Acute Inflammation (Rosser) Flashcards
inflammation
the reaction of vascularized, living tissue to local injuries
2 Major Goals of Inflammatory Reactions
- Eliminate the injurious stimulus
- Repair associated tissue damage
Five Cardinal Signs of Inflammation
- Redness
- Swelling
- Heat
- Pain
- Loss of Function
Can inflammation occur after death?
no - presence of inflammatory cells means something happened antemortem, not postmortem!
Variables in Inflammation
intensity, magnitude, duration
dependent on innate response, immunologic status of host, and the type of agent involved
Benefits of Inflammation
- Degrade foreign materials
- Provide wound healing factors
- Dilution/inactivation of biological or chemical toxins
- Killing/sequestration [of microbes, necrotic tissue, neoplasia]
- Restrict movement to allow for healing and repair
- Increase temperature (local or systemic) to induce vasodilation and inhibit microbial replication
5 Main Phases of the Inflammatory Response
- Recognize inflammatory stimulus
- Acute vascular response
- Acute cellular response
- Chronic cellular response
- Resolution
Exogenous Substances which Induce Tissue Injury
- Microbes
- Foreign Bodies
- Mechanical Action (traumatic injury)
- Physical Action (think burns, frostbite)
- Chemical Substances (think venoms, caustic agents)
Endogenous Substances Inducing Tissue Injury
- Autoimmune reactions
- Intracellular signals released from injured or dying cells
PAMPs
pattern/pathogen-associated molecular patterns highly conserved microbial ligands (so unique to microbes) and binding triggers release of inflammatory mediators
TLR-4
PRR which recognizes lipopolysaccharide (LPS) in gram-negative cell bacterial walls
TLR-3
PRR for double stranded RNA (viruses)
PRR
pattern recognition receptor located on host cells; binding of PAMPS from microbes to PRRs results in downstream induction of inflammatory mediators
DAMPs
Damage Associated molecular patterns
endogenous molecules released from damaged or dying cells within the host
Difference between PAMPs and DAMPs?
PAMPs are from microbes and differentiate self from non-self
DAMPs are from the host and differentiate healthy self from damaged self
Examples of DAMP Mechanisms/Sources (3)
- extracellular presence of certain molecules
- intracellular enzymes–> breakdown of components
- circulating antibodies
Do both PAMPS and DAMPs bind to PRRs?
yes
What vasoactive mediators are contained in mast cells?
histamine and serotonin
Histamine and Serotonin
released from mast cells at the site of injury to cause vasodilation and increased vascular permeability
Resident Tissue Macrophages
also bind PRRs in response to inflammatory stimuli
Epithelial Cells
can secrete cytokines when injured or recognize inflammatory stimuli via PRRs
What activates platelets?
the exposure of subendothelial collagen
Inflammatory Mediators from Platelets
histamine and serotonin (like mast cells) but also complement activators, platelet activating factor, and coagulation factors
bradykinin
released from damaged vascular endothelium and causes vasodilation
prostaglandins and leukotrienes
can come from many cell types in response to PRR activation; causes vasodilation and increased vascular permeability
platelet-activating factor (PAF)
can come from many cell types in response to PRR activation; causes increased vascular permeability and smooth muscle contraction
hyperemia
tissue redness d/t blood pooling
biphasic nature of vascular permeability response
Early Phase occurs immediately, rapid and short lived, in response to histamines (and kinins etc)
Later phase is cytokine dependent (IL-1, TNFa, and kinins)
Net Effect of the Acute Vascular Response
increased capillary hydrostatic (push) pressure
Edema
leakage of plasma proteins
First cell to make it out of the vasculature in response to injury?
neutrophils
macrophages in the inflammatory response
larger number with a longer duration of infection (chronicity)
Eosinophils respond to what stimuli?
parasitic disease and acute hypersensitivity reaction
lymphocytes and plasma cells respond to what stimuli?
antigenic, or delayed HST
3 Granulocytes
- Neutrophils
- Eosinophils
- Basophils
are granulocytes terminally differentiated?
yes (they are fully mature before leaving the bone marrow)
3 Steps of the Leukocyte Adhesion Cascade
1a. Rolling
1b. Adhesion/Pavementing
2. Migration
3. Chemotaxis
leukocyte adhesion cascade
how neutrophils move from vasculature into tissue
Rolling
blood flow slows, then neutrophil ligands (capital L goes with leukocytes) interact with selectins on the endothelial surface and will “roll along” before coming to an eventual stop
Pavementing/Adherence
final part of adhesion where after the leukocyte stops, it is flattened on the endothelial surface
Cytokines in Induction of Pavementing?
