46. Respiratory Disease/Obesity Flashcards
What has research shown about the relationship between obesity and asthma?
Increasing BMI is associated with increased odd of asthma
Obesity can both cause and complicate asthma
Which types of asthma is worsened by obesity?
Both T2- and Non-T2- type astham
What pathophysiological features are typical of asthma?
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
Which cell types are responsible for inflammation in T2-type and Non-T2 asthma?
eosinophils in T2-type asthma
neutrophils in non T2-type asthma
What causes airway hyperresponsiveness in asthma?
influence of inflammatory mediators and increased bulk of “sensitised” muscle leads to airways contracting “too easily and too much”
What are the drivers of allergic (T2) asthma?
Th2 cells
- IL-5
- IL-4, IL-13
Eosinophils
- leukotrienes, cytokines
Plasma cells, mast cells
- IgE
- histamine, leukotrienes, cytokines
What are the drivers of obese (T1) asthma?
Increased adipose tissue - adipokines
- more leptin (pro-inflammatory)
- less adiponectin (ant-inflammatory)
Macrophages
Neutrophils
- TNFα, IL-6, IL-17
What are the limitations of β2-adrenoceptor agonists?
- 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
How do inhaled corticosteroids work as preventers?
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
Why aren’t inhaled corticisteroids good for obese asthma?
Corticosteroids acts on eosinophils, Th2 cytokines (IL-4, IL-5, IL-13) which are not features of obese asthma (neutrophils, TNFα, IL-17)
What are the mechanisms of obese asthma?
- Decreased lung function
- Reduced FRC and ERV due to abdominal adiposity
- Inflammation
- Il-17 associated inflammation in the airways
- Th1 related inflammation in the airways
- Increased leptin in airways, reduced adiponectin
- Oxidative stress
- Low L-arginine/ADMA ratio and increased oxidative stress and lower NO
What causes the decreased lung function seen in obese asthma?
Reduced FRC and ERV due to abdominal adiposity
What causes the inflammation seen in obese asthma?
Il-17 associated inflammation in the airways
Th1 related inflammation in the airways
Increased leptin in airways, reduced adiponectin
What causes the oxidative stress seen in obese asthma?
Low L-arginine/ADMA ratio and increased oxidative stress and lower NO
In what ways does obesity impair lung function?
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
How does obesity contribute to systemic inflammation?
increased pro-inflammatory leptin, decreased anti-inflammatory adiponectin
macrophages infiltrate adipose tissue release TNF-α, IL-6
How does obesity contribute to lung inflammation?
decreased airway eosinophils (lumen, sputum)
increased airway neutrophils
predominately Th-1 and potential IL-17 related inflammation
True or False:
NO plays a protective role in asthma
True
NO is a dilator
How does obesity effect NO?
Obesity reduces NO, increases oxidative stress
↑ADMA in obesity
ADMA is a endogenous inhibitor of NOS enzymes that produce NO
How does obesity result in airway remodelling?
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
What are the mechanisms of reduced response to asthma therapy due to obesity?
Reduced response to:
- Dilators
- Reduced FRC and ERV due to abdominal adiposity
- Low L-arginine/ADMA ratio and increased oxidative stress and lower NO
- 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
What causes the reduced response to dilators in obese asthma?
Reduced FRC and ERV due to abdominal adiposity
Low L-arginine/ADMA ratio and increased oxidative stress and lower NO
What causes the reduced response to steroids in obese asthma?
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
True or False:
Obesity reduces responsiveness to dilator therapyin both T2-type asthma and non-T2-type asthma
True
