MBC - Inflammation Flashcards
What is inflammation?
Biological process designed to remove damaged cells and clear threats such as infections or toxins.
Where does inflammation occur?
Can occur in any vascularised tissue and can involve many other cells as well as those at the site of damage.
How is inflammation initiated?
When cells in damaged tissue release DAMPS or PAMPS
What type of cells are recruited first in inflammation?
Innate immune cells
Why do we have immune cell recruitment in inflammation?
Get rid of the inflammatory signal by repairing the damaged tissue.
What innate immune cell do we see especially in inflammation?
Neutrophils
How would you describe the first immune response?
Acute with a rapid onset.
What happens if innate immune cells cannot get rid of the inflammatory signal?
Adaptive immune cells are recruited to induce a state of chronic inflammation
What is the difference between acute and chronic inflammation in terms of damage?
Acute rarely causes damage to tissue.
Chronic can cause repetitive rounds of inflammation and thus tissue damage and repair, leading to scarring.
What are the 4 cardinal features of inflammation?
Heat (calor)
Pain (dolor)
Swelling (tumor)
Redness (Rubor)
What are some of the other features of inflammation?
Non specific response to cellular injury Designed to remove cause + consequence of injury Essential for healing wounds/infection Complex and tightly regulated Can occur anywhere in the body.
How is inflammation a universal process?
It is seen everywhere in all cells of then body and associated with so many different types of cell injury and deaths
How do we get redness and swelling with inflammation?
There is a change to local blood flow due to a change in microvascular structure.
Why do we get redness and swelling with inflammation?
This causes an accumulation of protein in the fluid and thus the recruitment of immune cells.
What are the 3 phases of acute inflammation?
- Steady state
- Damage
- Immune cell recruitment
In the steady state, what cells do we see in the interstitial layer?
Mast cells and macrophages
In the steady state, what cells do we see in the blood vessels?
Leukocytes and neutrophils
In the damage phase, what is step 1?
Inflammatory signals (PAMPS/DAMPS) from cell death activates the immune response in both tissue and vasculature. There is now a detection of foreign material.
In the damage phase, what is step 2?
Vasodilators (histamine and nitric oxide) are released from immune cells such as mast cells, increasing permeability, vasodilation, reduced blood flow and plasma leakage.
In the damage phase, what is step 3?
Increased permeability and leakage increase antibody recruitment to site of inflammation in hopes to remove damage signal
In the damage phase, what is step 4?
Increased protein leaking into tissue increases repair of tissue and activation of more immune cells
In the damage phase, what is step 5?
Increased recruitment of leukocytes as well as the formation of a protective physical barrier.
What other soluble mediators are involved in acute inflammation?
Prostaglandins
Cytokines e.g. TNF
Chemokines
What are prostaglandins responsible for?
Pain
What are cytokines such as TNF responsible for?
Fever, pain and anorexia
What is exudate?
Fluid that seeps out of blood vessels into tissue
What does exudate contain?
Proteins and cells
What is the purpose of exudate?
Forms a separating barrier between inflamed and healthy tissue to form a barrier between healthy and inflamed tissue to prevent pathogens from migrating to healthy tissue
Why does immune cell recruitment take place?
Due to inflammatory signals form immune cells at the site of inflammation
In immune cell recruitment, what is step 1?
Chemokine diffuse out of site to the nearby vasculature to form a gradient- they also act on endothelial cells themselves to promote cell recruitment
In immune cell recruitment, what is step 2?
Leukocytes within the vasculature express complementary chemokine receptors, allowing them to migrate towards the chemokine source which is the site of inflammation.
What is an example of chemokine receptors in immune cell recruitment.
Chemokine CXCL8 (IL-8) has the G-coupled receptors CXCR1 and CXCR2 which are expressed by neutrophils. This results in the early recruitment of neutrophils to the site of inflammation
What are the 4 steps of neutrophil extravasation?
- Chemo-attraction
- Rolling adhesion
- Tight adhesion
- Transmigration
What occurs in chemo-attraction?
Production of cytokines and chemokine at the site of inflammation that act on the endothelial layer to promote up regulation of adhesion molecules such as selectins
What occurs in rolling adhesion?
Carbohydrate ligands in a low affinity state on neutrophils bind to these selectins on the endothelial layer gently.
What occurs in tight adhesion?
Chemokine promote a switch from low to high affinity binding in integrins LFA-1, enhancing the binding of neutrophils to the endothelial layer.
What occurs in transmigration?