IL-1 and TNFa
Ligands on Surface of Neutrophils Involved in Adhesion
Sialyl Lewis and L-selectin
Ligands on Endothelium Involved in Adhesion
P-selectin and E-selectin
Ligands on Leukocyte involved in Pavementing
beta2 integrins (CD11/CD18)
Ligands on Endothelium involved in Pavementing
ICAM-1 and VCAM-1
diapedesis
actual passage of the leukocyte through wall of blood vessel
PECAM-1
ligand on both leukocyte and endothelium and binds to itself
Summary of Leukocyte Adhesion Cascade
Chemotaxis
migration of a leukocyte in response to chemotactic mediators (like IL-8)
pseudopedia
cytoplasm changes within the leukocyte that allows the cell to “ooze” towards the stimulus, with actin/myosin contracting behind to push through towards inciting agent
Heterophils in Rabbits/GPs/Elephants
function as neutrophils but appear with bright red granules on morphology
Heterophils in Birds and Reptiles
functionally different from neutrophils (lack myeloperoxidase) and have elongated red granules on morphology
Is phagocytosis receptor mediated?
yes - Fc receptors and Complement CR1 and CR3
opsonization
coat pathogen with plasma proteins (opsonins) to taget for phagocytosis
Can IgG and C3b directly recognize bacteria?
yes
respiratory burst steps
- Lots of oxygen
- Becomes superoxide anion, which is cytotoxic
- superoxide anion can form hydrogen peroxide
respiratory burst
needed to effectively kill bacterial and fungal agents
Fenton Reaction
requires iron to generate a hydroxyl free radical
Are free radicals produced during respiratory burst specific to the antigen?
no - can cause collateral damage to healthy tissue
source of iron for Fenton reaction
lactoferrin in neutrophil granules
Myeloperoxidase
enzyme in neutrophils which converts hydrogen peroxide and chloride ions into hypochlorous acid (oxidizing agent)
makes pus!
What species lack myeloperoxidase?
birds and reptiles
they’ll have more caseous/granulomatous inflammation
Neutrophil Extracellular Traps (NETs)
when neutrophils die, these are released and can physically entrap bacteria and can be microbicidal
2 Major Types of Degradative Neutrophil Granules
- Specific
- Azurophilic
specific granules
fuse with phagolysosome first and acidify the phagolysosomal compartment
includes lysozyme and lactoferrin (iron)
azurophilic granules
fuse with phagolysosome later
includes myeloperoxidase and also lysozyme
IL-8
the most specific chemotactic power for neutrophils; stimulates neutrophil production and release from bone marrow
proinflammatory cytokines
TNFa, IL-1, IL-12 (and more)
IL-5
chemotactic stimuli for eosinophils, and is SPECIFIC for eosinophils
Are eosinophils present in all lesions?
no, mainly parasitic and some immune mediated hypersensitivity reactions
Are eosinophils present in all tissues?
yes
Major Basic Protein (MBP)
most important component of eosinic granules which is parasiticidal
Push-Pull Relationship of Mast Cells and Eosinophils
Mast cells eat the MBP from the eosinophils and produces IL-5 to call more eosinophils in
Eosinophils degrade components from the mast cell granules (including histamine, PAF, and heparin)
IL-5 is produced by what cells?
eosinophils, mast cells, and Th2 lymphocytes
Are NK cells seen cyto or histologically?
no
IL-21
main cytokine involved in NK cell function and differentiation
perforin
in the granules in NK cells (and CD8 T cells); destroy target cells by creating pores in their membranes
Monocytes become what cell type?
macrophages
2 Types of Macrophages
M1 and M2
Which type of macrophage is involved in the inflammatory response?
M1
M2 Macrophages
fixed tissue macrophages that hang out under normal physiologic conditions to perform housekeeping functions (like removing cells and debris from tissue remodeling)
Cool Summary with Pictures
3 types of inflammatory mediators
- Preformed (histamine)
- Synthesized (cytokines, PGs)
- Plasma derivedF
Bradykinin
triggered from factor 12 of the coagulation cascade; is a slow-acting vasodilator and produces sustained redness, heat, and pain
What serves as the link between inflammation and coagulation?
kinins
Anaphylotoxins
C3a and C5a (increase vascular permeability and microbes destroyed by leukocytes)
C3b
opsonin to bind CR1 and 3 on neutrophils to cause phagocytosis of microbe
C5b
initiates formation of the membrane attack complex (MAC) resulting in lysis of the microbe
C5a
chemoattractant for leukocytes and increased vascular permeability
C3a and C5a
increase vascular permeability
Eicosanoids
synthesized mediators which are arachidonic acid metabolites from the COX and LOX pathways
prostaglandins and thromboxanes
prostaglandins cause vasodilation
thromboxane A2 causes vasoconstriction
leukotrienes
LTC4, LTD4, LTE4 all increase capillary permeability
IL-1 and TNFa
fever, T cell and macrophage activation
IL-6
acute phase protein production
IL-10
suppresses macrophage function
Positive Acute Phase Proteins
tend to increase in concentration during inflammatory response
C-reactive protein
Serum Amyloid A
Fibrinogen
Negative Acute Phase Proteins
tend to decrease in concentration during inflammatory response
Albumin
Transferrin
