S1: Acute Inflammation Flashcards
What is Acute Inflammation?
It is the initial response to tissue injury. It is relatively non specific and will occur with any type of injury. It is an innate immune response and occurs rapidly.
List some triggers of acute inflammation
- Pathogens (infection) such as bacteria, viruses and parasites
- Physical agents such as frost bite, radiation which damage tissue
- Chemical agents like chemical burns and irritants
- Mechanical Injury like trauma
- Foreign bodies like swallowed dentures
What is the purpose of inflammation?
- Alert the body
- Limit the spread of infection and/or injury
- It serves to protect the injured site from becoming more infected
- Eliminate dead cells/tissue
- Creating the conditions required for healing
Acute inflammation is a beneficial response
T/F?
True :)
What would happen if inflammatory response did not occur?
- No control of infections
- Injured tissues would not be repaired
- Impaired wound healing
What are the 5Rs in Acute Inflammation?
- Recognition of Injury
- Recruitment of Leucocytes
- Removal of injurious agents
- Regulation (closure of inflammatory response)
- Resolution/Repair of affected tissue
Signs of Acute Inflammation
They are local
- Redness (rubor): Due to increased blood flow (hyperaemia) to injured area
- Swelling (tumor): Due to fluid accumulation in tissue due to increased permeability of vessels
- Heat (calor): Due to increased blood flow and metabolic activity
- Pain (dolor): Release of pain mediators increase pressure on nerve ends causing tissue destruction
- Loss of function (laesa): Due to excessive swelling and pain
What are systemic changes caused by acute inflammation?
- Fever will be caused due to pyrogens
- Neutrophilia (neutrophil synthesis) increases.
- Acute phase reactants/proteins are produced in the liver. They cause an increase in fibrinogen (which is sticky) and will cause stacking of the RBC resulting in faster sedimentation rate.
What are pyrogens?
Give some examples
Pyrogens are substances that induce fever
IL-1 and TNF-a are exogenous pyrogens
What stimulates neutrophilia?
This occurs by G-CSF stimulation of the bone marrow. These neutrophils are needed to replace dead neutrophils as well as releasing immature neutrophils into the blood.
Give some examples of Acute phase reactants/Proteins
C-reactive protein Fibrinogen Complement
Serum amyloid A protein (SAP)
What induces production of acute phase reactants/proteins in the liver?
IL-6
IL-1
TNF-a
What is stacking of the RBCs called?
Rouleaux
What is Systemic Inflammatory Response Syndrome (SIRS)?
If the infection is very severe, it leads to a more generalised, widespread effect on the body (sepsis/septic shock).
This is a form of SIRS
What vascular events are caused by acute inflammation?
- Vasodilation of small vessels
- Increased blood flow to the injured area which results in an influx of white blood cells , oxygen and nutrients to that area
- The blood vessel permeability of micro vessels (capillaries) which also increases due to contraction of endothelial cells. Endothelial cell activation occurs increasing adhesion molecules allows cell from vessel to enter tissue
Overall effect: leucocytes and plasma proteins exit vessels and enter inflammation site to deal with infection/damage
What causes the vasodilation of small vessels?
Histamine and serotonin released from injured cells as well as sentinel cells that respond to trauma (e.g. mast cells or macrophages)
What is Transudate?
Fluid leaks due to altered osmotic/hydrostatic pressure
What is Exudate?
Fluid that leaks around the cells of the capillaries caused by inflammation
Inflammatory exudate gets into the tissue or serous cavities
Why does inflammatory exudate leak out of capillaries?
Increased vessel permeability due to contractions of endothelial cells and endothelial cell activation (increased inter-endothelial spaces allow fluid and protein to leak out)
What does inflammatory exudate contain?
Water
Salts
Small plasma proteins (e.g. fibrinogen)
Inflammatory cells
What are the 4 types of inflammatory exudate?
