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2 - MC > 5-6: Chronic Inflammation + Treatments > Flashcards

5-6: Chronic Inflammation + Treatments Flashcards

1
Q

What are the three outcomes of acute inflammation?

A
  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)
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2
Q

What are the distinguishing features of Chronic inflammation?

A
  • Slow, prolonged inflammation
  • Systematic signs
  • Mainly monocytes/macrophages and lymphocytes
  • Tissue Injury + Repair (fibrosis + angiogenesis)
  • Adaptive immune system involved
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3
Q

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

A
  • Replacement of alveoli with cuboidal-epithelium-lined spaces
  • Replacement by connective tissue
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4
Q

Describe the role of macrophages in chronic inflammation

A

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

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5
Q

Describe the “Vicious Cycle” of Leukocyte activation

A

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

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6
Q

Define atherosclerosis

A

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

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7
Q

Describe the four groups of risk factors for atherosclerosis

A
  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)
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8
Q

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

A

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

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9
Q

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

A
  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)
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10
Q

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

A
  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)
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11
Q

What are the treatment options for Atherosclerosis?

A
  • 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)
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12
Q

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

A

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

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13
Q

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

A

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

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14
Q

What anti-inflammatory actions do statins have?

A
  • 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
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15
Q

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

A
  1. Antihistamines
  2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
  3. Steroidal Anti-Inflammatory Drugs
  4. Disease-modifying Anti-Rheumatic Drugs (DMARDs)
  5. Anti-cytokines
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16
Q

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

A

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

Loratidine, Chlorphenamine

17
Q

How do NSAIDs affect inflammation?

A

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

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

18
Q

What are the three roles of NSAIDs?

A
  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)
19
Q

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

A
  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!

20
Q

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

A

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

21
Q

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

A
  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
22
Q

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

A

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

23
Q

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

A
  • Immunosuppressants (E.G. METHOTREXATE)
  • Anti-Malarials
  • Gold Salts
  • Miscellaneous
24
Q

How does methotrexate cause anti-inflammatory effects?

A

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

25
Q

Summarise the role of anti-cytokine drugs

A

They are biologics (selective but expensive, not first option)

Most either neutralise TNF, decoy receptors for TNF or antagonise Il1/6

26
Q

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

A

Adalimumab, Infliximab, Golimumab, Tocilizumab are all MONOCLONAL ANTIBODIES (-mab)

EtanerCEPT = Decoy ReCEPTor for TNF

Anakinra = IL-1 antagonist (just there for the vibes ig)

27
Q

State three drawbacks of using anti-cytokine drugs

A
  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
28
Q

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

A

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)

29
Q

How do steroids actually cause effects in cells?

A

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

30
Q

Describe the cellular effects of anti-inflammatory steroids

A
  • 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)
31
Q

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

A
  • Cytokines
  • Histamine
  • NO (iNOS inhibited)
  • Eicosanoids
  • Complement Proteins

Note: they also INCREASE IL-10 production (anti-inf)

32
Q

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

A

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

33
Q
A

2 - MC (5 decks)

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