Acute Inflammation Flashcards
What is acute inflammation?
Body’s initial response to tissue injury. It takes minutes/hours to develop and lasts for a short duration, hours/days.
It’s an innate immune response, thus it is relatively non-specific as it will respond to several types of injury. Protective response, but also a potentially harmful process: Components of inflammation that are capable of destroying microbes can also injury bystander normal tissue
List three triggers of acute inflammation.
1) INFECTIONS
such as bacteria, viruses, parasites, fungi, toxins
2) TISSUE DAMAGE DUE TO:
- Physical Agents: such as frost bites, burns, radiation
- Chemical Agents: such as chemical burns and irritants
- Mechanical Injury and Ischaemia: trauma, tissue crash, reduced blood flow
3) FOREIGN BODIES:
such as splinters, sutures, dirt, swallowed bones, dentures
What are a few general purposes of acute inflammation (i.e. how does it benefit the body)?
- it alerts the body
- it limits the spread of infection or injury
- it protects the injured site from becoming infected
- it eliminates dead cells/tissue
- it creates conditions required for healing i.e it is beneficial
IF ACUTE INFLAMMATION DID NOT EXIST
- No control of infections
- Impaired wound healing
- Injured tissues would not be repaired
If inflammatory response doesn’t reach a critical threshold, the mechanisms of regulation are not effectively promoted
What are some local signs of acute inflammation?
- REDNESS (RUBOR): increased blood flow (hyperaemia) to injured area
- SWELLING (TUMOR): fluid accumulation because of increased permeability of vessels
- HEAT (CALOR): increased blood flow and metabolic activity
- PAIN (DELOR): release of pain mediators, and increased pressure on nerve ends
- LOSS OF FUNCTION (FUNCTIO LAESA): due to excessive swelling and pain
List some systemic changes that occur in acute inflammation.
- Response is usually local but has systemic manifestations.
- A fever will be caused due to pyrogens [such as IL-1, TNF-α, which are both endogenous pyrogens], which are substances that induce fever.
- As well as this, neutrophil synthesis, called neutrophilia will be increased. This occurs by G-CSF (a protein, which appears as part of the inflammation response) stimulation of bone marrow. These neutrophils are needed to replenish dead neutrophils as well as releasing immature neutrophils into the blood.
- Acute phase reactants/proteins are substances involved in the inflammatory response, these include: C-reactive protein, fibrinogen, complement and serum amyloid A protein (SAP). These are produced in the liver and their production is induced by IL-6, IL-1 and TNF-α. An increase in fibrinogen (which is sticky) will cause stacking of the RBCs (called rouleaux) resulting in a faster sedimentation rate (which is used when the blood is centrifuged to see how fast this occurs).
- If the infection is very severe it can lead to a more generalised and widespread effect on the body - sepsis/septic shock - very rare. Form of Systemic Inflammatory Response Syndrome (SIRS)
- Area heats up when inflamed due to increased blood flow and metabolic activity
- Area goes red when inflamed due to increased blood flow to injured area
- Area swells up when inflamed because of fluid accumulation due to permeability of vessels
- Area become painful when inflamed due to release of pain mediators; pressure on nerve ends
What are the vascular events that occur in acute inflammation?
- Vasodilation will occur due to histamine and serotonin released from injured cells, as well as sentinel cells that respond to trauma such as mast cells and macrophages.
- There will also be increased blood flow (hyperaemia) to the injured area, which results in an influx of white blood cells, oxygen and nutrients to that area.
- Fibrinogen clots are formed in order to wall off the injured area.
Requires fluid, antimicrobial proteins and clotting factors - The blood vessel permeability also increases due to contraction of endothelial cells; this results in leakage of fluid (swelling) and cells into the injured tissue or serous cavities. Inflammatory exudate is fluid that gets into the tissue. The contents of this include- water, salts, small plasma proteins (e.g. fibrinogen), red blood cells and inflammatory cells. Endothelial cell activation: increased expression of adhesion molecules
ENDOTHELIAL CELL CONSTRICTION
- Loss of proteins
- Increases the osmotic pressure/ gradient, leading to fluid leakage to the area, causing oedema
- Gaps occur due to contraction of e.g myosin and shortening of individual endothelial cells.
