Inflammation Flashcards
What are the four cardinal features of inflammation?
Rubor - redness
Calor - heat
Tumor - swelling
Dolor - pain
What causes rubor?
Vascular leakage leads to an accumulation of blood contents, including red blood cells which causes the redness
What causes calor at a site of inflammation?
High metabolism of infiltrating immune cells all generate heat. Also the increased presence of fluid at core body temperature at a site that usually has limited exposure
What is inflammation?
A non specific immune response to cellular injury which is designed to remove damaged cells and clear threats such as infections and pathogens
It is a complex and tightly regulated process
What are the causes of inflammation?
Pathogens, allergens, physical damage, extreme temperatures, auto-antigens, non-apoptotic cell death (necrosis and necroptosis)
What diseases can lead to inflammation?
Infection
autoimmunity
hypersensitivity
trauma
fibrotic disease
cancer
What cells are involved with inflammation?
epithelial and endothelial cells
Neutrophils
macrophages
lymphocytes
eosinophils
mast cells
Where can inflammation occur?
Any vascularised tissue
Is acute inflammation a fast or slow response?
Rapid response, non-specific response to cellular injury
What does acute inflammation lead to?
Change in local blood flow–>
Structural changes in the microvasculature–>
Recruitment/ accumulation of immune cells and proteins
When is inflammation initiated?
When cellular damage leads to the release of Damage Associated Molecular Pathogens (DAMPs) or Pathogen Associated Molecular Pathogens (PAMPs)
What causes swelling at a site of inflammation?
Vascular leakage increases blood flow into the inflamed tissue, leading to tissue buildup
What causes pain in an inflamed area?
Many of the mediators that signal to endothelial and immune cells during inflammation also signal on local nerve cells
What is meant by acute inflammation?
A short term process occuring in response to tissue injury, normally associated with rapid onset and resolution
What is acute inflammation characterised by?
Neutrophil recruitment
What triggers the release of DAMPs and PAMPs?
Non-apoptotic cell death eg due to a wound for example
What vasodilators do mast cells release?
Nitric oxide and histamine
What are the vascular changes associated with the release of histamine and nitric oxide?
- Increase permeability of blood vessel wall
- Dilation
- Plasma leakage
After damage to a steady state of an organ ie., the skin, what 3 things happen?
- inflammatory signals
- non-apoptotic cell death
- detection of foreign material - vasodilators released
- Histamine
- Nitric oxide - vascular changes
- increased permeability
- dilation
- reduced flow
- plasma leakage
What 4 benefits does increased vascular permeability and leakage into an inflamed site bring? BALP
forms a BARRIER
more ANTIBODIES
more LEUKOCYTE migration
more PROTEINS to the site
What are soluble mediators released at injury?
Histamines, prostaglandins, cytokines (TNF, IL-1), Chemokines, Complement (C5a, C3a, C4a)
What are the principle sources and actions of histamines?
mast cells, basophils, platelets
vasodilation, increased vascular permeability, endothelial activation
What are the principle sources and actions of prostaglandins?
mast cells, leukocytes
vasodilation, pain, fever
What are the principle sources and actions of cytokines?
macrophages, endothelial cells, mast cells
endothelial activation (adhesion molecules), fever, malaise, pain, anorexia, shock
What are the principle sources and actions of chemokines?
leukocytes, activated macrophages
chemotaxis, leukocyte activation
What are the principle sources and actions of complement (C5a, C3a, C4a)?
Plasma (produced in the liver)
leukocyte chemotaxis and activation, vasodilation (mast cell stimulation), opsonisation
Why do we experience pain during inflammation?
Due to the release of prostaglandins
How do neutrophils move to areas of damage?
Via chemotaxis, following a concentration gradient of chemotoxins including C5a, LTB4 and bacterial peptides
What is exudate?
Fluid, protein and cells that have seeped out a blood vessel
What does the exudate form?
A separation between healthy tissue and the inflamed tissue - acts as a physical barrier
What is immune cell recruitment?
- recruitment and inflammation signals at the site of damage e.g., chemokines produced
- chemokines diffuse out to form a gradient
- leukocytes expressing complementary chemokine receptors migrate toward the chemokine source
What are examples of immune cell recruitment?
Chemokine: CXCL8 otherwise known as IL-8
Receptors: CXCR1 and CXCR2, g-coupled 7-transmembrane proteins
Cell type: Neutrophils. Often the first cell type recruited to the site of inflammation
How are neutrophils able to migrate towards the chemokine source?
