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Pharmacy Stage 2 > Alessio > Flashcards

Alessio Flashcards

inflammation

1
Q

What is inflammation?

A

“Is a complex reaction in tissues that consists mainly of responses of blood vessels and leukocytes (white blood cells)”

Is a protective response designed to rid the organism of the cause of a cell injury (e.g. microbes, toxins, healing from wounds etc.)

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2
Q

What are the characteristics of acute inflammation?

A
  • Rapid (minutes!) and of short duration
  • Associated with the presence of leukocytes (mainly neutrophils)
  • Characterized by exudation of fluids and plasma proteins (edema)
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3
Q

What are the characteristics of chronic inflammation?

A
  • Longer duration
  • Associated with the presence of lymphocytes and macrophages
  • Characterized by proliferation of blood vessels, fibrosis and tissue disruption
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4
Q

Is inflammation harmful and why?

A

inflammation inappropropriately directed against self tissues or uncontrolled) Contributes to a number of diseases (e.g. atherosclerosis, type 2 diabetes, Alzheimer disease, cancer)

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5
Q

Clinical features of inflammation

A
  • Rubor (redness)
  • Tumor (swelling)
  • Calor (heat)
  • Dolor (pain)
  • Functio laesa (loss of function)
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6
Q

What happens in acute inflammation?

A

“A rapid host response that serves to deliver leukocytes and plasma proteins to the site of infection or tissue injury”
• Vasodilation alters vascular calibre leading to an increase in blood flow
• Increased vascular permeability permits plasma proteins and leukocytes to leave the circulation (edema) • Leukocyte migration from the microcirculation and their accumulation in the site of injury and their activation to eliminate the cause of injury

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7
Q

Stimuli for acute inflammation?

A
  • Infections (bacteria, virus, fungi, parasites). Microbial toxins are sensed by Toll-like receptors (TLRs)
  • Tissue necrosis (ischemia, hypoxia, trauma, physical/chemical injury). Molecules released by necrotic cells activate inflammation (e.g. uric acid, ATP)
  • Foreign bodies (dirt, splinters, sutures). They cause traumatic tissue injury or carry microbes Immune reactions (hypersensitivity reactions).
  • The immune system damages the individual’s own tissue leading to autoimmune diseases and chronic inflammation
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8
Q

Acute inflammation step by step?

A

1) Vasodilation- Induced by several mediators (e.g. histamine and nitric oxide)
2) Increased blood flow -This causes redness and heat at the site of inflammation
3) Increased permeability of the microvasculature- Outpouring of a protein-rich fluid (exudate) into the extravascular tissues
4) Increased viscosity of the blood- Loss of fluid and increased vessel diameter lead to slower blood flow
5) Stasis- Dilation of small vessels that are packed with slowly moving red cells.
6) Neutrophils accumulation- As stasis develops, neutrophils accumulate bc they’re moving slower, and they adhere along the vascular endothelium

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9
Q

Describe the steps of leukocytes adhesion to the endothelium in the blood vessel.

A
  • Margination: leukocytes redistribute along the endothelium
  • Rolling: rows of leukocytes adhere transiently, detach and adhere again firmly. These interactions are mediated by a class of proteins called selectins
  • Adhesion: leukocytes are firmly adhered to the endothelium. These interactions are mediated by a family of proteins called integrins
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10
Q

Explain Leukocyte migration through the Endothelium to the point of diapedesis (leaving through the capillary walls).

A
  • The process involves interaction of leukocytes with endothelial cells mediated by adhesion molecules such as PECAM-1/CD31
  • Leukocytes pierce the basement membrane by secreting collagenases and enter the extravascular site
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11
Q

Explain the Chemotaxis of Leukocytes.

A
  • After exiting the circulation, leukocytes emigrate in tissues toward the site of injury by following chemoattractants
  • Exogenous chemoattractants: bacterial products
  • Endogenous chemoattractants: a number of chemical mediators
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12
Q

Explain the leukocyte response and removal of the offending agents.

A

Recognition and attachment:
• Mannose receptors: bind terminal sugars residues, which are part of molecules found on microbial cell walls
• Scavenger receptors: bind a variety of microbes
• Opsonin receptors: the efficiency of phagocytosis is greatly enhanced when the microbe is coated with opsonin proteins for which the phagocytes express high-affinity receptors. The major opsonins are IgG antibodies, C3b breakdown product of the complement and some plasma lectins.

Engulfment:
After a particle is bound to phagocyte receptors, the plasma membrane form a vesicle (phagosome) that encloses the particle. The phagosome then fuses with a lysosomal granule.

Killing and degradation:
Accomplished largely by reactive oxygen species (ROS) and reactive nitrogen species derived from NO, or by lysosomal enzymes (e.g. elastase, lysozyme, defensins and many more).

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13
Q

What happens to edema fluid that accumulates due to increased vascular permeability?

