesis) and fibrosis
  40. Predisposing factors in Chronic Inflammation
    • Persistent infections by microbes that are difficult to eradicate - E.g. Mycobacterium tuberculosis, Treponema pallidum, certain viruses and fungi, T cell mediated immune responses – DTH
    • Immune-mediated inflammatory diseases
    • (hypersensitivity diseases). May lead to autoimmune diseases- RA, IBD, psoriasis, bronchial
    • asthma
    • Prolonged exposure to potentially toxic agents: Inhaled non-degradable material- silica (silicosis); Cholesterol crystals (may lead to atheroslerosis)
    • Mild forms of chronic inflammation: Neurodegenerative disorders (e.g. Alzheimer disease); Metabolic syndrome and the associated type 2 diabetes; Some cancers
  41. Chronic Inflammatory Cells and Mediators
    • Lymphocytes
    • T cells (CD4+, CD8+)
    • B cells
    • NK cells
    • Plasma cells:
    • Abs to persistent antigens or altered self tissue components at sites of chronic inflammation
  42. Macrophages:
    • Dominant at sites of chronic inflammation
    • Derived from circulating blood monocytes after their emigration from the bloodstream
    • Found in organs such as the liver (Kupffer cells), spleen and lymph nodes (sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages)
    • Together these cells constitute the so-called mononuclear phagocyte system (MPS); Old name: reticuloendothelial system.
    • Monocytes arise from bone marrow and circulate in the blood for only about a day; Under the influence of adhesion molecules and chemokines, they migrate to a site of injury within 24 to 48 hours after the onset of acute inflammation
    • Classical macrophage activation (M1): IFN-γ, endotoxin, particulates; -> ROS, NO, lysosomal enzyme production -> microbialcidal; or -> IL-1, 12, 23, chemokines -> inflammation
    • Alternative macrophage activation (M2): IL-4 and IL-13; not microbicidal; involved in tissue repair – secrete GF, TGF-b, that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis; IL-10 and TGF-b -> antiinflammatory
  43. Principal Inflammatory Actions of Arachidonic Acid Metabolites
  44. Mechanism of angiogenesis
    • New blood vessel development from existing vessels, primarily venules
    • Critical in healing at sites of injury
    • Initiated by vasodilation in response to NO and increased permeability induced by VEGF
    • The most potent growth factor in angiogenesis is vascular endothelial growth factor (VEGF). Another important factor is basic fibroblast growth factor (FGF-2)
  45. Understand predisposing factors to inflammation (microbes, physical factors, chemical agents, and immunological)
  46. Know the vascular changes in acute inflammation (vasodilation, permeability, stasis- clinical examples
  47. Comprehend Leukocyte exudation and phagocytosis; margination, adhesion, emigration, chemotaxis, opsonization, phagocytosis, microbial killing, and release of leukocyte products
  48. Know chemical mediators of inflammation: plasma-derived (coagulation/fibrinolytic systems, kinin system, and complement components); cell derived (histamine, arachidonic acid and metabolites, cytokines, chemokines, lysosomal constituents)
  49. Acute vs. Chronic Inflammation
    • Onset: fast (min-hr) vs. slow (days)
    • Infiltrate: neutrophils vs. monocytes/macrophages/lymphocytes
    • Tissue injury/fibrosis: mild, self-limited vs. severe, progressive
    • Local & Systemic signs: prominent vs. subtle
  50. Understand granulomatous inflammation (causes, pathogenesis, morphology, specific disease categories)
Card Set
Gen Path L11, 12, 14, 15
Gen Path L11, 12, 14, 15 Host Response to Injury