Week 6 - Inflammation and Anti-inflammatory drugs Flashcards
(66 cards)
1
Q
What is inflammation
A
Inflammation is a fundamental response to injury or injection and is where plasma and leukocytes move into injured tissue
2
Q
What is the purpose of inflammation
A
- clear site of injury of debris and prepare for repair
- Destroy potentially harmful invaders
- Limits their spread
3
Q
What is acute inflammation
A
Acute inflammation is the body’s immediate and early response to injury, infection or harmful stimuli its
- non specific
- resolves in a few days
4
Q
How are inflammatory conditions names
A
Inflammatory conditions are named by adding suffix -itis to the affected organ or tissue e.g.
- gingivitis
- periodontitis
- pulpitis
- tonsilitis
5
Q
What are cardinal signs of inflammation
A
- redness
- swelling (increased movement of fluid into tissues, permeability)
- heat
- pain
- loss of function
6
Q
What are the mechanisms of inflammation
A
- Tissue injury
- release of chemical mediators of inflammation
- .
Vascular changes (Blood flow and permeability)
- Vasodilation and increased permeability of capillaries (plasma and proteins leak out to allow immune cells to reach the site of injury -> swelling)
- movement of plasma fluid and proteins into tissues (increased permeability)
Cellular response (WBC activation)
- Migration of phagocytes into tissue
- Phagocytosis of foreign material and cellular debris
- Wound repair
Vasoactive chemical mediators
7
Q
Why are chemical mediators of inflammation released
A
- tissue cell damage
- plasma system - (clotting, complement, kinins)
- Mast cell degranulation
8
Q
What are the 2 types of chemical mediators of inflammation
A
- Vasoactive
- Chemotactic
9
Q
What are vasoactive chemical mediators + examples
A
affects blood vessels either by vasodilation or vasoconstriction
- histamine - vasodilation
- bradykinin - vasodilation
- Leukotrienes (LTB4, LTC4,.) - increase permeability
- Prostaglandins - vasodilation
- C3a and C5a
- Platelet activating factor
10
Q
What are chemotactic chemical mediators of inflammation + examples
A
attracts immune cells to the site of infection or injury (chemotaxis)
- Leukotrienes (LTB4) - attracks neutrophils
- C3a and C5a (complement fragment) - attracts neutrophils and monocytes
- Certain interleukins (IL-8) - attracks neutrophils
- Tumor necrosis factor
- Microbial components
- Platelet activating factor
11
Q
What is histamine
A
vasoactive chemical mediator of inflammation
12
Q
What is histamine produced by
A
- mast cells
- basophils
- platelets
13
Q
What are the effects of histamine
A
- vasodilation
- increased permeability
14
Q
What is bradykinin and function
A
- peptide present in blood in inactive form (kininogen)
- vasodilation, permeability, pain
15
Q
What are C3a and C5a
A
complement proteins which trigger inflammation and immune cell recruitment
16
Q
What is the function of C3a and C5a
A
mediating chemotaxis, mast cell degranulation, and macrophage activation
Mast cell degranulation = process where mast cells release granules containing inflammatory mediators in response to triggers (allergens, infections or injury). These mediators play a key role in inflammation, allergic reactions and immune defense.
17
Q
What is the effect of platelet activating factor
A
permeability, platelet aggregation and histamine release
18
Q
What are prostaglandins
A
Lipid signaling molecules derived from arachidonic acid which play a crucial role in inflammation.
effects:
- increase sensitivity to pain
- vasodilation
- increased permeability
- chemotaxis
- fever
19
Q
How are prostaglandins and leukotrienes produced
A
Both are derived from arachidonic acid - a fatty acid found in cell membranes.
Prostaglandins is derived from the Cyclooxygenase (COX) pathway
Leukotrienes is derived from the Lipoxygenase (LOX) pathway
20
Q
What contributes to increased permeability
A
- histamine
- Leukotrienes
- C3a
- C5a
causes - redness, heat, swelling, pain
21
Q
What are the events in acute inflammation
A
- Chemotactic mediators are released (Leukotrienes, C5a, IL-8..)
- Migration of phagocytes into tissue (extravasation)
- Phagocytosis of foreign material, cell debris and production of chemicals to direct response
22
Q
what is nuclear factor kappa B (NFkB)
A
Protein complex that regulates immune response as it’s a critical transcription factor that controls the expression of pro-inflammatory genes.