They express complementary chemokine receptors which allow them to migrate towards the course
What is meant by neutrophil extravasation?
The movement of neutrophils from the vasculature into the surrounding tissue to reach the site of inflammation
What are the four steps of neutrophil extravasation?
- Chemo-attraction
- Rolling adhesion
- Tight Adhesion
- Transmigration
What is chemo-attraction?
Cytokines-> endothelial
up-regulation of adhesion molecules
e.g., selectins
What are the two adhesion molecules which are upregulated by cytokines?
P-selectin and E-selectin
How do neutrophils recognise selectin molecules on the endothelium?
They have complementary carbohydrate ligands which bind to the selectin molecules
What is rolling adhesion?
carbohydrate ligands in a low affinity state on neutrophils bind to selectins
e.g., PSGL1 (selectin P ligand) binds P and E-selectins
What is the name of the P selectin ligand?
PSGL1
What is tight adhesion?
Chemokines promote low to high affinity switch to integrins LFA-1, Mac-1- enhance binding to ligands e.g., ICAM-1/2
What promotes the low to high affinity switch in integrins?
Chemokines
What is meant by transmigration?
Cytoskeletal re-arrangement and extension of pseudopodia. Mediated by PECAM interactions on both cells.
(The movement of the neutrophil through the endothelial wall which involves the cytoskeleton of the neutrophil to be
rearranged)
What molecule mediates the transmigration of the neutrophil molecule?
PECAM
What are the three functions of neutrophils at the site of inflamation?
- Pathogen recognition
- Pathogen clearance
- Cytokine secretion
How do neutrophils recognise pathogens?
They use the TLR4 receptor and CD14 to identify lipopolysaccharides (LPS) that are present in gram negative bacteria for example
How do neutrophils clear pathogens?
By phagocytosis and netosis
What does cytokine secretion lead to?
recruitment and activation of other immune cells
Describe the process of phagocytosis?
- Pathogen is engulfed into phagosome
- Phagosome fuses with enzyme containing vesicles (lysosome) forming a phagolysosome
- This is degraded by enzymes through acidifcation
What are some enzymes that could be in lysosomes?
elastase and lysozyme
What is released during phagocytosis which causes oxidative damage?
ROS - reactive oxygen species
phagocyte NADPH oxidase
antimicrobial peptides e.g., defensins
Give 3 reasons why the release of exudate is helpful?
Leads to increased lymphatic drainage and also allows plasma proteins like fibrin to be directly delivered to site of inflammation. Also helps to form a physical barrier between inflamed and healthy tissue
Why are histamine molecules turned over rapidly?
They are small molecules and therefore are rapidly degraded
What are the 4 resolutions of acute inflammation in the resolution phase?
- pathogen recognition
- short half-life
- macrophages
- repair/ wound healing
How does pathogen recognition occur?
Immune cells (e.g., neutrophils) and antimicrobials (e.g., antibodies) will recognise infections or particulates
Do neutrophils have a short half-life?
Yes, (especially activated)
What produces anti-inflammatory mediators to resolve acute inflammation? And what else do they do?
Macrophages (they also clear apoptotic cells)
How can acute inflammation be resolved through repair?
Infiltrating WBC clear the wound of dead cells and pathogens and release growth factors which stimulate tissue repair - ECM deposition
How do macrophages clear apoptotic cells?
They engulf them
When does chronic inflammation occur?
When the acute response cannot clear the stimuli
What does chronic inflammation result in?
Scarring and loss of tissue function
What are some diseases characterised by chronic inflammation?
Rheumatoid arthritis
Asthma
Inflammatory bowel disease
Psoriasis
Multiple sclerosis
What are some diseases associated with granulomatous inflammation?
Tuberculosis
Leprosy
Tumour reactions
Foreign body granuloma
What are examples of persistent inflammatory stimulii?
- persistent/ prolonged infection e.g., TB, hepatitis B/C
- persistent toxic stimulii e.g., allergens, pollutants
- unclearable particulates e.g., silica
- autoimmunity e.g., self antigens
What drive continual inflammation in chronic inflammation?
Antigens
What are the distinct cell infiltrates in chronic inflammation?
inflammatory macrophages
T cells (and other lymphocytes)
Plasma (antibody secreting) cells
Why is chronic inflammation a vicious cycle?
no clearance of inflammatory agent
Bystander tissue destruction
Concurrent repair processes (fibrosis and angiogenesis)
Why is persistent neutrophil activation bad?
