L6 Response to Injury Acute inflammation 1 Flashcards
Define Inflammation
A protective response intended to eliminate the cause and consequence (necrotic cells and tissue) of cell injury.
− Part of the innate immune response, response to microbial infection
• Dilute: injury can be reversible
• Destroy
• Neutralize
• Initiate resolution (repair)
Which cells are the first cells to report to injury?
Neutrophil/polymorphonculear PMN leucocyte
− Neutral
Difference between acute and chronic inflammation
A: rapid onset, short duration
C: insidious onset, slow process, long duration
A: fluid and plasma protein exudation
Neutrophilic leukocyte accumulation
C: Lymphocytes and macrophages
Scarring
Mediators of vascular change
NO and histamine
(+ determinants of vascular permeability, transient: bradykinin, leukotrienes
Slow prolonged: cytokines- IL-1 and TNF)
What are the determinants of vascular permeability?
Vascular permeability results when there is a contraction of endothelial cells that result in an increased endothelial space.
Immediate & transient: histamine, bradykinin, leukotrienes
Slow prolonged: cytokines- IL-1 and TNF
Features of vascular change
Vasodilation
Increased permeability: plasma proteins and cells can get from the vascular space into the extravascular space
Steps of leukocyte recruitment
MR ATM Margination Rolling Adhesion Transmigration- PECAM1 adhesion molecule Migration/chemotaxis
Margination
leukocyte recruitment
stasis: slowed blood flow-
− Leukocytes are pushed to the ‘margins’ of the blood vessels and make contact with endothelial cells because there is a high concentration of RBCs
− Tumble along the endothelial surface- through a process called ‘rolling’
Rolling
leukocyte recruitment
At the site of injury rolling leukocytes make transient contact with particular receptors that slow down the movement of the leukocytes
− Weak transient adhesion
− Reduces rolling velocity
− Mediated by selectins (bind sugars)
L selectin on Leukocytes
P-selectin and E selectin on Endothelial cells
These receptors bind to sugars
− bind to: Sialylated oligosaccharides expressed on glycoproteins
− Low expression levels or absent normal endothelium
− Upregulated by chemical mediators in response to infection or tissue injury
Adhesion
leukocyte recruitment
− Mediated by intergins
− Intergins are expressed on leukocyte of plasma membrane
− Intergins are usually expressed at low affinity until activated by chemokines which are released at the site of injury
− Chemokines bound to proteoglycans on endothelial cells
− Leukocyte activation-> clusterings of integrins->high affinity receptor
− High affinity receptor binds to ligands of intergins which have been stimulated to be expressed on the endothelial cell surface
Ensures that neutrophils stop at the site of injury
− Inflammatory cytokines stimulate endothelial cell expression of integrin ligands (1-CAM, V-CAM)
• Stable attachments of leukocytes to endothelial cells at the site of inflammation
Transmigration
leukocyte recruitment
movement of neutrophil/leukocyte from vasculature into the extravascular space
− Diapedesis: movement of leukocytes between cells at the
intercellular junctions
• Gap between endothelial cells and increased permeability
• Process monitored by the recognition of PECAM1* expressed on leukocytes and endothelial cells
Leukocytes and endothelial cells recognise each other and facilitate the movement between the space
Collagenases digest collagen for cells to move into the extravascular space
− In response to chemical gradient produced at the site of inflammation
− Post capillary venule
What is diapedesis
Transmigration, leukocyte recruitment
movement of leukocytes between cells at the intercellular junctions
Migration
Leukocyte recruitment
Leukocyte recruitment
− Leukocytes in extravascular space
− Migrate towards infection/ injury
− Chemotaxis-a chemical gradient produced by exogenous (infection) and endogenous (host factors) sources
Cells follow a chemical gradient towards (the more concentration source of injury) site of injury
− Chemotactic molecules bind to specific cell surface receptors (chemokines)
− Interactions cause signaling and cytoskeletal changes -> cell makes it way through the tissue
cardinal signs of inflammation
Heat Redness (erythema) Swelling Pain Loss of function
Vascular events that cause heat
cardinal signs of inflammation
Vasodilation; increased blood flow to the injured region
