L12 Flashcards
Inflammation is
A non-specific response to infection or injury that is characterized by enhanced accumulation of immune cells and plasma proteins.
Hallmarks of Inflammation
Redness (Rubor) Heat (Calor) Swelling (Tumor) Pain (Dolor) Loss of Function (Functio laesa)
What causes inflammation?
injury, infection, disease
The inflammatory process is a
normal and necessary response to injury and infection.
Substances are produced which lead to vasodilation and increased permeability of blood vessels.
Pain receptors can also be stimulated due to protein and fluid leak from damaged cells
What would happen to wound healing if the inflammatory response was blocked or delayed?
Wound healing would be delayed, leaving the wound open and vulnerable to infection.
Causes of Chronic Inflammation
Persistent infection
Immune-mediated inflammatory disease
Toxic agents
Acute
Neutrophils, Monocytes/Macrophages, Mast cells, sometimes Eosinophils and Basophils
Chronic
Monocytes/macrophages, T cells, sometimes neutrophils
Proinflammatory cytokines:
Tumor Necrosis Factor (TNF)-α
Interleukin (IL)-1β
IL-6
Inflammatory Mediators
Histamine, bradykinin, leukotrienes
Involved in vasodilation
Prostaglandins
Derived from cell membrane phospholipids
Prostaglandins work in concert with
histamine and bradykinin to accomplish the following:
Causes constriction (PGE2) or dilation of blood vessels (PGF2a)
Involved in the production or inhibition of clots
Act on the thermoregulatory center of the hypothalamus (PGE1)
PGE2 is involved in redness, edema, and pain
Complement proteins
C5a is involved in monocyte/neutrophil recruitment
C3a and C5a can trigger mast cell degranulation
Resolution of inflammation
The original stimulant must be removed/healed.
As the inflammatory stimulus diminishes there are reductions of inflammatory mediators, immune cell recruitment, etc. and the tissue can return to homeostasis.
Cytokines involved in turning off inflammation:
IL-10, Transforming Growth Factor (TGF)-β
Want to stop inflammation? Acute:
The best way is to allow the body to heal.
Ice and elevation for swelling, Abx for infection, NSAIDs can also help.
Want to stop inflammation? Chronic:
Glucocorticoid steroids, immunosuppressants, anti-leukotrienes, biologics
Migration/Recruitment
the general process of leukocyte movement from blood to tissue
Selectins
Low-affinity adhesion molecules involved in the early stages of leukocyte capture
Integrins –
Adhesion molecules involved in later stages of leukocyte migration, can be low- or high-affinity
Chemokines –
Chemotactic cytokine. Named/classified based on the location of the N-terminal cysteine residues, C, C-C, CXC, CX3C
First Step: Tethering/Rolling
Slows the leukocyte down within the post-capillary venule
Selectin-mediated
Selectins
Plasma membrane adhesion molecules
Recognize sialylated carbohydrates
Low affinity
P-selectins are stored in cytoplasmic granules so they can be expressed almost immediately
E-selectins can take upwards of 2 hours to be expressed
Second Step: Integrin Activation
Chemokines produced by tissue immune cells or nearby epithelial cells act on the rolling leukocyte
Chemokine interaction with its chemokine receptor changes integrin affinity from low to high
Chemokines
Chemotactic cytokines
Can be produced by leukocytes, epithelial cells, fibroblasts
Upregulated by the recognition of microbes and proinflammatory cytokines
Different combinations of receptors are expressed on different types of leukocytes
Integrins
Cell adhesion molecules
Examples:
LFA-1 (leukocyte function-assoc. antigen 1)
Ligand is ICAM-1 (intercellular adhesion molecule-1)
VLA-4 (very late antigen 4)
Ligand is VCAM-1 (vascular cell adhesion molecule-1)
High-affinity selectins often cluster together to make more contacts with the endothelial cell
Step 3: Adherence
High-affinity integrins bind to their ligands on the endothelial cell
The leukocyte eventually makes so many contacts it stops and flattens out along the endothelium
Cytoskeleton rearrangements
Step 4: Migration (Diapedesis)
The leukocyte can now move from the blood into the tissue
But first…
The leukocyte must rearrange its cytoskeleton to squeeze through the endothelium
The tight junctions that hold the endothelial cells together must loosen
The leukocyte follows chemokines to the final site of infection.
