pathology acute inflammation Flashcards
inflammation definition
A well organized cascade of fluid and cellular changes within vascularized tissue
Host response to remove damaged/necrotic tissue or foreign invaders
5 cardinal signs of inflammation
- heat
- redness
- swelling
- pain
- loss of function
purpose of inflammation
Inflammation is part of the process of repair and healing
* destroys, dilutes, or walls off injurious agents
* initiates healing and tissue repair
Fundamentally a protective response
* Get rid of pathogens
* Remove necrotic debris (phagocytosis)
* Repair the damage = return to normal structure/function
acute inflammation
Rapid
Short Duration
minutes to days
Characterized by exudation of fluid and plasma protein (edema) and emigration of leukocytes (mostly neutrophils)
chronic inflammation
Longer duration: days to years
Macrophages and lymphocytes **
Proliferation of blood vessels and connective tissue (fibrosis**)
3 main components of acute inflammation
1) Vascular alteration (vasodilation) leading to increased blood flow (hyperemia)
2) Changes in microvasculature permeability (leaky) that allow plasma proteins and leukocytes to leave the circulation
3) Emigration of leukocytes into the perivascular area
exudate
Inflammatory extravascular fluid with
* high protein concentration (>5 g/dL)
* high cell content (>5000 leukocytes/mL)
* high specific gravity >1.020
Formed when there is significant alteration in small blood vessel permeability at the site of injury
ex: pus
transudate
Extravascular fluid with
* low protein concentration (<2 g/dL)
* low cell content (<1500 leukocytes/mL)
* low specific gravity <1.012
An ultrafiltrate of blood
Increased hydrostatic pressure (ie. congestive heart failure)
Decreased oncotic pressure (hypoproteinemia)
looks like serum (clear, straw colored)
effusion
fluid accumulates in body cavity
edema
An accumulation of fluid in interstitial or serous cavities
Increased vascular permeability
Increased intravascular hydrostatic pressure
Decreased intravascular osmotic pressure
Decreased lymphatic drainage
pus
Pus - a purulent exudate rich in leukocytes (mostly neutrophils) and cell debris
purrulent = adjective!!
vascular changes with acute inflammation
- Vasodilation – involves arterioles first, then results in opening new capillary beds; mainly induced by histamine and nitric oxide acting on vascular smooth muscle
- Increased permeability of microvasculature – protein rich fluid pours out into extravascular tissue
- Loss of fluid results in concentration of red cells in small vessels, increased blood viscosity and blood stasis
- Stasis – allows leukocytes to accumulate along the endothelium and stick to it (leukocyte emigration/diapedesis)
4 mechanisms for vasular leakage:
- endothelial contraction: Endothelial cells contract –> increase in interendothelial space (mediated by histamine, bradykinins, leukotrienes), Rapid and short-lived (15-30 minutes)
- direct endothelial injury: Direct damage to endothelium causes necrosis and detachment (burns, lytic bacteria), Starts immediately, lasts until thrombosis occurs or endothelium repaired
- leukocyte-dependent injury: Activated leukocytes may secrete free radicals and proteolytic enzymes, leading to cell damage
- Increased transcytosis: Increased transport of fluid and protein through endothelial cells
endothelial contraction
1st mechanism for vasular leakage
Endothelial cells contract –> increase in interendothelial space
mediated by histamine, bradykinins, leukotrienes
Rapid and short-lived (15-30 minutes)
endothelial direct injury
2nd mechanism for vasular leakage
Direct damage to endothelium causes necrosis and detachment (burns, lytic bacteria)
Starts immediately, lasts until thrombosis occurs or endothelium repaired
leukocyte mediated injury endothelial changes
3rd mechanism for vasular leakage
Activated leukocytes may secrete free radicals and proteolytic enzymes, leading to cell damage
transcytosis
