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MD4001 > Corticosteroids and Stress Response > Flashcards

Corticosteroids and Stress Response Flashcards

1
Q

Define stressor.

A

Stimulus that disrupts homeostasis and causes stress response.

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2
Q

Define stress response.

A

Suite of physiological and behavioral responses to a stressor that help to restore homeostasis.

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3
Q

Describe the main steps fo the physiological stress response.

A

1) Sympathetic NS
- Quick response system (within seconds)
- Through release of adrenaline

2) HPA Axis
- Slower response system (minutes to hours)
- Release of cortisol

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4
Q

Briefly describe the HPA axis for cortisol.

A

Hypothalamus releases CRH which acts on the pituitary, which subsequently releases ACTH, which then acts on the adrenal cortex to produce cortisol.

Cortisol has a negative feedback on the hypothalamus.

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5
Q

What are the main consequences of the stress response on the body ?

A
  • Increased HR
  • Increased oxygen intake
  • Increased blood glucose levels
  • Increased blood flow to muscles
  • Increased alertness
  • Inhibition of digestion, immune system
  • Release of endorphins
  • Dilation of pupils
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6
Q

Is the response response good, or bad ?

A

In general, stress is beneficial in the short-term or at mild levels (allows adequate changes), but can cause major long-term problems if stress is chronic

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7
Q

Identify examples of health problems related to chronic stress.

A 
– Heart disease
– Diabetes
– Ulcers
– Growth problems
– Compromised immune system
– Depression
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8
Q

Cortisol is elevated in what proportion of depressed patients ? Describe the relation between cortisol and depression.

A
  • Cortisol elevated in~ 50% of depressed patients
  • Cortisol is normally rhythmically produced (high in the morning 7-9 and low 11 pm-4 am), could this be related to sleep disturbance in depression ?
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9
Q

Explain the Dexamethasone Suppression Test, and its significance.

A
  • People usually have high cortisol in the morning
  • If given Dex HPA negative feedback turns this (i.e. normal production of cortisol) off, so no cortisol surge
  • Not true of depressed patients (no response to the test, cortisol still produced)
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10
Q

Describe the relationship between cortisol and mood.

A

May be biphasic (refer to slide 11)

  • Depression a symptom of Cushing’s disease (high cortisol)
  • but also typical of Addison’s disease (low cortisol)
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11
Q

Describe the effect of the stress response on the immune system. How may we use this therapeutically ?

A
  • 1st few minutes – immune system is enhanced
  • After about an hour of stress – immune system returns to normal
  • Chronic stress suppresses immune system functioning

If overactive immune system, can dampen it down by mimicking chronic stress using synthetic glucocorticoids

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12
Q

What is the role of corticosteroids in the anti-stress response ?

A

Helps reduce inflammation during stress, but it also act as immunosuppressants.

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13
Q

Identify possibly ways in which chronic stress may negatively affect the immune system.

A
  • May result in lowered T-helper 1 (Th1) cellular immunity (suppress ability to secrete cytokines including interferon gamma, from specific immune cells including T lymphocytes and NK cells)
  • May result in decrease in the number of macrophages, interferons, lymphocytes and natural killer (NK) cells
  • May cause increase in virus antigens (chronic stress may trigger replication) + levels of virus specific antibodies may decrease (following chronic stress) + may cause virus reactivation (e.g. EBV)
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14
Q

Identify the main modes of glucocorticoid action.

A

1) Transactivation (classical model)
- Glucocorticoid crosses membranes, into cytosol
- Reaches and interacts with glucocorticoid receptor, which interacts with GRE, which drives upwards production of anti-inflammatory gene. This dampens down immune response

2) Transrepression
- Glucocorticoid causes block in the production of inflammatory protein (pro-inflammatory cytokine e.g. TNF alpha binds onto its own response element, and drives inflammatory gene which subsequently causes production of inflammatory protein)

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15
Q

Describe changes in WBCs with glucocorticoids.

