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General Pathology > Inflammation: Process > Flashcards

Inflammation: Process Flashcards

1
Q

What is inflammation?

A
  • The host response to injurty
    • Has vascular and cellulat event
  • A complex and integrated response involving the microvasculature, blood elements (cells and fluid), and local EM
  • It overlaps with other host responses
    • hemostasis and immunity
  • It is essential for life, but can have adverse consequences
  • It can last for hours to years
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2
Q

What causes inflammation?

A
  • Microorganisms
  • Chemicals
  • Trauma
  • Thermal or radiation injury
  • Foreign bodies
  • Immune reactions
  • Necrosis
  • Neoplastic/altered cells
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3
Q

What is the purpose of inflammation?

A
  • To isolate, dilute, neutralize, confine and remove the offending agent
  • To clear the area of debris
  • To initiate healing and repair
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4
Q

What are the outcomes of inflammation?

A
  • Elimination of the agent and return to normal
  • Stalemate: ongoing inflammation
  • Death of the host
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5
Q

What are the cardinal lsigns of inflammation?

A
  • Celsus in 20AD described:
    • Rubor (Redness)
    • Tumor (Swelling)
    • Calor (Heat)
    • Dolor (Pain)
  • Rudolf Virchow 1860 added:
    • Function laesa (loss)
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6
Q

What are the vascular events of inflammation?

A
  • The pattern of vascular change associated with acute inflammation was originally described in 1867 by Julius Cohnheim
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7
Q

Review: How does blood flow through the microcirculation?

A
  • It is not constant
    • usually determined bsed on physiologic needs
    • canges flollowing injury
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8
Q

What are the sequential series of vascular events of inflammation?

A
  1. Transient arteriolar vasocaonstriction
  2. Arteriolar vasodilation (hyperemia)
  3. Capillary congestion (passive hyperemia)
  4. Increased vascular permeability
  5. Slowing of blood flow
  6. Redistribution of blood cell elements
  7. Blood flow stasis
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9
Q

What is transient arteriolar vasoconstriction?

A
  • Caused by direct effect of the inciting stimulus on ateriolar smooth muscle
    • regulated by the release of local meiators?
  • Does not occur with all stimuli
  • Vasoconstriction lasts several seconds, up to 5 minutes
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10
Q

What is arteriolar vasodilation?

A
  • A wave of vasodilation starting at the arteriole progressing to the venule causes hyperemia
    • Mediatos include:
      • Histamin
      • Bradykinin
      • Prostacyclin
      • Prostaglandin D2
      • Leukotriene B4
      • Nitric oxide
      • Local neurogenic substances
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11
Q

What is increased vascular permeability?

A
  • Endothelial junctions become leakiy resulting in fluid and molecule loss to the intersitium
    • Mediators:
      • Immediate transient response:
        • Histamine, bradykinin, leukotrienes B4C4D4E4, platelet activating factor, C3a and C5a, substance p
      • Delayed sustained response:
        • TNF, IL-1, gamma-IFN
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12
Q

How is edema and inflammation similar?

A
  • Increased vasular permeability is one of the mechanisms of edema formation
    • Increased intravascular hydrostatic pressure and increased extrvascular osmotic pressure also contribute to fluid loss
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13
Q

What is in the fluid that moves to the extravascualar space in inflammation?

A
  • Protiens involved in inflammation and helps dilute the institing stimulus
  • Fluid changes in character from a Transudate
    • SG < 1.012 (<3 g protein/dL)
    • <1,500 leukocytes/ml
  • to an Exudate
    • ​SG > 1.020 (> 3 g protein/dL)
    • >1,500 leukocytes/ml
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14
Q

Why does blood flow slow?

A
  • Large vascular diameter resulting in slower flow and increased numbers of blood cells (congestion)
  • Increased blood viscosity due to plasma loss
  • Increased adhesiveness of erythrocytes
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15
Q

What is the redistribution of blood cell elements?

A
  • laminar flow is disrupted due to vsodilation and congestion
    • Erythrcytes become centrally located
    • Leukocytes move to the periphery along the endothelial surface
      • Relocation is essential to begin the cellular changes associated with inflammation
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16
Q

What are the cellular events of inflammation?

A
  • A critial event in inflammation is the movement of cells from the blood vessel to the site of injury
  • Major step:
    • Margination and adhesion to endothelium
    • Emigration
    • Chemotaxis
    • Accumulation
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17
Q

What is margination and adhesion to endothelium?

