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BMS3052 > 46. Respiratory Disease/Obesity > Flashcards

46. Respiratory Disease/Obesity Flashcards

1
Q

What has research shown about the relationship between obesity and asthma?

A

Increasing BMI is associated with increased odd of asthma

Obesity can both cause and complicate asthma

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2
Q

Which types of asthma is worsened by obesity?

A

Both T2- and Non-T2- type astham

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3
Q

What pathophysiological features are typical of asthma?

A

Inflammatory cell infiltration

  • eosinophils in T2-type asthma
  • neutrophils in non T2-type asthma

Excessive mucus

  • obstruction & barrier to inhaler therapy

Basement membrane thickening

  • fibrosis

More smooth muscle

  • increased contraction
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4
Q

Which cell types are responsible for inflammation in T2-type and Non-T2 asthma?

A

eosinophils in T2-type asthma

neutrophils in non T2-type asthma

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5
Q

What causes airway hyperresponsiveness in asthma?

A

influence of inflammatory mediators and increased bulk of “sensitised” muscle leads to airways contracting “too easily and too much”

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6
Q

What are the drivers of allergic (T2) asthma?

A

Th2 cells

  • IL-5
  • IL-4, IL-13

Eosinophils

  • leukotrienes, cytokines

Plasma cells, mast cells

  • IgE
  • histamine, leukotrienes, cytokines
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7
Q

What are the drivers of obese (T1) asthma?

A

Increased adipose tissue - adipokines

  • more leptin (pro-inflammatory)
  • less adiponectin (ant-inflammatory)

Macrophages

Neutrophils

  • TNFα, IL-6, IL-17
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8
Q

What are the limitations of β2-adrenoceptor agonists?

A
  • SABA – salbutamol for acute relief of symptoms for T2 and non-T2 type asthma
  • efficacy wil be reduced if
    • airway contraction is increased (functional antagonism)
    • β2-adrenoceptor expression is reduced
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9
Q

How do inhaled corticosteroids work as preventers?

A

Transactivation

  • bind to GREs
  • increase anti-inflammatory proteins e.g. annexin A1

Transrepression

bind to transcription factors

decrease pro-inflammatory proteins e.g. COX-2, IL-1, TNFα

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10
Q

Why aren’t inhaled corticisteroids good for obese asthma?

A

Corticosteroids acts on eosinophils, Th2 cytokines (IL-4, IL-5, IL-13) which are not features of obese asthma (neutrophils, TNFα, IL-17)

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11
Q

What are the mechanisms of obese asthma?

A
  1. Decreased lung function
    • Reduced FRC and ERV due to abdominal adiposity
  2. Inflammation
    • Il-17 associated inflammation in the airways
    • Th1 related inflammation in the airways
    • Increased leptin in airways, reduced adiponectin
  3. Oxidative stress
    • Low L-arginine/ADMA ratio and increased oxidative stress and lower NO
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12
Q

What causes the decreased lung function seen in obese asthma?

A

Reduced FRC and ERV due to abdominal adiposity

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13
Q

What causes the inflammation seen in obese asthma?

A

Il-17 associated inflammation in the airways

Th1 related inflammation in the airways

Increased leptin in airways, reduced adiponectin

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14
Q

What causes the oxidative stress seen in obese asthma?

A

Low L-arginine/ADMA ratio and increased oxidative stress and lower NO

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15
Q

In what ways does obesity impair lung function?

A

abdominal adiposity increases with BMI

↓TV, increased rate

↓ FRC, ERV

TLC may be well preserved until morbidly obese

no airway obstruction so FEV1/FVC preserved

↑ airway stiffness

↑ airway contraction

↑ airway narrowing

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16
Q

How does obesity contribute to systemic inflammation?

A

increased pro-inflammatory leptin, decreased anti-inflammatory adiponectin

macrophages infiltrate adipose tissue release TNF-α, IL-6

17
Q

How does obesity contribute to lung inflammation?

A

decreased airway eosinophils (lumen, sputum)

increased airway neutrophils

predominately Th-1 and potential IL-17 related inflammation

18
Q

True or False:

NO plays a protective role in asthma

A

True

NO is a dilator

19
Q

How does obesity effect NO?

A

Obesity reduces NO, increases oxidative stress

↑ADMA in obesity

ADMA is a endogenous inhibitor of NOS enzymes that produce NO

20
Q

How does obesity result in airway remodelling?

A

Obesity causes an increase in Arginase

Gets converted to polyamines and L-proline (via L-orthinine and urea)

Polyamines = airway SM proliferation

L-proline = collagen

21
Q

What are the mechanisms of reduced response to asthma therapy due to obesity?

A

Reduced response to:

  1. Dilators
    • Reduced FRC and ERV due to abdominal adiposity
    • Low L-arginine/ADMA ratio and increased oxidative stress and lower NO
  2. Steroids
    • Il-17 associated inflammation in the airways
    • Steroid resistance, blunted response to MKP-1 and TNFa
    • Th1 related inflammation in the airways
    • Increased leptin in airways, reduced adiponectin
22
Q

What causes the reduced response to dilators in obese asthma?

A

Reduced FRC and ERV due to abdominal adiposity

Low L-arginine/ADMA ratio and increased oxidative stress and lower NO

23
Q

What causes the reduced response to steroids in obese asthma?

A

Il-17 associated inflammation in the airways

Steroid resistance, blunted response to MKP-1 and TNFa

Th1 related inflammation in the airways

Increased leptin in airways, reduced adiponectin

24
Q

True or False:

Obesity reduces responsiveness to dilator therapyin both T2-type asthma and non-T2-type asthma

A

True

25
Q

Why does obesity reduced responsiveness to anti-inflammatory therapy?

A
  • Obesity increases airway neutrophils, Th-1 and IL-17 related inflammation
  • Steroids are less effective against neutrophils and Th-1 type inflammation
  • Obesity
    • reduces steroid response in T2-type allergic asthma
    • further reduces response in non-T2-type asthma where steroids already lack efficacy
26
Q

What is the effect of non-surgical weight loss on obese asthma?

A

weight loss of > 10 % or greater showed improvement in Asthma Control Questionnaire (ACQ)

27
Q

What is the effect of surgical weight loss on obese asthma?

A

reduced AHR

improved FEV1, FVC

increased adiponectin (lung, serum)

decreased lepin

28
Q

How does surgical weight loss effect airway hyperresponsivness (AHR) in T2 and Non-T2 type asthma?

A

AHR decreased in non T2 asthma = asthma consequent to obesity

AHR persisted in T2 type allergic asthma

BMS3052 (26 decks)

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