Produces key drivers of inflammation - TNF-a, IL-1, IL-6
transcription factor for the transcription and production of pro inflammatory genes
23
Q
What are exudates
A
fluid, cells and other substances that are released from blood vessels into tissues during an inflammatory response. They occur due to a increased vascular permeability, which allows substances from the bloodstream to leak into the surrounding tissues
- sign of acute inflammation - swelling
- plasma fluid and proteins move into tissues
- limit spread of toxins or microbes
- facilitate wound repair
- serous fluid - causes blisters
- purulent - contain pus
24
Q
What are abscesses
A
localized area of inflammation containing a purulent exudate
25
What causes abscesses
Can be due to
- advanced carious lesion
- pyogenic bacteria (e.g. streptocci) resisting phagocytosis
Bacteria with capsules are the ones more associated with abscesses because they are harder to remove
26
What is the treatment for abscesses
surgical incision/draining
27
What is cellutitis
inflammation of connective tissue in response to a bacterial infection in the skin
28
What happens if abscesses are left untreated
- macrophages break down tissues
- bacteria can spread
- can become septicemia if bacteria enter blood
the bacteria can then go causes other fatal illnesses
29
What are ulcers
Ulcers are open sores caused by the breakdown of tissue
The body's inflammatory response to infection, injury, or chronic irritation can lead to the breakdown of tissue, forming an ulcer
30
What is systemic inflammation
Overall inflammatory response that affects the entire body.
occurs when inflammatory mediators leak into circulation as the pathogen is too strong and there is a build up of inflammatory mediators - results in a full body response
Signs are:
- fever
- acute phase response
- increased WBC count
Can cause septic shock (Blood pressure drop) if stimulus continues and level build up in the blood. - over production of cytokines
31
What is a fever and it's aims
- is apart of the systemic response to infection
Aims;
- stimulates phagocytosis
- slows bacterial growth
- slows viral replication
If the temperature is too high then it becomes a medical issue and will start damaging the body’s normal proceses
32
How does a fever form
1. Pyrogens, microorganism or their products (LPS, peptidoglycan) stimulate immune response
2. IL-1, TNF, IL-6 from macrophages and neutrophils are released
3. Temperature regulating center in the hypothalamus is stimulated
4. Increase in body temperature set point
5. fever
33
How does inflammation stop
- inflammatory mediators work in a negative feedback loop
- pro-resolution mediators produced (Lipoxin A4, resolving, protectins,) - blocks the production of pro inflammatory mediators
- Switchin macrophage prodile from pro-inflammatory (IL-1, IL-6, IL-12, TNF) to anti inflammatory (IL-10, IL-13)
- Chemokines decline
- promotion of apoptosis
- Blocking of NFkB
34
What causes chronic inflammation
Due to:
- persistent acute inflammation
- repeated bouts of acute inflammation
- response to some microbes that bypasses acute stage
predominantly involves macrophages and lymphocytes (produce inflammatory particles)
Continued production of inflammatory molecules (e.g. IL-1, IL-6, TNF) leads to damage of tissue
Chronic inflammation can cause many different illnesses- associated with development of diseases and cancer
35
What are the 2 primary goals of managing inflammation
- relief of pain
- slowing tissue damaging processes
36
What are the 2 main types of drugs used to manage inflammation
- NSAIDS
- corticosteroids
effective but significant side effects
37
What are Non Steroidal Anti-Inflammatory Drugs - NSAIDs
- 50 on the market e.g. ibuprofen (Nurofen, Advil), Voltaren
- Used for arthritis, sports injuries, post operative pain, dental pain, headaches, migraines etc
- Function = inhibits the production of prostaglandins by inhibiting COX
Pharmacological actions:
- relieve inflammatory systems
- Analgesic
- Anti-pyretic
38
How do NSAIDs function
Inhibits enzymes cyclooxygenases (COX). COX-2 play a key role in the production of prostaglandins which are chemicals that promote inflammation, pain and fever.
39
What are the 2 types of COX enzymes
1. COX-1 - responsible for producing prostaglandins that help protect the stomach lining, maintain kidney function and support platelets in blood clotting
2. COX-2 - responsible for producing prostaglandins that promote inflammation and pain in response to injury or infection
40
What are the 2 types of NSAIDs
1. Non selective - inhibits the production of both COX-1 and COX - 2
2. Selective - only inhibits COX-2
Targets PG12, PGE2 and PGD2
41
What does non selective NSAIDs inhibit
prostacyclin PGI2 - causes vasodilation, inhibits platelets aggregation
TXA2 - causes vasoconstriction, promotes platelet aggregation
PGD2, PGE2 - causes vasodilation, increased vascular permeability
42
What are the side effects of non selective NSAIDs
- gastric irritation
- Prostaglandins stimulate mucous production in stomach and bicarbonate production - makor cause of peptic ulcers
- Can cause prolong bleeding - as it inhibits TXA2 (produced from prostaglandins)
43
What do selective NSAIDs inhibit
prostacyclin PGI2 - causes vasodilation, inhibits platelets aggregation
PGD2, PGE2 - causes vasodilation, increased vascular permeability
NOT TXA2 - hence problems with blood clots
44
What are the side effects of selective NSAIDs
e.g. celecoxib
- Target COX-2 (which stimulates macrophage production of inflammatory mediators and causes vasodilation)
- Shouldn’t have the same effect on gastric mucosa
- Increased risk of heart attacks and stroke due to increased risk of blood clots
Shouldn’t use selective NSAIDs if:
- history of stroke
- corocnary artery bypass surgery
- liver failure
- allergic reaction to another NSAID, aspirin or sulfonamide drug
45
What is corticosteroids and it's functions
Is a synthetic drug related to cortisol (cortisone, prednisone, dexamethasone)
Functions:
- reduce capillary permeability
- Affect leukocytes - suppression of immune cells
- affect production of prostaglandins - block production
- influence activity of transcription factors e.g. NFkB - turning down the expression of pro inflammatory genes and increasing expression of anti inflammatory genes
- blocks phospholipase A2 (PLA2)
46
What is the mode of action of glucocorticoids
- Blocks translocation of NFkB from the cytoplasm into the nucleau- reduces transcription of pro inflammatory cytokines
- Binds to GR, and acts as it's own transcription factor producing anti inflammatory mediators
- Glucocorticoids act at the level of **gene expression** inside the nucleus of cells.
