5-6: Chronic Inflammation + Treatments

Question 1

What are the three outcomes of acute inflammation?

Answer 1

1. Resolution - normal function restored (usually after minimal injury) macrophages clear stimuli, mediators and cells, edema reabsorbed by lymphatic
2. Healing - normal function lost; fibrosis (after more substantial tissue damage where regeneration is not possible)
3. Progression to CHRONIC INFLAMMATION (usually immune-mediated, persistent infection, hypersensitivity or prolonged exposure to toxic agents)

Question 2

What are the distinguishing features of Chronic inflammation?

Answer 2

• Slow, prolonged inflammation
• Systematic signs
• Mainly monocytes/macrophages and lymphocytes
• Tissue Injury + Repair (fibrosis + angiogenesis)
• Adaptive immune system involved

Question 3

What microscopic features of chronic inflammation might be seen in lung tissue?

Answer 3

• Replacement of alveoli with cuboidal-epithelium-lined spaces
• Replacement by connective tissue

Question 4

Describe the role of macrophages in chronic inflammation

Answer 4

They are the DOMINANT cell type
- Derive from stem cells -> monoblasts -> monocytes -> ENTER TISSUES
- Names: Microglia in brain, osteoclasts in bone, Kupffer cells in liver, alveolar macrophages etc
- Two pathways of activation - classical and alternative:
- Classical -> microbicidal and inflammatory actions
- Alternative -> Tissue repair, fibrosis and anti-inflammatory actions

Question 5

Describe the “Vicious Cycle” of Leukocyte activation

Answer 5

Classically activated macrophages present antigens to T cells, activating them
-> Release TNF, IL1-17, Chemokines
-> Recruit more macrophages!

Question 6

Define atherosclerosis

Answer 6

A form of arteriosclerosis in which atheromatous plaques - lesions with a lipid core and white fibrous cap - make the arteries stiff

Question 7

Describe the four groups of risk factors for atherosclerosis

Answer 7

1. Modifiable (e.g., hypertension, LDL levels, smoking/obesity/diabetes)
2. Non-modifiable (e.g., age, sex, genetic predisposition)
3. Inflammatory (e.g., CRP, ILs, Adhesion Molecules, Coagulation Factors)
4. Other (e.g., insulin resistance, hyperhomocysteinaemia)

Question 8

What are the differences observed in an endothelial cell in Endothelial Dysfunction?

Answer 8

Instead of a non-adhesive, non-thrombogenic surface:
- Increased procoagulent expression
- Increased adhesion molecule expression
- Chemokine, Cytokine and GFs expression

Question 9

What factors mediate the migration of leukocytes through the vascular endothelium in plaque formation?

Answer 9

1. Increased permeability (mediated by NO, PGL2, etc)
2. Chemokines (MCP-1 from Monocytes, CCL5 and CXCL4 from platelets)
3. Leukocyte adhesion (esp. monocytes and T cells - due to upregulation of adhesion mol’s e.g. VCAM-1, IAM-1, selectins)

Question 10

What three changes can be seen in endothelium during plaque formation BESIDES leukocyte adhesion?

Answer 10

1. VSM aggregation (stimulated by PDGF, FGF2 and TGF-ß)
2. Platelets (stimulated by integrins, P-selectin, fibrin, TXA2)
3. Fatty streaks (as macrophages and VSM cells engulf lipids)

Question 11

What are the treatment options for Atherosclerosis?

Answer 11

• NON-Pharmacological (e.g., diet, exercise, quit smoking, less alcohol)
• Lipid-lowering drugs that either:
• inhibit cholesterol absorption (bile and binding resins)
• reduce cholesterol synthesis (statins e.g. simvastatin, atorvastatin)
• promote cholesterol metabolism (fibrates e.g. bezafibrate - these reduce VLDL, LDL-C, triglycerides and increase HDL-C)

Question 12

What is the key, rate limiting step in cholesterol synthesis that is targeted by statins?

Answer 12

Conversion of HMG-CoA to mevalonic acid by HMG-CoA reductase

Question 13

How does targeting cholesterol synthesis in the liver affect plasma LDL?

Answer 13

Less cholesterol synthesis -> upregulated LDL receptor expression -> more LDLs cleared from blood into cells -> lower plasma LDL

Question 14

What anti-inflammatory actions do statins have?

Answer 14

• Supress platelet activation
• Stabilise plaque to prevent rupture (reduced Matrix Metalloproteases so less collagen breakdown)
• Inhibit proliferation and migration of VSM cells
• Reduce production of cytokines by reducing TLR2/4 receptors
• Upregulate IL-10

Question 15

What are the 5 (mentioned) groups of anti-inflammatory drugs?

Answer 15

1. Antihistamines
2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
3. Steroidal Anti-Inflammatory Drugs
4. Disease-modifying Anti-Rheumatic Drugs (DMARDs)
5. Anti-cytokines

Question 16

How do anti-histamines reduce inflammation and what are some key examples?

Answer 16

Reduce the pro-inflammatory effects of Histamine (vasodilation, pro-inf mediators, eosinophil activation)

Loratidine, Chlorphenamine

Question 17

How do NSAIDs affect inflammation?