- Cell transmigration
Transudate
- Fluid leaks due to altered osmotic/hydrostatic pressure; vessel permeability normal
Exudate
- High protein content, and may contain some white and red cells
- Accumulation of exudate means pressure increases, and nerve endings are stimulated by the excess fluid and inflammatory mediators (pain)
Overall effect of increased vascular permeability: leucocytes and plasma proteins exit vessels and enter inflammation site to deal with infection/damage
List the different types of inflammatory exudate.
- SEROUS: clear, thin, watery. Serous cavities (pleura, peritoneum, pericardium)
Skin blisters (burns, viral infections). A few cells, no/few microbes
Fluid derived from plasma / secreted by mesothelial cells - PURULENT: contains pus (pus contains dead neutrophils, microbes, etc.), opaque, thick, viscous. Abscess (localised collection of purulent inflammation)
- FIBRINOUS: Fibrin deposition (derived from fibrinogen in plasma). Large vascular leaks (fibrinogen exits blood & enters tissue). Serous cavities (meninges, pleura, pericardium).
Can lead to scarring if not cleared (fibroblasts => collagen) - HAEMORRHAGIC: bloody, as red blood cells predominate. Blood vessel rupture, trauma
What are some cellular events that occur in acute inflammation?
Tissue resident macrophages are generally the first tissue resident cell to recognise an invading pathogen through pattern recognition receptors (PRRs) on their cell surface.
* The macrophage becomes activated to engulf the bacterium and:
– Immediately produces mediators of inflammation for example, prostaglandins, leukotrienes and platelet activating factor (PAF)
– Next the macrophage secretes inflammatory cytokines and chemokines
First, there is the migration and accumulation of cells into the area that is affected; the first cells to populate the damaged area are the neutrophils.
Their exit from the blood vessel is quite complex. The reason for this is they can help remove dead or injured cells (debris) as well as combat infection inflicted by the pathogens by phagocytosing the dead pathogens and dead tissue. They only live briefly, and dead neutrophils form the pus.
There is then migration and accumulation of monocytes at the injured site, which differentiate into macrophages. Macrophages are very good at phagocytosis and help clear up the injured site. They also release factors that promote tissue repair (TGF- β)
What are the five steps of neutrophil recruitment?
Acute inflammation involves neutrophil recruitment, which is very important. It is a multistep process involving the neutrophils having to adhere to the luminal surface of the endothelium and then migrate through the vessel wall.
1) Margination and rolling
2) Integrin activity by chemokines
3) Firm adhesion to endothelium
4) Transmigration through endothelium into tissue
5) Chemotaxis to inflamed site
Describe the neutrophil recruitment to the endothelial cells on the blood vessel wall.
When the leucocytes 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 the blood travels slower. The leucocytes, as a result, start leaving the centre and going towards the wall of the blood vessel (endothelial layer).
Next, a series of molecules will regulate the transient adhesion of the leucocyte to the endothelial cells that have been changed/activated. It is a transient process, so when the leucocyte binds the flow of the blood causes it to soon detach and re-attach and repeat as it starts rolling down the endothelium.
Then if the conditions are right and there are chemokines present, the integrins will get activated and the cell will be immobilised and stay fixed to the endothelial cell. Without this step, there can be no progression to the cell squeezing through the blood vessel wall and into the tissue.
MOLECULES INVOLVED
- SELECTINS
- INTEGRINS
- IMMUNOGLOBULIN SUPERFAMILY CELL ADHESION MOLECULES (CAMs)
Describe what selectins do, and the different types of selectins.
Mediate the rolling of neutrophils on the surface of endothelial cells. They are expressed by the activated endothelium (i.e. endothelium in an area of the blood vessel where there is acute inflammation, because in a normal blood vessel leucocytes should not adhere to the vessel wall).
There are two types: P-selectin and E-selectin.
P-selectin is present in pre-formed granules.
E-selectin is actively induced by IL-1 and TNF-α (cytokines produced by macrophages, mast cells, endothelial cells at site of inflammation)
L-selectin
- Leucocytes (neutrophils, monocytes, lymphocytes) express L-selectin; ligands on endothelium
The selectins bind to ligands on the neutrophils. These ligands are carbohydrate molecules(PSGL-1, sialyl-Lewisx).
This is a low-affinity interaction and so is disrupted by blood flow causing repetitive binding and detaching of the neutrophil which is why it rolls down the endothelium.
Describe integrin activation via chemokines.