- Serous
- Purulent (fibrinopurulent)
- Fibrinous
- Haemorrhagic
Describe serous exudate
It has few cells and no microbes
The fluid is derived from plasma/secreted by mesothelium cells
In serous cavities (burns, viral infections)
—> skin blisters
Describe purulent exudate
Pus: contains may leucocytes (neutrophils), dead cells, microbes
- pus producing bacteria (pyogenic)
Eg. Staphylococci
Describe fibrinous exudate
Fibrin deposition (derived fribrinogen in plasma)
- Large vascular leaks (fibrinogen exits blood and enters tissue)
Occurs in serous cavities (meninges, pleura, pericardium)
Can lead to scarring if not cleared
Describe haemorrhagic exudate
-Mainly red blood cells
Occurs when blood vessels rupture- trauma
What cellular events are caused by acute inflammation?
- Migration and accumulation of cells into the area that is affected
- Neutrophils help remove dead or injured cells as well as combat infection by the pathogens (by phagocytosing dead pathogens and dead tissue).
- Migration and accumulation of monocytes at the injured site which diffrentiate into macrophages. Macrophages are very good at phagocytosis and help clear up the injured site. They also release factors that promote tissue repair (TGF-B).
Acute inflammation as explained above involves neutrophil recruitment
What are the first cells to populate the site of inflammation?
Neutrophils
What are the stages of neutrophil recruitment?
- Multistep process
- Adherence to luminal surface of endothelium
- Migration through vessel wall
i) Margination and Rolling (selectins)
ii) Intergrin activation by chemokines resulting in…
iii) Firm adhesion to endothelium
iv) Transmigration through endothelium into the tissue
v) Chemotaxis to inflamed site
Explain margination and rolling
When WBC travel in the blood vessel, they generally travel in the middle to avoid hitting the wall.
Upon inflammation, the blood vessels dilate in the inflamed area and blood travels slower.
The leucocytes as a result start leaving the centre and travel towards the wall of the blood vessel (endothelial layer)
Next, selectins will regulate the transient adhesion of the leucocyte to the endothelial cells that have been activated. It is a transient process, so when the leucocyte binds, the flow of the blood causes it to detach and reattach repeatedly and it starts rolling down the endothelium.
What are selectins?
They mediate the rolling of the neutrophil
- They are expressed by the activated endothelium
What is activated endothelium?
Endothelium in an area of blood vessel where there is acute inflammation because in a normal blood vessel leucocytes should not adhere to the vessel wall
What are the 3 types of selectin?
P-selectin : is present in pre-formed granules, so is already there
E-selectin: Actively induced by IL-1 and TNF-a
L-selectin: Ligands on the endothelium expressed by leucocytes
What are IL-1 and TNF-a?
They are cytokines produced by macrophages, mast cells, endothelial cells at the site of inflammation
What do the selectins (e.g. P-selectins) on the endothelial cell bind to?
The selectins bind to ligands on the neutrophils. The ligands are carbohydrate molecules.
Why does the neutrophil role down endothelium after binding?
The selectin and ligand bond is a low affinity interaction so it can be easily distrupted by blood flow. This causes repetitive binding and detaching of the neutrophil which is why it rolls down the endothelium.
Explain Integrin activation by chemokines and firm adhesion to the endothelium
If there are chemokines present, the integrins will get activated and the cell will be immobilised and stay fixed to the endothelial cell.
What are integrins?
The rolling neutrophils express intergrin. The integrins are normally at a low affinity configuration so there is no binding to ligands on the endothelium.
What is integrin activation and what causes it?
Activated endothelial cells produce chemokines and these chemokines bind to receptors on the neutrophils.
This causes integrin activation and they move up the a high affinity configuration.
What do activated integrins do?
They bind to the ligands on the endothelium causing firm adhesion of neutrophils to the endothelium.
What produces chemokines?
Activated endothelium
What are the 2 integrin ligands (on endothelium) called?
ICAM-1 (intracellular adhesion molecules -1) and VCAM-1 (vascular cell adhesion molecule -1)
What are the integrin ligands induced by?
The chemokines IL-1 and TNF-a
What are integrins on the neutrophil called?
