Acute Inflammation Flashcards
Inflammation
Definition + Design
reaction of vascularized living tissue to local injury
inflammatory reactions are designed to:
- eliminate injurious stimulus
- repair associated tissue damage
evoked, defensive response
- doens’t happen spontaneously or proactively
stereotypical phenomenon
- limited # + type of inflammatory responses
- different stimuli can elicit same response
can also cause harm by doing more damage than original stimuli
5 cardinal signs of inflammation
heat
redness
swelling
pain
loss of function
not all 5 have to be present at once
Inflammation + Death
cannot or begin after death
identifying inflammatory changes can differentiate anthemortem necrosis from postmortem autolysis
Not all inflammatory responses are created equal
altho responses are stereotyped, they can vary significantly in:
- intensity
- magnitude
- duration
depends on multiple factors:
- innate immune response
- immunological status of host
- type of agent involved
Inflammation is a key component of host defense
5 Phases of Inflammation
1) recognition of inflammatory stimulus
2) acute vascular response
3) acute cellular response
4) chronic cellular response
5) resolution
Exogenous Substances v Endogenous Substances Inducing Tissue Injury
Exogenous:
- microbes = viruses, bacteria, protozoa, etc.
- foreign bodies = suture, plant material, etc.
- mechanical action = injury
- physical actions = thermal/freezing injury
- chemical substances caustic agents, venoms, etc.
Endogenous:
- autoimmune reactions = antibodies directed at self-antigens
- IC signals released from injured/dying cells
PAMPs
Pathogen-Associated Molecular Patterns
highly conserved microbial ligands
recognized as “non-self” by host cells = macrophages, leukocytes, mucosal epithelium
recognized by PRRs on/within host cells
binding results in downstream induction of inflammatory mediators
DAMPS
Damage-Associated Molecular Patterns
endogenous mol. released from damage/dying cells
their presence extracellularly alters nearby cells to presence of injury
binds PRRs for downstream induction of inflammatory mediators
Mechanims:
- EC presence of some mol. signals for damaged cell membranes
- release of IC enzymes causes breakdown of EC components which can also be recognized as DAMPs
- circulating antibodies may recognize IC antigens to activate complement system
PAMPs v DAMPs
Mast Cells
1st responders
1st responders = already present in tissues
often close to site of injury = situated around vessels + close to peripheral nerves
contained preformed vasoactice mediators within granules:
- histamine
- serotonin
Receptors:
- FcE = Binds IgE
- PRRs
- complement receptors
- other
degranulate in response to receptor binding, physical trauma, temp extremes, etc. = release histamine + serotonin
- vasodilation
- increased vascular permeability
Resident Tissue Macrophages
1st responders
recognize inflamatory stimuli + initiate inflammatory response via binding of PRRs
already present in tissue = no need to recruit from distant sites
Epithelial Cells
1st responders
may secrete cytokines when injured or recognize inflammatory stimuli via PRRs
Platelets
as initiators of inflammation
active role in inflammation + coagulation
aggregate + accumulate at sites of endothelial injury
activated by collagen to release inflammatory mediators
- vasoactive amines (serotonin + histamine)
- complement activators
- platelet activating factor
- coagulation factors
other vasoactive mediators
Bradykinin
- released from damaged vascular endothelium
- causes vasodilation
Prostaglandins + Leukotrienes
- produced by many cell types in response to PRR activation
- cause vasodilation + increased vascular permeability
Platelet-Activating Factor (PAF)
- produced by many cell types in response to PRR activation
- causes increased vascular permeability + smooth muscle contraction
these become active later in the inflammatory response
Vascular Permeability Response is Biphasic
initial arteriolar dilation + increased vascular permeability occur almost immediately
- histamines, kinins, etc.
second wave of vascular permeability changes occurs following de novo synthesis synthesis of inflammatory mediators
- IL-1, TNFα, kinins, etc.
Histamine Effects on Capillary Beds
arteriolar dilation drives increased blood flow
venule dilation causes blood stasis
net effect = increased capillary hydrostatic pressure
- leakage of fluid + plasma proteins
- compounded by increased vascular permeability
Vascular permeability mechanisms
Effects of Acute Vascular Response
“active hyperemia” = aka redness
- vasolidation
- blood stasis
tissue swelling
1) leakage of plasma proteins
- increased hydrostatic pressure
- increased vascular permeability
2) +/- leakage of macromolecules + leukocytes
- endothelial gaps
- endothelial injury
Fluid leaks from vasculature during inflammatory responses
usually rich in both cells + protein
cell types may reflect cause + duration of inflammation
characteristics change with time = reflect duration
analyzing cell makeup of inflammatory lesion is an important tool in diagnosis of many infectious diseases + other pathologic processes
Neutrophils
Inflammation Respose
often predominant if response is acute +/or bacterial
key effector cell in acute inflammatory response
1st cell to enter area of injury from bloodstream
- move rapidly by amoeboid motion (crawl on substrate)
segmented nucleus (2-5 nuclear segments)
intensely phagocytic
granules are lyzosomes which contain powerful degradative enztmes
unstable + short-lived in circulation
- more persistent in tissue
Neutrophils + Macrophages
Inflammation Respose
lesions which are subacute to chronic
relative # of macropjages tends to increase with chronicity
Eosinophils
Inflammation Respose
parasitic disease + acute hypersensitivity reactions
Lymphocytes + Plasma Cells
Inflammation Response
antigenic stimulation or delayed-type hypersensitivity
appearance signifies chronic
Movement of cells into inflammatory lesion
PMNCs
Polymorphonuclear cells
aka granulocytes
contian distinctively lobulated/segmented nuclei
granules contain enzymes + mediators of inflammation
- neutrophils = nonstaining/pink granules
- eosinophils = bright red/orange granules
- basophils = dark blue/purple granules
terminally differentiated = do not divide + short half-life
found circulating in blood + tissues
- normal conc. in blood varies by species
H
Heterophils
Birds + Reptiles
elongate red granules
not as antibacterial as mammalian neutrophils
- lack myeoloperoxidase
- both morphologic + functional difference
Heterophils
Rabbits, Guinea Pigs, Elephants, etc.
bright red granules
no difference in function compared to neutrophils
- only diff is morphology on blood smear
- heterophils based on appearance, neutrophils based on function
- terminology is pathologist or clinician dependent
How do neutrophils move from vasculature to tissue?
3 step process:
- adherence
- migration
- chemotaxis
Adherence
Stasis + Margination
Stasis = blood flow through affected tissues is slowed
Margination = neutrophils move toward endothelial surface as blood stasis occurs
Endothelium expresses selectins = P-selectin + E-selectin
- in response to histamine, thrombin, PAF, etc
- preformed in endothelial granules (Weibel-Palade bodies)
Adherence
Rolling
neutrophil ligands specifically interact with endothelial selectins
- Slialyl Lewis X-modified glycoproteins
- L-selectin (variable by species)
Rolling = continued binding + unbinding slows neutrophils to an eventual stop along endothelial surface
memory tip for selectins = L for lekocytes
still reversible
Adherence
Pavementing
aka stable adhesion
irreversible process
flattening of neutrophil on endothelial surface
induced by IL-1 + TNFα
Mediated by:
- β2-integrins (CD11/Cd18) on neutrophils
- ICAM-1 + VCAM-1 on endothelial cells
Migration
neutrophils exit vessel by diapedesis
- PECAM-1 in endothelial cell junctions + on leukocytes bind to itself
- leukocytes squeeze through endothelial cell junctions = occurs at post-cap venules + capillaries
Leukocyte Adhesion Cascade
