Inflammation: Process

Question 1

What is inflammation?

Answer 1

• 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

Question 2

What causes inflammation?

Answer 2

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

Question 3

What is the purpose of inflammation?

Answer 3

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

Question 4

What are the outcomes of inflammation?

Answer 4

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

Question 5

What are the cardinal lsigns of inflammation?

Answer 5

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

Question 6

What are the vascular events of inflammation?

Answer 6

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

Question 7

Review: How does blood flow through the microcirculation?

Answer 7

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

Question 8

What are the sequential series of vascular events of inflammation?

Answer 8

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

Question 9

What is transient arteriolar vasoconstriction?

Answer 9

• 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

Question 10

What is arteriolar vasodilation?

Answer 10

• 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

Question 11

What is increased vascular permeability?

Answer 11

• 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

Question 12

How is edema and inflammation similar?

Answer 12

• 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

Question 13

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

Answer 13

• 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

Question 14

Why does blood flow slow?

Answer 14

• 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

Question 15

What is the redistribution of blood cell elements?

Answer 15

• 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

Question 16

What are the cellular events of inflammation?

Answer 16

• 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

Question 17

What is margination and adhesion to endothelium?

Answer 17

• 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

Question 18

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

Answer 18

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

Question 19

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

Answer 19

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

Question 20

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

Answer 20

• ß-2 integrins

Question 21

What are ß-2 integrins?

Answer 21

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

Question 22

What is Emigration?

Answer 22

• 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

Question 23

What order do cells emigrate?

Answer 23

• 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

Question 24

What is Chemotaxis?

Answer 24

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

Question 25

What are teh cehmical attractants that can initiate chemotaxis?

Answer 25

• 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

Question 26

What is the mechanism of Chemotaxis?

Answer 26

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

Question 27

How do the inflammation response cells accumulate?

Answer 27

• 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

Question 28

What is Phagocytosis

Answer 28

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

Question 29

What is the purpose of phagocytosis?

Answer 29

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

Question 30

What are the stages of phagocytosis?

Answer 30

1. Opsonization
2. Attachment
3. Ingetion
4. killing and degradation

Question 31

What is Opsonization?

(phagocytosis)

Answer 31

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

Question 32

What are the major opsonins?

(phagocytosis)

Answer 32

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

Question 33

What happens during Attachment?

(phagocytosis)

Answer 33

• 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

Question 34

What happens during Ingestion?

(phagocytosis)

Answer 34

• 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

Question 35

What happens during Killing?

(phagocytosis)

Answer 35

• 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
      *

Question 36

What are the Oxygen-independent Killing mediators?

(phagocytosis)

Answer 36

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

Question 37

What happens during Oxygen-dependent Killing?

(phagocytosis)

Answer 37

• 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

Question 38

How does the Myeloperoxidase-Independent pathway work?

(Phagocytosis: Killing)

Answer 38

• 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

Question 39

How does the Myeloperoxidase-Dependent pathway work?

(Phagocytosis: Killing

Answer 39

• 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)

Question 40

What happens during Degradation?

Answer 40

• 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

Question 41

What can go wrong with Phagocytosis?

Answer 41

• 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

Question 42

What can go wrong with cellular events?

Answer 42

• 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

Question 43

Phagocytosis process summary:

Answer 43

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