A
  • Margination is a vascular event that moves leukocytes to the periphery of the vessel (adjacent to the endothelium)
    • At site of inflammation, leukocytes will completely line the endothelial surface
      • “Pavementing”
    • This occurs in the capillaries and postcapillary venules
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18
Q

What is the process of margination and adhesion to the endothelium?

A
  1. Marginated leukocyts transiently adhere (roll) along the endothelial surface
    • Mediated by endothelial E- and P-Selectins
      • bind specific glycopeotin ligands on leukocytes
    • Mediated by leukocyte L-selectin
      • binds endothelial sialyl Lewis X receptor and other glycoproteins
  2. Leukocts firmly adhere to endothelium
    • Endothelial receptors
      • Intracellular Adhesion Molecule 1 (ICAM-1)
      • Vascular Cell Ahesion Molecule 1 (VCAM-1)
    • Leukocyte receptors
      • ß-2 integrins
        • increased expression on activated leukocytes
19
Q

What are the endothelial receptors involved in adhesion of leukocytes to the endothelium?

A
  • Intracellular Adhesion Molecule 1 (ICAM-1)
  • Vascular Cell Adhesion Molecule 1 (VCAM -1)
20
Q

What are the leukocyte receptors involved in adhesion of leukocytes to the endothelium?

A
  • ß-2 integrins
21
Q

What are ß-2 integrins?

A
  • Includes”
    • Mac-1
    • LFA-1
    • p150,95 and αdß2
  • All share the ß-subunit CD18
    • MAC-1 = CD11a/CD18
22
Q

What is Emigration?

A
  • Movement of leukocytes from the endothelial surface into the extravascular space
    • Facilitated by theenlarged gaps between endothelial cells (increased permeability)
    • Leukocyte-endothelial interctions occur within the inter-endothelial junction
      • Pltelet-Endothelial CellAdhesion Molecule 1 (PECAM-1)
      • Junctional Adhsion Molecules (JAMs)
    • Active mobility of leukocytes enable them to exert pseudopods into interendothelial junctions to pull themselves through to the extravascular space
23
Q

What order do cells emigrate?

A
  • Neutrophils emigrate first
    • can occur within 30-40 miutes
    • predominate for 6-24 hours
  • Monoctes emigrate next
    • predominate by 24-48 hours
  • Lymphocytes are last
    • sluggish, much, much later
24
Q

What is Chemotaxis?

A
  • The directed movement of leukocytes to the site of an inflammatory stimulus
    • It occurs in response to a concentration gradient of a chemical attractant
25
Q

What are teh cehmical attractants that can initiate chemotaxis?

A
  • Activated complement components (C5a)
  • Bacterial products (N-formyl methionine amino acids)
  • Archidonic acid metabolites (Leukotriene B4)
  • Kinins
  • Collagen and fibrin breakdown products
  • Leukocyte products (various cytokines)
  • Chemokines
26
Q

What is the mechanism of Chemotaxis?

A
  1. Chemotactic factors interact with specific leukocyte membrane receptors
  2. Membrane phospholipase C is actvated and results in localized release of Ca2+ in the cytoplasm
  3. Fluxes in Ca2+ concentrations result in localized assembly and disassembly of microtubules and microfilaments
  4. Leukocyte ß1 integrins bind to ECM components to pull themselves in teh direction of the stimulus
27
Q

How do the inflammation response cells accumulate?

A
  • Neutrphils are the first cell to accumulate at the site of the stimulus
    • They are teh first to emigrate
    • they are teh most motile of teh leukocytes
    • They are short-lived in the tissues (6-72 hours)
  • Macrophages become more numerous after 24-48 hours
    • They emigrate later, but emigration is more sustained
    • Macrophags are long-lived and can replicate locally
  • Lymphocytes may accumulate later in response to persistet immunologic stimulation
28
Q

What is Phagocytosis

A
  • The uptake and degradation of particulate material by leukocytes
    • neutrophils and macrophages are the most important phagocytes in inflammation
29
Q

What is the purpose of phagocytosis?

A
  • Destroy and remove he inflammatory stimulus
  • Clean up debris to stimulate the healing process
30
Q

What are the stages of phagocytosis?