- They bind to **glucocorticoid receptors (GRs)**, which are present inside most cells.
- Upon binding, this **receptor-hormone complex** moves into the nucleus and interacts with DNA to **regulate the expression of specific genes**.
- **Anti-inflammatory genes** are **upregulated**, while **pro-inflammatory genes** (such as those producing cytokines like **TNF-α**, **IL-1**, and **IL-6**) are **downregulated**. This helps reduce the inflammatory response.
47
What are side effects of corticosteroids
Major side effects:
- “moon” face
- fat redistribution (buffalo hump)
- thinning of the skin
- steroid induced acne
- insomnia
- altered behaviour
Consequences from extended use:
- osteoporosis
- diabetes (type 2)
- peptic ulcers
- susceptibility to infection
- adrenal suppression
48
When should you not use corticosteroids
use with caution in patients with:
- peptic ulcers
- heart disease and hypertension
- infections
- diabetes
- osteoporosis
- psychoses
49
What are pro-resolution lipid mediators
Molecules that help to resolve inflammation and promote the return to tissue homeostasis after inflammatory response has been activated.
- involved in resolution of inflammation
50
What are examples of pro resolution lipid mediators
specialized pre-resolving mediators
- lipoxins
- resolvins
- protectins
- maresins
51
52
What is a lot of ATP extracellularly a sign of
too much inflammation
- ATP should be inside a cell
- If there's too much inflammation it causes tissue damage causing there to be a lot of ATP in the extracellular
- This causes P2X7 receptor which will cause an intracellular receptor which stops NFkB from binding to CBP which is required so it can bind to the DNA
This inhibits production of inflammation mediators
53
What are eicosanoids
signaling molecules derived from arachidonic acid e.g.
- prostaglandins (COX pathway)
- leukotrienes (LOX pathway)
- thromboxanes
54
What are leukotrienes LTB4 function
- recuits neutrophils, CD4, CD8
- ROS production
- Stimulates AMP e.g. a-defensins
- enhances phagocytosis
55
How is nitric oxide involved in inflammation and phagocytosis
- produced from arginine by nitric oxide synthase
NOS1 and NOS3 are always around
- stimulate neurotransmitter release
- anticoagulent
NO
- are in macrophages and neutrophils and is used to kill pathogens
56
What are the pro inflammatory cytokines
- TNF-a
- IL-1
- IL-6
- IL-8
57
What are anti inflammatory cytokines
- transforming growth factor beta (TGF-B)
- IL-4
- IL-10
- IL-13
58
What are type 1 interferons
Produced by virus infected cells, macrophages
Function: antivral defense by hibiting viral replication
IFN-a - produced by leukocytes used in viral infection and cancer
IFN-B - produced by viral epithelial cells, macrophages and epithelial cells used in multiple things
59
What does the liver do and produce during the acute phase response of inflammation
- C-reactive protein increases (in response to IL-6 and IL-8)
High CRP = active inflammation
- Albumin levels decrease to priorities the making of CRP
60
What is the function of C-reactive protein
- enhancing phagocytosis - opsonization
- activating the complement system
- inflammation marker (releasing pro inflammatory cytokines)
61
What is the function of albumin
- maintain blood pressure
- transports molecules
62
What does NFkB need to bind to to transcribe DNA
CBP - CREB blinding protein
a transcriptional co-activator which activates NFkB
63
What blocks the transcription of NFkB
CREB by interfering with the CBP - (CREB binding protein)
64
What are systemic signs of inflammation
- appearance of cellulitis with accompanying facial swelling
- swollen lymph nodes will be swollen and can be palpated
- there will be increased levels of cytokines leading to a fever and an increased white blood cell count
- acute phase response
65
What is phospholipase A2 (PLA2)
enzyme which releases arachidonic acid which is a precursor for
- prostaglandins
- leukotrienes
- thromboxanes
initiating the production of key inflammatory mediators
66
What blocks phospholipase A2 (PLA2)
corticosteroids