Cytoskeletal arrangement and extension of pseudopodia mediated by PECAM molecules of both the endothelial side and the neutrophil side of the interaction.
What do neutrophils do?
- Identify pathogens with innate receptors to recognise lipopolysaccharides.
- Kill bacteria via phagocytosis or netosis
- Cytokine secretion into inflamed tissue to amplify immune cell recruitment/activation
What happens if neutrophils can contain infection and clear damaged tissue?
- Neutrophils will die very rapidly due to their short lifespan.
- Inflammatory mediators are rapidly degraded.
- Recruited macrophages clear apoptotic cells and produce anti-inflammatory mediators
What happens if neutrophils cannot contain infection and clear damaged tissue?
Chronic inflammation will proceed
What is an antigen?
Any molecule or molecular structure that can be recognised by an antibody or the adaptive immune system.
What are the different types of antigen?
Foreign
Self
Immunogen (independently drives immune response)
Hapten - only acts as an antigen when bound to a larger molecule
What is the difference between acute and chronic inflammation with respect to antigenic stimulation?
Acute: doesn’t always involve it but sometimes will
Chronic (/granulomatous): involve antigenic stimulation
What conditions are associated with chronic inflammation?
Rheumatoid arthritis Asthma Inflammatory bowel disease MS Hepatitis
What conditions are associated with granulomatous inflammation?
TB
Leprosy
Tumour reactions
Crohn’s disease
How does chronic inflammation differ to acute in its progression?
Chronic is very similar to acute in the initial phases, however there is persistence of inflammatory stimuli in chronic inflammation.
What does the cell infiltrate from chronic inflammation contain?
T cells, inflammatory macrophages and antibody secreting plasma to get rid of signal.
How can chronic inflammation give off a ‘vicious cycle’?
No clearance of inflammatory agent leads to bystander destruction and concurrent tissue repair
What is the benefit of macrophages in inflammation?
Recruited from vasculature as monocytes. They are phagocytic so clear apoptotic cell bodies and can be cytotoxic to mediate cell death.
What is the disadvantage of macrophages in inflammation?
They produce inflammatory molecules and are inflammatory themselves - promote recruitment of more immune cells to inflamed site if left unchecked. They are also pro-fibrotic and can cause the excess formation of collagen
How are T cells pro-inflammatory?
Can be pro-inflammtory and are very cytotoxic and regulatory.
Are B cells anti or pro inflammatory?
Both as they generate plasma cells to clear infection but can operate remotely by secreting antibodies to inflammatory site via lymph nodes.
What is granulomatous inflammation?
Chronic inflammation with distance pattern of granuloma formation - disruption of surrounding tissue with clear scarring.
What is a granuloma?
Aggregation of activated macrophages to act as a barrier for clearance.
How is granulomatous inflammation triggered?
By strong T cell responses
What’s the difference between acute and chronic inflammation with respect to onset?
Acute: immediate - lasts a few days
Chronic: Delayed onset - weeks to years
What’s the difference between acute and chronic inflammation with respect to initial effects?
Acute: vasodilation, vascular permeability, leukocyte response
Chronic: persistent inflammation, ongoing tissue injury, attempts at healing
What’s the difference between acute and chronic inflammation with respect to immune cell population?
Acute: Neutrophils predominate
Chronic: Monocytes/ macrophages predominate
What’s the difference between acute and chronic inflammation with respect to mediator release?
Acute: Histamine release
Chronic: Ongoing cytokine release
What’s the difference between acute and chronic inflammation with respect to necrosis/scarring?
Acute: Prominent necrosis
Chronic: Prominent scarring
What’s the difference between acute and chronic inflammation with respect to their outcomes?
Acute: Complete resolution, progression to chronic
Chronic: Scarring, loss of function
What determines the sequelae of inflammation?
Tissue site, type and length of inflammation
What are some of the sequelae of acute inflammation?
- Cleared quickly mostly
- Sometimes leads to puss/abscess formation
- Restoration of normal tissue function
How may we get organ failure from acute inflammation?
May be a progression of changes and angiogenesis and fibrosis of tissue leading to a fibrotic scar tissue deposition or vascular alternation, these may hinder function and potentially lead to organ failure
How may inflammation cause scarring?
Wound healing may lead to collagen deposition - the issue can arise when it’s difficult to remove the collagen that’s been deposited in the ECM which leads to scarring.
What can scarring (collagen deposition) of the airways lead to?
Broncho-pneumonia or interstitial pneumonia.
What else can scarring lead to?
Hinderance of motility, and scarring on the heart muscle can cause loss of function and organ failure.
