PATH 3610 Lecture Notes - Lecture 7: Vascular Permeability, Cd63, Endothelium
14 May 2018
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Acute inflammation
- First part of inflammatory and repair process and extends the defences in the
blood to the tissues
- 3 main components:
o 1) vascular changes resulting in increased blood
o 2) increased permeability of he microvasculature
o 3) cellular changes that result in leukocyte emigration and
accumulation
- Vascular events (fluidic phase)
o Vasodilation:
▪ Change in vascular flow and calibre
▪ With an injury, there is a transient vasoconstriction initiated by
the direct effect of the traumatic agent on blood vessels
▪ Net effect = increase in the volume of blood in tissues and total
increase in blood flow
▪ Circulation slow in tissue partly because of increased
permeability
▪ Environment allows leukocytes to marginate in the vessels and
to begin their process of migration
o Increased vascular permeability
▪ Vascular permeability increases dramatically in cap beds and
venules in areas of injury and inflammation and results in
exudation of protein rich fluid
▪ Increases when endothelial cells contract and retract widening
the gaps between
▪ Occurs with endothelial cytoskeletal reorganisation, direct
endothelial injury, leukocyte dependent injury, increased
transcytosis, delayed prolonged leakage and from new caps
that are leaky
- Cellular events (phase)
o Margination and rolling
▪ Leukocytes move out of the central axial column of the vessels
and are closer to the endothelim, esp ostcapillary venules
o Adhesion and transendothelial migration
▪ Cells must first adhere to endothelial to migrate into tissues
▪ Cytokines and chemokines from cell, tissue and microbes
upregulate expression of cell adhesion molecules (CAMs) on
endothelium and interact with receptors and ligands on
leukocytes
▪ Leukocytes have a surface ligand – a glycoprotein that attached
to P- and E- selections (CD63) on endothelium and then adhere
to it
▪ Cells have integrins on their surface that bind to their ligand
intracellular adhesion molecule 1 (ICAM-1) on endotheliym
▪ Platelet endothelim cell adhesion molecule 1 (PECAM-1, CD31)
is a molecule expressed on leukocytes and endothelial cells at
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gaps between endothelial cells, and these direct the leukocyte
to move between or though cells
▪ Actual steps: capture/tethering, rolling, activation, adhesion,
locomotion, diapedesis and transendothelial migration
o Chemotaxis and activation
▪ Leukocytes (neutrophils) attracted to site of injury by chemical
→ CHEMOTAXIS
▪ Neutrophils swarm to bacteria or any chemotactic factor
▪ Substances that are chemotactic also activate leukocytes so
that the function is maximal
o Phagocytosis and degranulation
▪ Once a neutrophil or macrophage has recognized a foreign
agent or substance, it attached to that substance, engulfs it and
kills and degrades it → PHAGOCYTOSIS
▪ As phagocytes engulf, their granules contain the enzymes and
substances to degrade the foreign substance are released into
surrounding tissues
▪ These substances include lysosomal enzymes, oxygen derived
free radicals and metabolites of arachidonic acid
- Chemical mediators of inflammation
o Originate from plasma or from cells
o Mediators in plasma: usually inactive that must be activated (like
coagulation cascade)
o Cell derived mediators must be synthesized and stored in granules or
are occasionally synthesized when they are required
o Mediators very tightly regulated and very short lives because many
may have harmful effects, esp I produced to excess
o Some examples:
▪ Vasoactive amines: histamine is most well known mediator of
inflammation, histamine produced by mast cells in tissues and
are vasodialatory and increase in permeability, antihistamines
are used to inhibit them
▪ Plasma proteases: protein components of plasma
• when active are enzymes
• Include complements, kinins and proteins of the
coagulation cascade, involved in stages of inflammation
like vascular and cellular effects
▪ Arachidonic acid metabolites
• Most cells produce these
• Arachidonic acid produced from phospholipid
membranes such as cell membranes
• Target for many anti-inflammatory agents (cortisone,
aspirin, ibuprofen)
• Common non-steriodal anti-inflmmatory drugs
(NSAIDs) inhibuit all isoforms of clyclooxygenase (COX)
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but newer drugs (Vioxx, celebrex) only inhibit the
inflammatory COX (COX2)
• COX1 – involved in formation of forms of prostaglandin
responsible for regulatory functions such as gastric and
renal blood flow
▪ Cytokines
• Polypeptide products of cells that modulate the action
of the other cells
• Immune and inflammatory functions
• Growth factors, interleukins and chemokine’s
• IL1 and tumor necrosis factor very imp to cytokines,
responsible for system acute phase responses
▪ Chemokines
• Small proteins activators and chemoattactants for
leukocytes
• Bind to extracellular matric components
▪ Nitric oxide and oxygen derived free radicals
• Wide range of actions in inflammation
• Macrophages produce them for effector functions
• Mediators of vascular and cellular events
▪ Lysosomal constituents
• Frustrated phagocytosis results in release of large
number of compounds from leukocytes – may have
inflammatory effect
o
Major Principle of Disease: therapy
- Therapy – treatment → allow healing rapidly
o Specific
o Symptomatic
o Replace function
- Cost benefit analysis
o Beneficial effect
o Adverse reaction
▪ mid adverse reaction – side effect
▪ serious adverse reaction – idiosyncratic reaction
• death, life threatening, hospitalization
o in USA, about 50% of population take prescription medication
o average number of prescriptions per person ~ 4
o 1.3 million went to the ER with adverse reactions; 124000 died
- Amoxicillin side effects
o Get help if you see allergic reactions or signs: hives, difficulty
breathing, swelling of your lips, tongue or throat
Healing: Inflammation
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Document Summary
First part of inflammatory and repair process and extends the defences in the blood to the tissues. 3 main components: 1) vascular changes resulting in increased blood, 2) increased permeability of he microvasculature, 3) cellular changes that result in leukocyte emigration and accumulation. Increases when endothelial cells contract and retract widening the gaps between: occurs with endothelial cytoskeletal reorganisation, direct endothelial injury, leukocyte dependent injury, increased transcytosis, delayed prolonged leakage and from new caps that are leaky. Immune and inflammatory functions: growth factors, interleukins and chemokine"s. Major principle of disease: therapy: specific, symptomatic, replace function. Therapy treatment allow healing rapidly: mid adverse reaction side effect, serious adverse reaction idiosyncratic reaction, death, life threatening, hospitalization, beneficial effect, adverse reaction. Cost benefit analysis in usa, about 50% of population take prescription medication: average number of prescriptions per person ~ 4, 1. 3 million went to the er with adverse reactions; 124000 died.