A

In inflammation lymph flow is increased and help drain edema fluid that accumulates due to increased vascular permeability. The lymphatic vessels drain into the lymph nodes

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14
Q 
Which of the following is not a feature of acute inflammation? 
A) Heat 
B) Pain 
C) Presence of Leukocytes 
D) Long duration
A

D

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15
Q

Which of the following statements is true? (2 right answers)
A) Acute inflammation is characterized by vasodilatation.
B) Increased vascular permeability allows plasma proteins and leukocytes to leave the circulation.
C) Leukocytes stable adhesion to the endothelium is mediated by selectins.
D) Leukocyte diapedesis is mainly mediated by integrins

A

A,B

C wrong bc integrins NOT selectins
(D wrong bc PECAM-1/CD31)

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16
Q

What are Cell-derived mediators?

A

Produced locally by cells at the site of inflammation
• Pre-accumulated In intracellular granules and are rapidly secreted upon cellular activation (e.g. histamine in mast cells) or are synthetized in response to a stimulus (e.g. prostaglandins and cytokines)

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17
Q

What are Plasma-protein-derived mediators?

A

Produced in liver and circulating in the plasma as inactive precursors that are activated at the site of inflammation
• Complement proteins, kinins, which undergo proteolytic cleavage to acquire their biologic activities

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18
Q

What happens to mediators once they are activated and released from the cell?

A

They are then inactivated by enzymes, eliminated or inhibited.

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19
Q

Name 2 mediators of inflammation.

A

Prostaglandins and leukotrienes. During inflammation, prostaglandins and leukotrienes are generated by the action of several enzymes

20
Q

How are prostaglandins generated? Explain.

A

1) Phospholipase A2 releases arachidonic acid from membrane phospholipids.
2) COX-1 (constitutively expressed) COX-2 (inducible) converts arachidonic acid to PGH2 (prostaglandins).
3) Thromboxane synthetase (present in platelets) converts PGH2 to thromboxane (TXA2).
Prostacyclin synthetase (present in endothelial cells) converts PGH2 to Prostacyclin (PGI2).
(Unbalance between PGI2 and TXA2 is implicated in thrombus formation/fever).

21
Q

How are leukotrienes generated? Explain.

A

1) Phospholipase A2 releases arachidonic acid from membrane phospholipids.
2) 5-lipoxygenase (present in neutrophils) converts arachidonic acid to 5hydroperoxyeicosatetranoic acid (5HPETE), the precursor of the leukotrienes.

22
Q

How do COX 1/2 inhibitors work as anti-inflammatory drugs?

A

COX1/2 inhibitors:
Aspirin, Ibuprofen, Indomethacin, paracetamol etc. (NSAIDs)
• Anti-inflammatory effect: by blocking PGs production (reduce vasodilatation and edema).
• Analgesic effect: reduce pain by inhibiting PGs production that sensitize nociceptors (pain receptors) to inflammatory mediators.
• Anti-pyretic effect: Lower high body temperature.

23
Q

Is paracetamol (COX inhibitor) only used for inflammation?

A

No. Paracetamol has weak anti-inflammatory activity compared to other NSAIDs, but also less side effects.

24
Q

What does prostacyclin (PGI2) do?

A

Vasodilation.

Inhibits platelet aggregation.

25
Q

What does thromboxane (TXA2) do?

A

Vasoconstriction.

Promotes platelet aggregation.

26
Q

How do COX 2 inhibitors work as anti-inflammatory drugs?

A

COX2 inhibitors: Celecoxib, Etoricoxib
More selective for inflammation (COX-2 is mainly expressed in inflammatory cells after stimulation)
• Less gastrointestinal toxicity but increased risk for arterial thrombosis
• Potential role in colon cancer therapy!

27
Q

How do lipoxygenase inhibitors work as anti-inflammatory drugs?

A

Lipoxygenase inhibitors: Zileuton, Montelukast
•They reduce inflammation by inhibiting LTs production or blocking leukotriene receptors
•Particularly useful for asthma

28
Q

How do glucocorticoids work as anti-inflammatory drugs?

A

Glucocorticoids: Cortisone, Prednisolone
• Reduce transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines, and iNOS (Nitric oxide synthase), many more
• Most powerful anti-inflammatory
• They also suppress the defence reactions that provide protection to infection (immunosuppressive effect)

29
Q 
Celecoxib targets…
A) COX2 enzyme 
B) Both COX1 and COX2 
C) Phospholipase A2 
D) Lipoxygenase
A

A

30
Q

Gastrointestinal toxicity is typical of…

A) Paracetamol B) Ibuprofen C) Celecoxib D) Zileuton

A

B

not A bc paracetamol weaker

31
Q

What is leukocytosis?

A

The local increase in number of leukocytes.

32
Q

What is the effect of acute inflammation?

A

Microbial products, toxins, other cytokines>activation of macrophages (and other cells) > TNF/IL-1 released > systemic effects:

  • fever
  • leukocytosis
  • acute-phase proteins
  • decreased appetite
  • increased sleep
33
Q

What is a fever?

