Lecture 2: Inflammation Flashcards
4 classical signs
Redness
Swelling
Heat
Pain
Inflammation purpose
Remove pathogens
Remove injured tissues
Promote healing
Eg. Leukocyte adhesion deficiency
Acute inflammation
Rapid response with fluid and neutrophils
Chronic inflammation
Lymphocytes and macrophages
Deposits of extra cellular matrix
Resolution phase of inflammation
Removing agents and repairing tissues
Or abscess to wall off an infection
Or scarring
Process of inflammation
- Macrophages have pattern recognition receptors to eat the pathogen and alerts the immune system
- Mast cells are alerted of the pathogen and release histamine. The complement system C5a activates mast cells
- TNF IL-1 and IL-6 cytokines and histamine act in the vasculature to allow for leukocytes to leave and enter the tissues
Vasodilation
NO, prostaglandins, histamine
Increased vascular permeability
Histamine, bradykinin, leukotrienes and PAF
Chemotaxis, leukocyte recruitment and activation
TNF, IL-1, chemokines C3a and C5a, leukotriene B4, bacterial products (PAMPS)
Fever
IL-1, TNF, prostaglandins
Pain
Prostaglandins and bradykinin
Tissue damage
Lysosomal enzymes of leukocytes, reactive oxygen specifies, NO
Microbe entry
Activated complement system leading to generation of C5a
C5a then …
Acts in the masts cells to release histamine and prostaglandin D2
Histamine
Causes contraction of endothelial cells results in plasm leakage into the site. Also promote EC to release of vasodilators (NO)
Heat and redness and swelling
Prostaglandin D2
- Lipid mediator of inflammation
Causes pain - Bonds to receptors on smooth muscles and acts as a vasodilator
- Synthesis is prevented by NSAIDs
Arachidonic acid
Becomes prostaglandins via cyclooxygenase
The target for NSAIDs
Hageman factor (factor XII)
Released by the basement membrane via negatively charged collagen.
Acts on the clotting cascade
Acts on kallikrein- produces C5 and C5a and C5b without he complement system
Act on plasminogen–> to release C3, C3aand C3b without the complement system
Activates the kinin system= bradykinin causes pain and swelling
The process of chemotaxis and leukocyte recruitments
Microbe activates complement C3a and C5a, also the microbe has PAMP eg LPS and TLR4 resulting in the release of pro-inflammatory cytokines
Adhesion molecules are provoked by…
Histamine, TNF and IL-1
C3a and C5a…
Stimulate chemotaxis toward the site of inflammation
The WBC then leaves and follows the chemokine gradient towards the infection sites
Inflammasomes
NLRP3 inflammasomes forms a complex with caspase 1. Cleaves pro-IL 1 beta then is secreted as IL-1 beta, a pro inflammatory cytokine
Autoinflammatory syndromes
Causes by disregulated inflammasomes- gain of function and unregulated IL-1
Neutrophil extravasation
Slowing-causes by fluid leaving the vasculature
Rolling-p-selectin and PSGL-1
Binding- LAF-1 and ICAM-1
Extravasate - PECAM-1
Follow chemokine gradient to find bacteria
Neutrophil rolling
Mediated by P-selectin on the endothelial cell and PSGL-1 on the neutrophils
Selectins mediate the rolling step. They bind to selectin ligands.
Weibel-Palade bodies
Store p-selectin in the endothelium
Binding
ICAm-1 is up-regulated on the endothelial surface to create a high affinity bind to LFA-1 on the neutrophils surface. This causes the neutrophils to stop rolling
LFA1/ICAM-1
Both are increasingly present after the neutrophil rolling, the LFA-1 on the neutrophils and the ICAM-1 on the EC have a high affinity bind which cause the cell to stop rolling and adhere to the endothelium
These molecules are called integrins and integrin ligands… these create high affinity reactions
Extravasation
Mysterious Process….WBC squeezes through the endothelium to go fine the infection…. PECAM-1 is concentrated at the intracellular Junctions, present on neutrophils and the Endothelial cells
Monocyte extravasation
Usually occurs on day two after the neutrophils have invaded
Same mechanism but different specific molecule to neutrophils.
EC selectin- ?
Monocyte selectin ligand-?
EC INTEGRIN-?
Monocyte intgegrin ligand- ?
Macrophages
Have both anti microbial activity (M1 type releasing IL-1, IL-12 and IL26)
and anti inflammatory activity/pro-resolving activity (M2) producing IL-10 and TGF beta
IL-6
Causes the liver to make acute phase proteins
TNF, IL-1 and IL-6
Effects the brain to Promote fevers
And causes generation of leukocytes in the bone marrow
Fever
Generate by cytokines - IL-1 and TNF, which trigger arachadonic acid then the formation of prostaglandins PGE2 which signals the hypothalamus to produce neurotransmitters cAMP which elevated body temp.
NSAIDs block prostaglandin E synthesis to lower fevers
Neutrophilia
TNF and IL-1 increase the release of nuetrophils from the bone marrow. More band cells are present in the blood
Acute phase response
IL-6 cytokines aft in livers to produce CRP- a molecule to measure inflammation. Many of these proteins are opsinins.
The result of increased acute phase proteins results in a fast ESR or erythrocytes sedimentation rate
Shock
TNF reaches high levels during sepsis or severe injury
May result in hypercoagulation DIC
Or hypotension and shock
