Inflammation Flashcards
What is inflammation?
INTRO
protective biological process designed to remove damaged cells + clear threats such as infections and toxins
What cells does inflammation involve?
not only cells at the site of damage but also the recruitment immune cells, fluid and molecular components from the circulation
How is inflammation initiated?
- when cellular damage (non-apoptotic cell death) leads to the release of damage associated molecular patterns (DAMPs) or
- the body detects pathogen associated molecular patterns (PAMPs)
What does the release of DAMPs and PAMPs cause?
causes the cells in the damaged tissue to secrete a range of signals designed to induce inflammation including molecules that alter the structure of nearby blood vessels and chemokines that promote the recruitment of immune cells to the site of injury
What is the aim of immune cell recruitment?
to clear the source of the initial inflammatory signal, and eventual resolution and repair of the inflamed tissue
How is the majority of inflammation categorised?
acute, with a rapid onset and resolution, and characterised primarily by the recruitment of innate cells into the tissue, in particular neutrophils
When can the state of chronic inflammation occur?
If the acute inflammatory response cannot remove the inflammatory stimuli however then other immune cells including adaptive immune cells are recruited
What is the difference between acute inflammation and chronic inflammation?
acute inflammation often resolves without any substantive damage to the surrounding tissue
– chronic inflammation can lead to repetitive rounds of inflammation, tissue damage and repair, resulting in scarring and loss of tissue function.
What is inflammation?
non-specific response to cellular injury
What is the role of inflammation?
to remove the cause and consequence of injury
universal process in health and disease
What are the 4 main signs of acute inflammation?
- redness (RUBOR)
- heat (CALOR)
- swelling (TUMOR)
- pain (DOLOR)
What are the causes of inflammation?
- Pathogens
- Allergens
- Auto-antigens
- Physical damage
- Extreme temperatures
- Non-apoptotic cell death
What cell types can be inflamed?
any cell types from epithelial and endothelial to specialised blood cells
Inflammation is a universal process
immunity and infection
haematology
cell biology
genetic
What is the pathway of inflammation?
change in local blood flow
structural changes in the microvasculature
recruitment/ accumulation of immune cells + proteins
What is the structure the skin?
epithelium interstitium (mast cells + macrophages) vascular endothelium (leukocytes + neutrophils)
What happens when theres a wound?
- inflammatory signals
- vasodilators released
- vascular changes
What are the inflammatory signals?
- non-apoptotic cell death
- detection of foreign material
What vasodilators are released?
- histamine
- nitric oxide
What vascular changes occur?
- increased permeability
- dilation
- reduced flow
- plasma leakage
What are the benefits of increased vascular permeability and leakage?
more antibodies
more protein
more barrier
more leukocyte migration
What is histamine?
sources: mast cells, basophils, platelets
actions: vasodilation, increased vascular permeability, endothelial activation
What are prostoglandins?
sources: mast cells, leukocytes
actions: vasodilation, pain, fever
What are cytokines? (TNF, IL-1)
sources: macrophages, endothelial cells and mast cells
actions: endothelial activation (adhesion molecules), fever, malaise, pain, anorexia, shock
What are chemokines?
sources: leukocytes, activated macrophages
actions: chemotaxis, leukocyte activation
What are complement? (C5a, C3a, C4a)
sources: plasma (produced in the liver)
actions: leukocyte chemotaxis and activation, vasodilation (mast cell stimulation), opsonisation
What is exudate?
Fluid, proteins and cells that have seeped out of a blood vessel
how are immune cells recruited?
- 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 is often the first cell type recruited to the site of inflammation?
neutrophils
What is the 4 step process of neutrophil extravasation?
- Chemo-attraction
- Rolling adhesion
- Tight adhesion
- Transmigration
What happens during chemo-attraction?
Cytokines -> endothelial upregulation of adhesion molecules e.g. selectins
What is rolling adhesion?
Carbohydrate ligands in a low affinity state on neutrophils bind selectins
e.g. PSGL1 (selectin P ligand) binds P and E-selectins
What is tight adhesion?
- Chemokines promote low to high affinity switch in integrins LFA-1, Mac-1 – enhance binding to ligands e.g. ICAM-1/2
What is transmigration?
- Cytoskeletal re-arrangement and extension of pseudopodia. Mediated by PECAM interactions on both cells.