Mediate adhesion alongside adhesion molecules
The rolling neutrophils express integrins (LFA-1). These integrins are initially in a low-affinity configuration and so there is no binding to ligands on the endothelium.
Activated endothelial cells produce chemokines, these chemokines bind to receptors on the neutrophils. This causes integrin activation and they move up to a high-affinity configuration.
Now the integrins on the neutrophil can bind to the ligands on the endothelium; this is a firm adhesion of the neutrophils to the endothelium. The integrin ligands are called ICAM-1 and VCAM-1- induced by IL-1 and TNF-α
ICAM-1
- Intercellular adhesion molecule-1
VCAM-1
-Vascular cell adhesion molecule-1
Describe neutrophil transmigration and phagocyte mobilisation (chemotaxis).
Neutrophils migrate through the interendothelial spaces, pass through the vessel wall and enter the tissue. They then migrate (chemotaxis) through the tissue toward inflamed site.
The neutrophils leave the blood vessel wall and once in the tissue, they follow the chemoattractant gradient towards the site of infection. This would’ve been detected by sentinel cells like dendritic cells and macrophages that are present and then release chemokines to alert the rest of the immune system and attract more phagocytes to site of infection. The chemokines act on the endothelial cells.
The chemoattract molecules [chemokines (IL-8), complement components (C5a), bacterial components (formyl-methionyl peptides)] are released by the microbe/ macrophages at site of infection and diffuse into adjacent tissues to form a gradient. The neutrophils bind to these chemoattractant molecules and move closer to the site of infection.
Monocytes use a similar mechanism to leave the blood vessels and enter the sites of inflammation. They differentiate into macrophages in tissues. Promote dead cell clearance and tissue repair.
MACROPHAGES - secrete anti-inflammatory and reparative mediators and orchestrate the reparative processes
- Neutrophils (6-24h); short lived; die in tissues (24/48h)
- Monocytes (24-48h); survive longer, proliferate
Eosinophils (allergies, parasite infections)
Lymphocytes (viral infections)
How do neutrophils destroy pathogens?
To destroy the pathogen, the neutrophils may release their granule content (which contains enzymes that are toxic to the pathogen), phagocytose the pathogen, or they may generate reactive oxygen species to destroy it.
They could also form neutrophil extracellular traps (NETs), which are very sticky that pathogens stick to and get trapped.
Pathogen destruction
- Once at sites of inflammation immune cells (neutrophils, monocytes/macrophages) destroy & clear pathogens and dead cells
Neutrophils - pathogen destruction mechanisms
- Recognition of microbes/dead cells to oxygen-independent and oxygen-dependent killing
Examples of neutrophil granules include: Azurophil granules, specific granules, gelatinase granules, secretory granules. Content can cause tissue damage if unregulated.
NETs
- Mesh of nuclear content (chromatin)
- Mesh traps microbes
- Contains anti-microbial molecules
Specific granules
- Contains lysozyme, collagenase, gelatinase, lactoferrin, alkaline phosphatase
Azurophil granules (large)
- Contains myeloperoxidase, lysozyme, defensins, acid hydrolases, proteases (elastase, cathepsin G, collagenases, proteinase 3)
List some acute inflammation mediators.
INFLAMMATORY MEDIATORS
- Inflammatory cytokines: IL-8, TNF- α
- Histamine, prostaglandins, leukotrienes (latter two occur when inflammation)
- Chemokines –IL-8 (cytokines that have chemoattractive functions)
- Complement (C5a)
CELLULAR MEDIATORS
- Macrophages
- Neutrophils
- Mast cells - secrete histamine
These chemical signals released by activated macrophages and mast cells at the injury site cause endothelial activation, vasodilation and increased vascular permeability
Fluid, antimicrobial proteins, and clotting elements move from the blood to the site. Clotting begins.The complement system is also activated very soon after initial
infection producing the various complement fragments. Chemokines released by inflammatory cells attract more phagocytic cells from the blood to the injury site.
Neutrophils are recruited to kill pathogens and remove cell debris at
the site. Monocytes are recruited and differentiate into macrophages which
enhances clearance by phagocytosis. Regulation and tissue repair is promoted by the release of immunoregulatory factors (TGF-β)
- Platelets
All of these belong to the innate immune system, but TNF-α can also be made by the adaptive immune system.