4th mechanism for vasular leakage
Increased transport of fluid and protein through endothelial cells
Leukocyte Extravasation Stages
- Margination, rolling, and adhesion: in normal blood flow endothelium does not “catch” cells, it must be activated by cytokines to do so
- Transmigration across endothelium (mainly venules), also called diapedesis
- Migration – in interstitial tissue toward a chemotactic stimulus
selectins
initiate low affinity rolling of leukocytes
binds and releases like velcro
Margination, Rolling, and Adhesion in leukocyte extravasation
Blood stasis
* helps leukocytes stack up at periphery (against vessel wall)
Rolling
* leukocytes adhere transiently to endothelium
* roll until becoming firmly attached to endothelium
Neutrophils, monocytes, eosinophils, basophils, lymphocytes all use the same method described above
integrins
high affinity binding
low affinity binding of leukocytes extravasation
Mediated by selectins expressed on surface of endothelium and leukocytes
high affinity binding of leukocyte extravasation
Integrins on leukocytes bind to immunoglobulin family receptors on endothelial cells
genetic deficiencies in leukocyte adhesion
Heritable deficiencies in type and amount of adhesion molecules (selectins/integrins) can inhibit leukocyte transmigration and acute inflammation
This may result in poor inflammatory response to pathogens and dead tissue
Causes recurrent infections
transmigration of leukocyte extravasation
Leukocyte inserts a pseudopod into the junction between endothelial cells and squeezes through
Made possible by adhesion molecules located on leukocytes and endothelial cells
chemotaxis of leukocyte extravasation
Movement of leukocytes in tissue along a chemical gradient
can be due to:
* Exogenous products – bacteria
* Endogenous products – complement system components (C5a, leukotriene B4, cytokines)
Cell moves by extending a filopodia that pulls the back of the cell forward.
steps of phagocytosis
- Recognition and Attachment
- Engulfment
- Killing or degradation of ingested material
recognition and attachment in phagocytosis
microbe binds to phagocytic receptor
engulfment in phagocytosis
phagocyte membrane zips up around membrane and makes pseudopods
Pseudopods flow around particle to form a phagosome
Phagosome fuses with lysosome in cell creating the phagolysosome
killing and degredation in phagocytosis
Reactive oxygen species (ROS)
* Produced within the lysosome
* Respiratory burst – rapid oxidative reaction
* Primary mode of microbial killing
Lysosomal enzymes
Release of Leukocyte Products During Killing (phagocytosis)
Collateral damage
when neut dies while killing in a phagolysosome
Release of lysosomal enzymes and ROS into extracellular space
Cytotoxic release – crystals (eg. urates) can puncture the cell during phagocytosis and lead to leakage of enzymes and other leukocyte products
Neutophil extracellular traps (NETs)
Produced by neutrophils in response to infectious pathogens and inflammatory mediators
Mechanism of killing microbes
Extracellular fibrillar network composed of:
* Meshwork of nuclear chromatin
* Antimicrobial peptides and enzymes
genetic defects in leukocyte function
Inherited defects in leukocyte adhesion
* Leukocyte Adhesion Deficiencies (LAD)
Inherited defects in phagolysosome fusion
* Chediak–Higashi syndrome
Inherited defects in microbicidal activity
ALL CAUSE RECURRENT INFECTIONS
genetic defects in leukocyte function
Inherited defects in leukocyte adhesion
* Leukocyte Adhesion Deficiencies (LAD)
Inherited defects in phagolysosome fusion
* Chediak–Higashi syndrome
Inherited defects in microbicidal activity
ALL CAUSE RECURRENT INFECTIONS
Cell derived mediators
Vasoactive amines (Histamine, Seratonin)
Arachidonic acid metabolites
Nitric oxide (NO)
Cytokines
Plasma derived mediators
complement system
histamine
- vasoactive amine
- Present in a PREFORMED state in mast cells, basophils and platelets in cytoplasmic granules
- can be released instantly, as needed
