Biology of Lung Disease Flashcards
Define pulmonary hypertension
Pulmonary arterial pressure >25mmHg
Normal is 14mmHg
What is the difference between pulmonary hypertension and pulmonary arterial hypertension?
Pulmonary arterial hypertension (pulmonary vasoconstriction) is a subgroup of pulmonary hypertension (high blood pressure in the lungs, multiple aetiologies)
What are the models of pulmonary hypertension?
Classic = chronic hypoxic model Monocrotaline model (MC) = inject it; it gets metabolised into MC pyrrole and causes vascular injury
Using the Dana Point classification, summarise the groups for pulmonary hypertension.
1- PAH- idiopathic and heritable 1'- Venous/ capillary cause 2- Left heart pathology 3- Lung disease/ hypoxaemia 4- Chronic thromboembolic disease 5- Unclear/ multifactorial etiologies
What are the clinical stages of pulmonary hypertension?
I- no limitation in physical activity
II- mild limitation
III- marked limitation with less than ordinary activity
IV- can’t perform physical activity/signs of right ventricular failure at rest.
What is the pathophysiology of pulmonary arterial hypertension?
Neomuscularisation
Hypertrophy of large muscular arteries
Neointima - myofibroblast and extracellular matrix layer forms between endothelium and internal elastic lamina
Plexiform lesions containing endothelial cells, PASMCs, lymphocytes and mast cells.
Continuing thrombosis and vasoconstriction.
What are the problems with the animal models of PH and PAH?
Animal models of PH have all the classic symptoms except plexiform lesions.
In animal models of PAH, the main problem is vasoconstriction unlike human PAH where it is angioproliferation.
Why is the pulmonary endothelium thought to play a central role in the pathogenesis of pulmonary arterial hypertension?
Evidence of:
Abnormal endothelial cell function
Abnormal endothelial derived factors and markers
Role of cells in plexiform lesion formation
Current treatments target the endothelium derived factors
What is the role of endogenous nitric oxide synthase (eNOS) in vascular tone?
L-arginine activates eNOS which makes NO-> vasodilation
eNOS inhibition via ADMA or L-NMMA reduces NO -> reduced vasodilation -> vasoconstriction
What is the association between eNOS inhibitors and pulmonary arterial hypertension?
Too much ADMA in PAH patients - Pulamsett et al.
ADMA may not be cleared properly by DDAH
What are factors positively associated with pulmonary arterial hypertension?
Endothelium like factor 1 (ET-1)
bFGF
PDGF
What is the genetic basis of pulmonary arterial hypertension?
Familial: autosomal dominant mapped to chromosome 2
Reduced expression/ function of BMPR-2 which activates Smad proteins 1, 5, 7.
Mutations in ALK1 (which dimerises with BMPR2)
These mutations ultimately lead to loss of function of the receptors they code for.
Mutations increase risk of PAH by 10000.
What is proposed association between serotonin (5-HT) and pulmonary arterial hypertension?
Increased 5-HT (via drug administration) correlated with PAH, those drug side effects could have caused it too.
Eliminate 5-HT and it has a protective effect on PAH.
Excess 5-HT increases risk of PAH.
Describe the oestrogen paradox in pulmonary arterial hypertension
PAH seen more in younger women than older women.
Women with PAH survive longer than the male patients.
Decreasing oestrogen appears to protect against PAH (despite them being protective in animal models of PH as well as CVD).
Why may low oestrogen protect against pulmonary arterial hypertension (PAH)?
Oestradiol is metabolised into two CYPs:
CYP1B1 codes for 16alpha-OHE1 which is proliferative.
Other CYPs code for 2-OHE which is anti- proliferative
In PAH, the ratio of other CYPs to CYP1B1 is lower.
Wild-type CYP1B1 predisposes to PAH in those at risk of BMPR2.
How do plexiform lesions develop?
Increased blood pressure increases pulmonary artery (PA) sheer stress/ high sheer stress environment.
High stress increases endothelial cell apoptosis.
Some (abnormal) endothelial cells become resistant to apoptosis and these are capable of proliferating into lesions.
What are the roles of PPAR-gamma and caspase-3 in plexiform lesion formation?
PPAR-gamma is over expressed to reduce cell proliferation. Sheer stress inhibits PPAR-gamma, encouraging lesion formation.
Caspase-3 is a marker of apoptosis; abnormal cells in the lesion don’t die, so don’t release it.
What are signs and screening methods for pulmonary arterial hypertension?
Signs:
Split S2 with loud P2
Increased jugular venous pressure
Screening: Right heart catheterisation is the gold standard for pulmonary artery pressure. Echocardiogram Cardiac MRI Chest X-Ray
What are treatments for pulmonary arterial hypertension?
Diuretics
Supplementary oxygen
Prostacyclin inhibitors
Digoxin
Guanylate cyclase stimulator- helps produce more nitric oxide
Endothelin receptor antagonists- blocks ETA and ETB receptors
What are the features of COPD?
Dyspnoea- progressive, limits exercise Cough Acute deterioration This symptom burden gets worse with time. Spirometry is 0.7 FEV1: FVC ratio
What are common causes of COPD?
Tobacco
Bio-mass fuel exposure
Describe the pathophysiology of sleep apnoea.
Weaker breathing muscles collapse
Closure during sleep
Hypoxia
Feedback to the brain
Muscles open the airway again (increasing oxygen concentration)
Reduced feedback results in muscle closure
What are the treatments of COPD?
Smoking cessation in smokers
Anti-muscarinics
Supplemental oxygen
What is the only known genetic cause of COPD?
Alpha-1-antytrypsin deficiency