A

A body temperature elevation of 1°-4°C

34
Q

Effect of NF-ĸB transcription factor on inflammation.

A
  • Activated by a huge number of stimuli (e.g. cytokines, virus & bacteria, cell stress)
  • Master regulator of inflammation
  • It regulates expression of cytokines (IL-1, IL-6, TNF), chemokines, adhesion molecules, enzymes and many more factors involved in inflammation!
  • Implicated in a number of chronic inflammatory diseases (e.g. inflammatory bowel disease, rheumatoid arthritis, chronic obstructive pulmonary disease etc.)
35
Q

Describe anti-inflammatory drugs targeting NF-ĸB.

A
  • IKK inhibitors
  • Proteasome inhibitors (Bortezomib)
  • Inhibitors that block nuclear translocation of NF-ĸB (Tacrolimus)
  • Inhibitors of NF-ĸB DNA-binding activity (Glucocorticoids)
36
Q

Why are glucocorticoids the most powerful anti-inflammatory drugs?

A

Block transcription factors that cause expression of all 3 of the inflammation pathways.
They are more suppressive drugs.

37
Q

Describe a complete resolution outcome of acute inflammation?

A

Injury limited/short lived.
Damaged tissue can regenerate.
Complete removal of debris and microbes by macrophages and reabsorption of edema fluids by lymphatics.

38
Q

Describe outcome of acute inflammation turning into fibrosis.

A

Extended injury.
Damaged tissue cannot regenerate.
Connective tissue grows in the area of damage, converting it into a mass of fibrous tissue.

39
Q

Describe outcome of acute inflammation turning into chronic inflammation.

A

Persistence of injury/prolonged duration (weeks/months).
Damage persists/interference with repair process.
of the lung.
Peptic ulcers/ Bacterial infections of the lungs.

40
Q

What is chronic inflammation?

A

“Is inflammation of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repairs coexist, in varying combination”

It may follow acute inflammation or emerge as a low-grade smoldering response without any manifestations of an acute reaction (e.g. rheumatoid arthritis, atherosclerosis, Alzheimer, cancer etc.)

41
Q

Causes of chronic inflammation?

A
  • Persistent infections – Some microorganisms are difficult to eradicate (e.g. mycobacteria, some viruses, fungi and parasites). They can lead to a granulomatous reaction (aggregation of macrophages that are transformed into epithelial-like cells, surrounded by other immune cells)
  • Immune-mediated inflammatory diseases – Excessive and inappropriate activation of the immune system.
  • Immune reactions against the individual’s own tissues leading to autoimmune diseases.
  • Unregulated immune-reactions against microbes (e.g IBDs)
  • Immune-responses against harmless environmental substances (e.g. Asthma).
  • Prolunged exposure to toxic agents – Long exposure to exogenous (e.g. silica) or endogenous (e.g. toxic plasma lipids)
42
Q

Describe the cells involved in chronic inflammation and their role.

A
  • Macrophages– The products of activated macrophages serve to eliminate injury agents and to initiate the process of repair. They are responsible for much of the tissue injury in chronic inflammation!
  • Lymphocytes – They communicate with macrophages in a bidirectional way, through release of cytokines. This makes the inflammatory reaction chronic and severe
  • Plasma cells – Develop from activated B lymphocytes and produce antibodies against the persistent foreign agent or self antigens at the inflammatory site.
43
Q

Explain what happens in chronic inflammation.

A
  • Infiltration with mononuclear cells – Macrophages, lymphocytes and plasma cells
  • Tissue destruction – Induced by the persistent offending agent
  • Attempts at healing – Connective tissue replacement of damaged tissue accomplished by proliferation of small blood vessels (angiogenesis) and fibrosis.
44
Q 
Which of the following mediators of inflammation can cause fever? (2 right answers) 
A) Leukotrienes 
B) Prostaglandins 
C) Histamine 
D) IL-1, TNF
A

B,D

45
Q

Which of the following is true? (2 right answers)
A) NF-kB is implicated in a number of chronic inflammatory diseases
B) Many drugs target NFkB specifically in inflammation C) NF-kB is a transcription factor
D) NF-kB is a kinase

A

A,C

B incorrect bc nf-kb is not just specific to inflammation. It does many more things.

46
Q

Which of the following is NOT a feature of chronic inflammation?
A) Associated mainly with infiltration of macrophages
B) Tissue destruction
C) Associated mainly with infiltration of leukocytes
D) Attempts at healing

A

C bc that’s acute inflammation

47
Q

Which of the following is true? (2 right answers)
A) Most chronic inflammatory diseases develop following an acute reaction
B) Chronic inflammation may be caused by unregulated immuneresponses
C) Macrophages are mostly responsible for tissue destruction in chronic inflammation
D) Lymphocytes are mostly responsible for tissue destruction in chronic inflammation

A

B,C

Pharmacy Stage 2 (8 decks)

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