LFA-1
Explain neutrophil transmigration
Neutrophils migrate through the interendothelial spaces, pass through the vessel wall and enter the tissue.
Explain phagocyte mobilisation (chemotaxis)
Once the phagocytes are in the tissue, they follow the chemoattractant gradient towards the site of infection. This is detected by sentinel cells that then release chemokines to alert the rest of the immune system.
- Chemoattract molecules are released by the microbe/macrophages. There are produced at the site of infection and diffuse into adjacent tissue and form a gradient. Neutrophils bind to these chemoattractant molecules and move closer to site of infection.
Give some examples of sentinel cells
Dendritic cells
Macrophages
Give some examples of chemoattract molecules
- chemokines (IL-8)
- complement components (C5a)
- bacterial components (formyl-methionyl petides)
How do monocytes leave blood vessels?
Chemotaxis enables monocyte mobilisation
What is the difference between monocytes and macrophages?
Monocytes are in the blood. Once they are in tissues, they diffrentiate into macrophages.
Compare the life span of neutrophils and monocytes
Neutrophils (6-24h); they are short lived and die in tissues
Monocytes (24-48h); they survive longer and proliferate
List ways in which neutrophils destroy pathogens
- The neutrophils may release their granule content (which contain enzymes which are toxic for the pathogen)
- Phagocytose the pathogen
- They may generate reactive oxygen species to destroy it
- They could form neutrophil extracellular traps (NETs) (which are very sticky and pathogens stick and get trapped).
What are NETs?
Neutrophil extracellular traps
- Mesh of nuclear content (chromatin)
- Mesh traps microbes
- Contains anti-microbial molecules
Name 2 types of neutrophil granules
Specific granules (small) Azurophil granules (large)
Recap of acute inflammation mediators - innate immunity
- Vasoactive amines: histamine, serotonin
- Lipid derived mediators
- Inflammatory cytokines: IL-1, IL-6, TNF-a
- Chemokines: IL-8
- Complement: C3a, C5a
What happens during termination of acute inflammation?
- Anti-microbial mechanisms
Inflammatory mediators are not specific to microbes/dead tissues so normal tissues can get damaged during inflammation.
What are the outcomes of acute inflammation?
- Complete resolution: Affected tissue is restored to normal state
- Repair: Lost tissue replaced by connective tissue (scarring, fibrosis)
- Chronic Inflammation: Acute inflammation cannot be resolved
What are the ways tissue resolution can be undertaken?
- Regeneration: You need the damaging agent to be removed and the injured tissue replaced by cells of the same type, there is no change in tissue structure or function. Restoration of normal tissue structure only if residual tissue is structurally intact.
- Repair by replacement (fibrosis): Where the injured tissue is replaced with connective tissue, this results in scarring which can alter tissue function. This occurs if there is excessive tissue damage and the structure is affected. TGF-b Is a mediator released by macrophages that promotes fibrosis.
- Acute inflammation could also result in an abscess. Which is a mass of necrotic tissue caused by pyogenic (pus-forming) bacteria. It can become chronic if not reabsorbed/drained.
What are the different regeneration abilities?
Epithelial cells and blood cells have high regeneration ability
Intermediate regeneration ability tissues may regenerate when injured but there may be scarring e.g. liver
There are permanent tissues with little/no regeneration ability e.g. neurones. Where the regeneration capacity isn’t good, there is more likelihood it will heal by fibrosis resulting in scarring and potentially loss of function.
Factors that favour resolution
§ Minimal destruction
§ Minimal cell death
§ Good regeneration ability of injured tissue
§ Fast clearance of infection
§Quick removal of dead tissue (debris) and foreign material
Factors that prevent healing
○ Extensive injury ○ Poor vascular supply ○ Haemorrhage ○ Infection ○ Poor general health/nutrition; diabetes ○ Old age ○Pressure/torsion/movement on wound edges (dehiscence) ○Drugs such as corticosteroids
What is chronic inflammation?
This occurs if the damaging/infective agent persists, it will result in persistent inflammation and possible tissue destruction.