It is highly toxic and leads to rapid tissue destruction
What is a foreign antigen?
an antigen derived from molecules not found in the body
What is a self antigen?
An antigen derived from molecules produced by our bodies
What is an immunogen?
An antigen independantly capable of driving an immune response in absence to additional substances
What is a hapten?
A small molecule that alone does not act as an antigen but when bound to a larger molecule it can create an antigen
What is granulomatous inflammation?
Chronic inflammation with distinct patterns of granuloma formation
How are macrophages recruited to the site of inflammation?
As monocytes, they can also be tissue residents
What are the benefits of macrophages being recruited to the site of inflammation?
Phagocytosis
Cytotoxic
Anti-inflammatory (e.g., TGF-B, IL-10)
Help repair wound by building ECM
What are the bad things associated with macrophages being recruited to the area?
They can cause damage to healthy surrounding tissue (cytotoxic)
Inflammatory
Pro-fibrotic, deposit excess collagen
What pro-inflammatory signals do T cells release?
TNF, IL-17 and IFN-gamma
How do T cells promote remodelling and suppression of the immune system (aka act in a regulatory way)?
TGF-beta
How do T cells act in a cytotoxic manner?
through the release of perforin and granzymes
What do B cells do in an chronic inflammatory response?
Generate plasma cells that secrete antibodies that help to clear infection
Which white blood cell can act remotely during chronic inflammation?
B cells
What are granulomas?
Aggregation of activated macrophages
What triggers granuloma formation?
Strong T cell responses
What is the job of the granulomas?
To form a physical barrier to prevent pathogenic material from leaking out granuloma, thus allowing macrophages to clear the material
What is granulomatous inflammation?
(type of chronic inflammation)
Inflammation with distinct pattern of granuloma formation
What are the differences between acute and chronic inflammation?
Acute:
- Rapid onset
- Lasts a few days
- Vasodilation
- Neutrophils predominate
- Histamine release
- Prominent necrosis
- Scarring
- Either resolved or moves on to chronic inflammation
Chronic:
- Delayed onset
- Lasts years
- Persistent inflammation
- Ongoing tissue injury and attempts at healing
- Monocytes and macrophages dominate
- Ongoing cytokine release
- Prominent scarring
- Outcomes: scarring, loss of function
What type of cell dominates during chronic inflammation?
Monocytes / Macrophages
How long may a chronic inflammatory reaction last for?
Weeks, months or even years
What is continually released during chronic inflammation?
Cytokine release
What are the long term consequences of inflammation called?
The sequelae
What are the three possible outcomes of injury?
- Regeneration
- Repair / scar formation
- Tissue scarring categorized by chronic inflammation
What does resolution after injury involve?
The clearance of injurious stimuli, and inflammatory mediators, replace injured cells and return to normal function
What does fibrosis involve as an sequalae of inflammation?
the deposition of collagen leading to excess tissue scarring and therefore the inability of the tissue to carry out its function
What is deposited when wounds heal?
ECM deposited
How do scars form?
When the collagen is unable to be removed from the site of endothelial repair
Why does an inflammed area become hot?
the increased presence of fluid at core body temperature at a site that would otherwise have a limited exposure to this. During inflammation infiltrating immune cells are also highly metabolically active, which may also contribute to the generation of heat as a by-product.
What are the positive outcomes of inflammation?
Clear inflammatory agent.
Remove damaged cells
Restore normal tissue function
What are the negative outcomes of inflammation?
Excess tissue damage
Scarring
Loss of organ function -> organ failure
What does a histopathologist do?
Deals with tissues, examines them and notes the architecture of the tissue and identify what it tells us about a particular condition
Describe how neutrophils are able to emigrate through the blood vessel walls?
Through the relaxation of inter-endothelial cell junctions and digestion of vascular basement membrane
Which chemokines released by macrophages cause chemo-attraction of neutrophils to the site of injury?
TNF and IL-1
Which epithelial ligand mediates transmigration of neutrophils to into the site of damage?
PECAM
Which chemokines cause the switch from low affinity ligands to high affinity ligands?
LFA-1 and MAC-1
What are the consequences of inflammation?
Broncho-pneumonia
Scarring
Wound healing in sensitive tissues