What is the neutrophil function at the site of inflammation?
- Pathogen recognition
- Pathogen clearance
- Cytokine secretion.
How do neutrophils recognise pathogens?
e.g. use of TLR4 and CD14 to identify lipopolysaccharides (LPS) present in gram-negative bacteria
What is pathogen clearance?
Phagocytosis
Netosis
What is cytokine secretion?
Recruitment and activation of other immune cells
What is phagocytosis?
- Large particles engulfed into membrane bound vesicles (phagosomes)
- Phagosome fuses with lysosome (vesicles containing enzymes e.g. elastase and lysozyme) -> phagolysosome
- Ractive oxygen species (ROS) – phagocyte NADPH oxidase
- Antimicrobial peptides – e.g. defensins.
What is the resolution of acute inflammation?
- pathogen recognition
- short half life
- macrophages
- repair/ wound healing
What is an antigen?
a molecule or molecular structure that can be recognised by an antibody
or
any substance to which your immune system can mount an antibody or adaptive immune response
What are the antigen types?
- foreign antigen
- self antigen
- immunogen
- hapten
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 independently capable of driving an immune response in the absence of additional substances
What is a hapten?
a small molecule that alone does not act as an antigen but when bound to a larger molecule can create an antigen
Name some diseases characterised by chronic inflammation?
rheumatoid arthritis, asthma, inflammatory bowel disease, glomerulonephritis, hepatitis, psoriasis and multiple sclerosis
Name some diseases associated with granulomatous inflammation?
tuberculosis and leprosy, foreign body granulomas, tumour reactions, sarcoidosis, Crohn’s disease
How is chronic inflammation different from acute?
- Persistent inflammatory stimuli
- Distinct immune cell infiltrate
- A vicious cycle
What can cause persistent inflammatory stimuli?
- 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 are the distinct immune cells that infiltrate during chronic inflammation?
- Inflammatory macrophages
- T cells (and other lymphocytes)
- Plasma (antibody secreting) cells
What does the visious cycle of chronic inflammation include?
- No clearance of inflammatory agent
- Bystander tissue destruction
- Concurrent repair processes (fibrosis and angiogenesis)
What are macrophages?
recruited as monocytes to the site of inflammation, but also tissue resident.
Which are the good macrophages?
Phagocytic
Cytotoxic
Anti-inflammatory (e.g. TGF-β, IL-10)
Wound repair
Which are the bad macrophages?
Cytotoxic
Inflammatory
Pro-fibrotic
How are T cells involved in inflammation?
- pro-inflammatory (e.g. TNF, IL-17, IFN-γ)
- Cytotoxic (e.g. granzymes, perforin)
- Regulatory (e.g. TGF-β)
How are B cells involved in inflammation?
- Generate plasma cells that secrete antibody.
- Protective, clearing infection
- Inflammatory, driving reactions against self
- Can either be local to inflammatory site, or operate remotely
What is granulomatous inflammation?
- Chronic inflammation with distinct pattern of granuloma formation
What is granulomatous inflammation triggered by?
Triggered by strong T cell responses. Resistant agents (e.g. mycobaterium, tumour)
acute vs chronic inflammation
ACUTE
Acute: - Immediate onset; lasts a few days - Vasodilation, increased vascular permeability, leukocyte response - Neutrophils predominate - Histamine release - Prominent necrosis - Outcomes include: Complete resolution Progression to Chronic Inflammation
acute vs chronic inflammation
CHRONIC
- Delayed onset; may last weeks, months or years
- Persistent inflammation, ongoing tissue injury, -attempts at healing
- Monocytes / Macrophages predominate
- Ongoing cytokine release
- Prominent scarring
- Outcomes include:
Scarring
Loss of function
What are the sequelae of inflammation?
long term consequences
What are the positive outcomes of acute inflammation?
- clear inflammatory agent
- remove damaged cells
- restoration of normal tissue function
What are the negatives of inflammation
- excess tissue damage
- scarring
- loss of organ function –> organ failure
What is wound healing?
leads to extracellular matrix (eg collagen) deposition
hard to remove collagen deposition(fibrosis) -> permanent scar
What are the consequences of inflammation?
- broncho-pneumonia
- scarring
- wound healing in sensitive tissue