Answer 17

They don’t actually stop the inflammatory process - just suppress the symptoms

They inhibit Cyclo-oxygenase (COX1/2) -> reduce Prostaglandins and Thromboxanes -> Reduced Symptoms

Question 18

What are the three roles of NSAIDs?

Answer 18

1. Anti-inflammatory (decrease in PGE2 and PGI2, indirect inhibition of edema)
2. Analgesic (decreased PG synthesis therefore reduced sensitisation of nociceptors to bradykinin)
3. Anti-pyretic (less Il-1 -> less PGEs in CNS)

Question 19

What are the four main groups of NSAIDs? (And give examples for each)

Answer 19

1. Selective COX-1 inhibitors (e.g. low-dose aspirin)
2. Non-selective COX inhibitors (e.g. ibuprofen, high-dose aspirin)
3. Selective COX-2 inhibitors (e.g. meloxicam)
4. HIGHLY selective COX-2 inhibitors (e.g. celecoxib)

DO MORE BR TO FIND OTHER EXAMPLES IF ESSAY IS ON THIS!

Question 20

Describe COX1 and COX2 in terms of their functions and targeting by NSAIDs

Answer 20

COX1 is constitutive, and has roles in homeostasis, GI protection, renal blood flow
When inhibited long-term, increased acid secretion and decresed renal blood flow can lead to gastric ulcers

COX2 is inducible (by IL-1 and TNFa, inhibited by glucocorticoids)
Inhibition does not directly affect cytokines, but does indirectly reduce recruitment via blood flow

Question 21

What other Eicosanoid-related targets are there besides Cyclo-oxygenase?

Answer 21

1. Glucocorticoids inhibit PLA2 (and thus COX activation)
2. 5-lipoxygenase inhibitors
3. TXA2-synthase inhibitors
4. PG antagonists
5. Leukotriene-receptor antagonists -> TREAT ASTHMA
6. PAF antagonists

Question 22

What are the main group of anti-inflammatory steroids (and key examples of both exogenous and endogenous steroids from that group)?

Answer 22

Glucocorticoids:
- Endogenous (e.g., Cortisol, Hydrocortisone)
- Exogenous (e.g., Hydrocortisone, Prenisone, Dexamethasone)

Question 23

What are the main groups of Disease-Modifying Anti-Rheumatic Drugs (DMARDs)? + the most important example

Answer 23

• Immunosuppressants (E.G. METHOTREXATE)
• Anti-Malarials
• Gold Salts
• Miscellaneous

Question 24

How does methotrexate cause anti-inflammatory effects?

Answer 24

It inhibits AICAR Transformylase -> Adenosine builds up and leaves cell -> Increased Extracellular Adenosine + AMP

Adenosine + AMP outside the cell STIMULATE IL-10(!)
+ inhibit production of ROS, TNF and IL6/8
+ reduce E-selectin expression

Question 25

Summarise the role of anti-cytokine drugs

Answer 25

They are biologics (selective but expensive, not first option) Most either neutralise TNF, decoy receptors for TNF or antagonise Il1/6

Question 26

Name some examples of Anti-Cytokine drugs and the significance of their suffixes

Answer 26

Adalimumab, Infliximab, Golimumab, Tocilizumab are all MONOCLONAL ANTIBODIES (-mab) EtanerCEPT = Decoy ReCEPTor for TNF Anakinra = IL-1 antagonist (just there for the vibes ig)

Question 27

State three drawbacks of using anti-cytokine drugs

Answer 27

1. Expensive (biologics) 2. Route of administration - lack of oral bioavailability so usually injection 3. Long-term risk of infection (e.g. TB, septicaemia, lymphoma) when using TNFa antagonists - need to balance Anti-Cytokines with need for a host immune response

Question 28

Describe the pathway for cortisol production, and state the type of pathway this represents

Answer 28

Hypothalmus releases Corticotropin-Releasing Hormone (CRH) -> Anterior Pituitary Gland releases Adrenocorticotropic Hormone -> Zona Fasciculata (middle layer of adrenal cortex) releases glucocorticoids (e.g. cortisol) Cortisol inhibits CRH release (NEGATIVE FEEDBACK)

Question 29

How do steroids actually cause effects in cells?

Answer 29

They diffuse into the cytoplasm (lipophilic), then bind Class1 steroid receptors -> dimerisation -> SS-RR dimers bind Hormone Response Element (HRE) -> Up/Down-regulate protein production

Question 30

Describe the cellular effects of anti-inflammatory steroids

Answer 30

- Descreased transcription of genes for Adhesion Proteins and Cytokines - Reduced migration of neutrophils from blood vessels - Reduced activation of neutrophils/macrophages/mast cells/T-helpers - Reduced proliferation of T-cells - Reduced fibroblast action (less healing and repair)

Question 31

Name the mediators (or groups of mediators) that anti-inflammatory steroids inhibit the release of

Answer 31

- Cytokines - Histamine - NO (iNOS inhibited) - Eicosanoids - Complement Proteins Note: they also INCREASE IL-10 production (anti-inf)

Question 32

What is an Addisonian Crisis and how can it be avoided?

Answer 32

When on steroid therapy for more than 3 weeks, CRH and ACTH release is inhibited If steroid treatment is suddenly stopped, ADDISONIAN CRISIS due to cortisol deficiency Must be weaned off treatment gradually