A
  1. Opsonization
  2. Attachment
  3. Ingetion
  4. killing and degradation
31
Q

What is Opsonization?

(phagocytosis)

A
  • The coating of foreign material by factors that enhance phagocytosis (opsonins)
32
Q

What are the major opsonins?

(phagocytosis)

A
  • C3b
  • IgG
  • Collectins
    • leukocyte proteins that bind to mannose in micrbial cell walls
33
Q

What happens during Attachment?

(phagocytosis)

A
  • Phagocyte attaches to the foreign material
    • Phagocytes readily attach to opsonized material
      • phagocytes have specific membranre receptors for C3b and the Fc portion of IfF
    • Phagocytes can attach to unopsonized material, but less efficently
34
Q

What happens during Ingestion?

(phagocytosis)

A
  • Cell membrane pseudopods extend around the material to internalize it into an intra-cytoplasmic vacuole (“phagosome”)
  • Ingestion is an active process similar to that which occurs with chemotaxis
    • Ca+2 fluxes regulate cytoskeletal changes
35
Q

What happens during Killing?

(phagocytosis)

A
  • A lysosome fuses to a phagosome ot form a phagolysososme
    • Lysosomal enzymes are released into the phagolysososme (degranulation)
    • If the material in teh phagolysosome is a microorganism, it mustfirst be killed
      • Oxygen-independent killing mechanisms
      • Oxygen-dependent killing mechanisms
        *
36
Q

What are the Oxygen-independent Killing mediators?

(phagocytosis)

A
  • Acid hydrolases
  • Bacterial Permeability Increasing Protein
  • Major Basic Protein
  • Lysozyme
  • Lactoferrin
  • Defensins
  • Cathepsin G
37
Q

What happens during Oxygen-dependent Killing?

(phagocytosis)

A
  • Increased O2 uptake results in the production og a varient of oxygen metabolites
    • These metabolites are hightly reactive and potent killing agents
  • 2 killing pathways:
    • Myeloperoxidase-independent pathway
    • Myeloperoxidase-dependent pathway
38
Q

How does the Myeloperoxidase-Independent pathway work?

(Phagocytosis: Killing)

A
  • Killing is mediated by the direct oxidative effects of oxygen metabolites
    • Superoxide anion
    • Hydrogen peroxide
    • Hydroxyl radical
  • Formation of NADPH oxidase during the respiratory burst initiates the process
39
Q

How does the Myeloperoxidase-Dependent pathway work?

(Phagocytosis: Killing

A
  • H2O2 + Cl = HOCl
    • Hypochlorus acid: Bleach
  • Considered the most potent killing mechanism
    • Is present in neutrophils (contain high levels of myeloperoxidase), but plays an insignificcant role in macrophages (contains very little myeloperozidase)
40
Q

What happens during Degradation?

A
  • Following killing, degradation and digestion of the material occur
    • Acid hydrolases and other proteolytic enzymes liquefy the debris
    • Unliquified debris persists as a residual body
  • Following phagocytosis, neutrophils undergo apoptosis and are removed
  • Magrophages persst and continue to function at the site until no longer needed
41
Q

What can go wrong with Phagocytosis?

A
  • Some organisms survive within the phagolysosome
  • Some organisms are viulent to phagocytes
  • Timing errors in phagosome-lysosome fusion may occur
  • Large or indigestible substances can’t be internalized
  • Reactive metabolites damage the cell
42
Q

What can go wrong with cellular events?

A
  • Decreased circulating leukocytes
  • Defective adhesion to endothelium
  • Defective movement (emigration and chemotaxis0
  • Defective phagocytosis
  • Defective intracellular killing

Result is decreased host response to the inflammatory stimulus

43
Q

Phagocytosis process summary:

A
  1. Opsonization:
    • coating of foreign material with opsonins
  2. Attachement:
    • phagocyte attaches to foreign material either opsonized or not
  3. Ingestion:
    • phagocyte cell-membrane pseudopods around foreign material and internalizes it into a phagosome
  4. Killing and Degredation:
    • lysosome fuses to phagosome and relesases enzymes to kill microorganisms (oxygen depended/independent)
    • Acid hydrolases and other proteolytic enyzymes liquify debris
      • unliquified debris persist
    • Neutrophils undergo apoptosis - Macrophages continue to function until no longer needed

General Pathology (34 decks)

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