Pathophysiology of Inflammations Flashcards
Physiology And Pharmacology Of Inflammation
What is inflammation?
A protective response to rid the organism from the cause of cell injury. There are 2 types of inflammation:
Acute and chronic
Factors associated with acute inflammation:
1) rapid
2) short duration
3) associated with the presence of leukocytes
4) characterised by fluid and plasma protein secretion (edema production )
Factors associated with chronic inflammation:
1) long duration
2) associated with the presence of lymphocytes and macrophages
3) characterised by proliferation of blood vessels, fibrosis and tissue disruption
Clinical features of inflammation are…?
1) rubor (redness)
2) tumor (swelling)
3) calor (heat)
4) dolor (pain)
5) functio laesa (loss of function)
What is acute inflammation?
A rapid host response that serves to deliver leukocytes and plasma proteins to the site of infection or tissue injury.
Three stages of acute inflammation?
1) Vasodilation
2) Increased vascular permeability
3) Leukocyte migration
Explain what happens in stage 1 of acute inflammation?
stage 1 is vasodilation. This is when the blood vessels dilate and alter the vascular calibre resulting in increased blood flow
Explain what happens in stage 2 of acute inflammation?
stage 2 is increased vascular permeability. This is when the membrane of the blood vessels allow for plasma proteins and leukocytes (white blood cells) to leave the circulation and form an edema.
Explain what happens in stage 3 of acute inflammation?
stage 3 is leukocyte migration from the microcirculation to the site of injury where they accumulate. They become activated and eliminate the cause of injury.
Four stimuli for acute inflammation:
1) infections - microbial toxins
2) necrosis - molecules released by necrotic cells
3) foreign bodies - splinters, dirt
4) immune reactions - autoimmune diseases
Explain how vascular permeability is increased?
1) endothelial cells contract due to histamine, NO and other mediators. This results in increased inter-endothelial spaces.
2) Endothelial injuries are caused by burns and microbial toxins and results in endothelial cell necrosis and detachment
3) Vascular injury caused by neutrophils attaching to endothelium.
4) Increased transport of fluids and proteins (transcytosis) induced by VEGF (vascular endothelial growth factor)
Explain how leukocytes adhere to the endothelium?
1) Margination: redistribute along endothelium
2) Rolling: leukocyte adhere transiently (for a short time) then detach, the reattach firmly. Controlled by proteins called selectin.
3) Adhesion: Firmly adhere to endothelium by proteins called integrins.
Explain how leukocyte migrate through the endothelium (aka diapedesis/transmigration).
leukocytes pierce the basement membrane of endothelial cells by secreting collagenase enzymes and enter the extravascular site. This is mediated by PECAM-1/CD31 (an adhesion molecule).
Explain the chemotaxis process of leukocytes
They emigrate towards the site of tissue damage by following chemoattractants: exogenous and endogenous.
What are endogenous and exogenous chemoattractants?
Exogenous: bacterial products
Endogenous: chemical mediators
Three types of receptors on leukocytes for microbe recognition and attachment?
1) Mannose receptor
2) Scavenger receptor
3) Opsonin receptor
What does the mannose receptor do?
Binds to terminal sugar residues which are part of the molecules found on microbial cell walls
What does the scavenger receptor do?
binds to a variety of microbes.
What does the opsonin receptor do?
Major opsonins are IgG antibodies and plasma lectins. The opsonin receptors detect opsonin around microbe coated in opsonin protein and leukocytes have a high affinity for this.
What are the three stages of the phagocytosis of stimuli causing tissue damage?
1) recognition and attachment
2) engulfment
3) killing and degradation
Explain the process of engulfment of microbe?
Plasma membrane of phagocyte (leukocyte) forms a vesicle that encloses the microbe (forming a phagosome). The phagosome fuses with the lysosome forming a phagolysosome.
Explain the process of killing and degradation of microbe?
Accomplished by reactive oxygen species (ROS) and reactive nitrogen species derived from NO, or by lysosomal enzymes.
What happens to the lymph flow during inflammation?
Increases and helps drain edema fluid into lymph nodes from lymphatic vessels.
Two types of mediators of inflammation?
Cell-derived mediators and
plasma-protein-derived mediators
What are Cell-derived mediators?
They are produced locally by cells at the site of inflammation. They’re either pre-accumulated in granules and rapidly secreted upon cellular activation, or they’re newly synthesised in response to a stimulus.