A

Short term may increase, because may increase polymorphonuclear leukocytes (including neutrophils) (but NOT lymphocytes) so overall increase in WBC

Long term WBC will stay the same

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16
Q

Which arm of the immune system is affected by steroid treatment ?

A

Adaptive arm affected (B and T cells) because steroid treatment stops new gene synthesis, which doesn’t affect pre-made cells (i.e. cells of innate immunity e.g. neutrophils which phagocytose things) but will affect cells that will have to make new genes (e.g. antibodies by B cells, cytokines by T cells)

17
Q

Identify examples of synthetic glucocorticoids. Differentiate between potency and half life of these.

A
  • Hydrocortisone
  • Cortisone Acetate
  • Prednisone (less potent, and shorter half life)
  • Prednisolone (less potent, and shorter half life)
  • Dexamethasone (very potent and long half life)
18
Q

Identify immunosuppressive actions of glucocorticoids.

A

• Glucocorticoids suppress cell-mediated immunity
• Inhibit production of pro-inflammatory cytokines including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-alpha
• Suppress humoral immunity - B cells express
less IL-2R and secrete less IL-2
• Downregulation of Fc receptors on macrophages- reduced phagocytosis of opsonised cells and bacteria

19
Q

Identify side effects of glucocorticoid use.

A
  • Global immunosuppression
  • Hyperglycemia due to gluconeogenesis, insulin resistance, impaired glucose tolerance
  • Skin fragility, bruising
  • Osteoporosis
  • Weight gain
  • Adrenal insufficiency
  • Muscle breakdown
  • Irregular menstruation
  • CNS
  • Cushing’ s syndrome

ALSO

  • Excess use of high dose steroids suppress CRH and ACTH
  • Prolonged use leads to adrenal atrophy - recovery can take months
20
Q

Describe procedure for withdrawal of glucocorticoids for different lengths of glucocorticoid treatment.

A
  • Careful use of treatment withdrawal - less than one week treatment, usually ok to withdraw abruptly, 1 week recovery
  • 6-10 days - reduce to replacement and taper over 4 more days. Recovery in 4 weeks.
  • 11-30 days, reduce to twice replacement, then by 25% every 4 days. 3 months to recover
  • > 30 days - reduce to twice replacement, then by 25% per week, then 0800h check with cortisone. Recovery may take 1 year.
  • Monitor for flare-up of underlying condition
21
Q

Identify the main stages of type 1 diabetes.

A
  • 1st stage: insulitis - lymphocyte invasion of pancreatic islets (does not usually show because large amount of lost cells before clinical problems)
  • 2nd stage: overt diabetes, massive death of islet B cells - loss of glucose homeostasis
22
Q

Identify hypothesized pathways leading to type 1 diabetes.

A

• Immune assault on beta-cells mostly T lymphocytes

• Naïve, beta-reactive T cells meet antigen in pancreatic lymph nodes (PLN)
⬇
Antigens delivered to PLN by dendritic cells
⬇
Thus PLN is site where tolerance to pancreatic beta cells is first broken down

• Possible link of alimentary problems to type 1 diabetes:
- Enteroviruses (coxsackievirus), gluten, coeliac disease (30% in some patient groups)

23
Q

If inject lymphocytes into the intestinal cavity, which lymph node do they mainly go to ?

A

Pancreatic lymph nodes

hence lot of migration of material from gut area to pancreas

24
Q

When does lymphocyte access to PLN occur, in terms of type 1 diabetes ?

A

Lymphocyte access to PLN occurs during infancy (timecourse is very similar to when dendritic cells capable of presenting pancreatic autoantigens also appear)

25
Q

Describe the effect of altering status of the gut with DSS on insulitis, explaining the rationale behind it.

A

-When introduced, DSS disturbs gut permeability, and causes insulitis in pancreatic lymph nodes

-PLNs sample self-antigens from pancreas and also gut. Non-specific gut pertubations influence beta-reactive
T cells (potential explanation for relationship between diseases like coeliac and type 1 diabetes)
  • Link between neonatal immune system development and gut development
  • Viral infection early in life can result in insulitis, leading down pathway towards type 1 diabetes

MD4001 (74 decks)

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