- mast cells typically are found in connective tissue near blood vessels
Histamine is released in response to:
- physical injury (heat, cold, trauma)
- immune reactions (IgE binding, type 1 hypersensitivity)
- presence of complement fragments C3a and C5a (anaphylatoxins)
Actions of histamine
vasoactive amine
* dilatation of arterioles
* increases vascular permeability of venules
* causes endothelial contraction in venules
serotonin
vasoactive amine
also known as 5-hydroxytryptamine
preformed in platelets
Released in response to platelet aggregation
actions are similar to histamine in acute inflammation
Arachidonic acid metabolites
The degradation of cell membrane phospholipids by phospholipases yields AA
Eicosanoids
* Products of AA metabolism
* regulate inflammation and hemostasis
Two primary classes of inflammatory metabolites
* prostaglandins
* leukotrienes
Eicosanoids
- Products of AA metabolism
- regulate inflammation and hemostasis
Arachidonic acid cascase
- cell membranes broken into arachidonic acid by phospholipase (glucocorticoids inhibit)
- arachidonic acid turned into prostaglandin by cyclooxygenase (NSAIDS inhibit)
- lipooxygenases cleave arachidonic acid into leukotrienes
lipoxygenase
Enzyme that produces leukotrienes and lipoxins from AA
leukotrienes
Chemotactic for leukocytes
Vascular effects: vasoconstriction, ↑ vascular permeability
produced from arachidonic acid by lipoxygenase
lipoxins
produced from arachidonic acid by lipoxygenase
Lipoxins inhibit inflammation
Inhibit leukocyte recruitment and cellular components of inflammation
Nitric oxide
- Produced by endothelial cells, macrophages, neurons
- Synthesized by nitric oxide synthase
NO: 2 functions in inflammation
* Vasodilation (contributes to vascular reaction)
* Inhibits cellular inflammatory response
* reduces platelet aggregation and adhesion (anti-inflammatory)
* inhibits leukocyte recruitment (anti-inflammatory)
As a free radical kills microbes
cytokines
polypeptides produced primarily by macrophages and lymphocytes
Primary action is modulation of activities of other cells
The main cytokines involved in acute inflammation are IL-1 (interleukin-1) and TNF (tumor necrosis factor)
The main cytokines involved in acute inflammation
IL-1 (interleukin-1) and TNF (tumor necrosis factor)
TNF/IL-1 actions
vascular:
* leukocyte adhesion molecules
* procoagulant activity
leukocytes:
* activate
* produce cytokines
fibroblasts
* proliferate, repair
* increase collagen synthesis
systemic
* fever
* leukocytosis
* decrease appetite
* increase sleep
complement
Defense against microbes
* formation of MAC - membrane attack complex
Complement activation causes
* ↑ vascular permeability
* Chemotaxis
* Opsonization
Main components are present as inactive plasma precursors (C1-9)
complement activation pathways
alternate: microbe antigens directly activate c3 convertase
classical: antibodies bind to antigens activating c3 convertase
lectin: mannose-binding lectin binds to antigen activating c3 convertase
c3b causes:
* recruitment lymphocytes
* phagocytosis
* formation of MAC
classical complement pathway
reaction with IgG or IgM containing antigen-antibody complex
alternate complement pathway
contact with microbial surfaces and polysaccharides (cobra venom, endotoxin)
lectin complement pathway
plasma mannose-binding lectin binds to microbes
C3 convertase
The initial steps in complement activation lead to formation of an enzyme - C3 convertase - which cleaves C3
C3 cleavage leads to:
* release of C3a (anaphylatoxin)
* covalent attachment of C3b (initiates formation of C5 convertase)
* formation of C5-9 (MAC)
C5a
facilitate histamine release from mast cells (vasodilate, increase permeability)
activates lipoxygenase pathway of AA metabolism in neutrophils and monocytes
chemotactic for neutrophils, monocytes, eosinophils, basophils
complement
C3b
act as opsonins when fixed to bacteria; facilitate phagocytosis by neutrophils and macrophages (receptor)
complement