What are plasma-protein-derived mediators?
They’re produced in the liver and circulate in the plasma. They become activated at the site of inflammation.
What happens to mediators once activated?
They’re inactivated by enzymes or they’re eliminated or inhibited.
Two examples of cell derived mediators of inflammation are?
Prostaglandin and Leukotrienes
Explain the process of prostaglandin and leukotrienes formation?
Phospholipase A2 releases arachidonic acid (AA) from phospholipid membrane.
Prostaglandin: AA acts on COX enzymes and are converted to prostaglandins.
Leukotrienes: AA is converted to 5-HPETE and then leukotrienes.
Explain thromboxane and prostacyclin formation?
Prostaglandin formed from AA and Cox interaction is PGG2, which gets converted to PGH2. PGH2 becomes Prostacyclin (PGI2) which is found in endothelial cells. PGH2 also becomes thromboxane (TXA2).
Where are prostacyclin and thromboxane found and what do they cause?
Prostacyclin: found in endothelial cells. Causes vasodilation and inhibits platelet aggregation.
Thromboxane: found in platelets. Causes vasoconstriction and promotes platelet aggregation.
What cause thrombus formation?
When there’s more thromboxane formed than prostacyclin.
what are the effects of taking NSAIDs?
1) Anti-inflammatory - block prostaglandin production hence less vasodilation, hence less chance of edema formation.
2) Anti-pyretic - Lower high temperature
3) Analgesic - Reduce pain by inhibiting prostaglandin production that sensitise nociceptors to inflammatory mediators.
Pro’s for using COX2 specific inhibitors?
E.g. celecoxib and Etoricoxib
1) more selective for inflammation as COX2 is mainly expressed in inflammatory cells after stimulation.
2) Less GI toxicity but increased risk of arterial thrombosis
3) potential role in colon cancer therapy
Explain how lipoxygenase inhibitors reduce inflammation
By inhibiting leukotrienes production or by blocking leukotriene receptors. (useful for asthma)
Explain how glucocorticoids reduce inflammation?
They reduce the transcription of genes encoding COX2, phospholipase A2, iNOS, pro-inflammatory cytokines and many more. This makes the most powerful anti-inflammatory drug. However, they have an immunosuppressive effect.
What does NF-kB transcription factor do?
Regulates the expression of cytokines (IL-1, IL-6, TNF) and many other factors involved in inflammation. It is activated by a number of stimulus and causes the transcription of inflammatory gene in DNA to mRNA.
Four inhibitors that can be used to prevent NF-kB from transcribing the inflammatory DNA gene?
1) IKK inhibitors
2) Proteasome inhibitors
3) Inhibitors to block nuclear translocation
4) Inhibitors to block NF-kB DNA-binding activity.
What is chronic inflammation?
Inflammation of prolonged duration. Attempts at repair exists. Can develop from acute inflammation or emerge as a low-grade response without any acute reaction visible
Three causes of chronic inflammation?
1) persistent infections
2) immune-mediated inflammatory diseases
3) prolonged exposure to toxic agents.
Explain how persistent infections cause chronic inflammation?
microorganisms that are difficult to eradicate lead to granulomatous reactions (aggregation of macrophages transformed into epithelial cells surrounded by immune cells)
Explain how immune-mediated inflammatory disease leads to chronic inflammation?
caused by excessive and inappropriate activation of the immune system. 3 types: 1) immune reactions against individuals own cells (autoimmune disease)
2) unregulated immune-reactions against microbes (IBDs)
3) immune response against harmless environmental substances (asthma)
Explain how prolonged exposure to toxic agents cause chronic inflammation?
Long exposure to endogenous (toxic plasma lipids) and exogenous (silica) agents.
Features of chronic inflammation?
1) Infiltration with mononuclear cells (macrophages, lymphocytes and plasma cells)
2) Tissue destruction induced by persistent offending agent
3) Attempts at healing (connective tissue replace damage tissue by proliferation of small blood vessels and fibrosis)
Cells used in chronic inflammation?
1) Macrophages (to eliminate injury agents and initiate process of repair. Responsible for most of the tissue injuries)
2) Lymphocytes (Communicate with macrophages through the use of cytokines. Makes inflammatory reaction chronic and severe).
3) Plasma cells (Develop from B lymphocytes and produce antibodies against foreign body or self antigens at inflammatory site.)
