Transcript Phenotypic Determinants in Chronic airflow limitation

Phenotypic Determinants in
Chronic airflow limitation
M.C.F.Pain
Obvious that there is a spectrum of clinical patterns in patients with a
common feature of a reduced FEV/VC%.
Differences in underlying pathology
Chronic asthma- airway remodelling with some potential
for reversibility
Obstructive bronchitis- airway remodelling with no reversible
component
Emphysema –irreversible breakdown of pulmonary elastic
tissue.
Differences in compensatory mechanisms within normal subjects
Translated to patients
Interplay of these factors possibly determines the clinical presentation
and prognosis.
“Lumpers” (COAD,CAL,COLD) versus “Splitters” (chronic asthma,
obstructive bronchitis, emphysema.
Compensatory mechanisms.
1. Bronchial hyper-responsiveness
“Asthma is the inflammatory modulation of intrinsic bronchial reactivity
to a degree that produces symptomatic airflow obstruction”
About 5% of the “normal” population have increased bronchial reactivity
to methacholine to a level found in asthmatics
Syndromes of non-asthmatic bronchoconstriction
2, Chemoreceptor sensitivity
Controllers of ventilation and hence of respiratory work, in the
maintenance of adequate gas exchange
CO2 balance designed to keep pCO2 about 40mmHg.
O2 little function in normals but rugged in adverse hypoxic
situations
A wide range of chemoreceptor sensitivity in normals for both aspects.
3. Oxygen delivery preservation
blood flow x oxygen tension x haemoglobin
Secondary polycythaemia.
4. Vascular reactivity
Hypoxic vasoconstrictive response
5. Temporal adaptation
6. Respiratory proprioception
airway lumen pathology
elastic tissue loss
↓
↓
bronch. reactivity
↓airway support
↓
↓
ventilation maldistribution
↓
ventilation/blood flow imbalance
↑
loss of a-c units
↓
↓ ↑ventilation
↑
hypoxia
hypercapnia
polycythaemia vasoconstriction→remodelling
↑ pulmonary vascular resistance
↓
cor pulmonale
Balance between “compensation” and progression
Emphysema preserves V/Q imbalance longer than other pathologies
because of anatomical destruction of capillary bed in poorly
ventilated areas
But regional hypoxic vasoconstrictiojn will also preserve V/Q balance
Hypoxic subjects more likely to develop cor pulmonale because of
hypoxic vasoconstriction and increases in blood viscosity.
But, hypoxaemia may represent a failure of vasoconstriction and
hence a delay in elevation of pulmonary vascular resistance.
Pulmonary hypoxic vasoconstrictive response.
A response to alveolar hypoxia not hypoxaemia
Well recognised that this response varies in the normal population.
“Rule of thirds” (brisk, mild, absent)
High altitude dwellers
Acute mountain sickness
Normals studied at sea level.
Precise pathway still obscure
Is it blocked by Bosentan?
Some genetic basis?
V.Faoro et al.Chest 2009.135;1215-1222
Genetic associations with hypoxaemia and pulmonary arterial
pressure in COPD. Castaldi PJ et al. Chest 2009.135:737-44
389 subjects from National Emphysema Treatment Trial
(NETT) enrolled and further 139 subjects from the Boston Early-onset
COPD study subsequently studied. A1AT deficiency excluded.
Examined five candidate genes
EPHX1 –involved in metabolism of polycyclic hydrocarbons in tobacco
smoke
SERPINE2- on 2q, has been linked to FEV/VC%
SFTPB- involved in normal surfactant synthesis
GSTP1- binds electrophilic compounds to reduced glutathione
TGFB1- associated with experimental emphysema in animal models
Single nucleotide polymorphism examined and association analysis with
hypoxaemia,hypercarbia and pulmonary hypertension carried out.
Postulated that certain genetic polymorphisms would be associated
with these factors independent of severity of airflow obstruction.
Subjects with mean PASP >35mmHg,PaO2 <45mmHg, PaCO2>60
mmHg excluded.
Polymorphisms in EPHX1 and SERPINE2 contribute to the
development of hypoxaemia and polymorphisms in SFTPB contribute
to pulmonary hypertension.
Mixed pathologies of a lumper cohort
Since the pathway to hypoxaemia is complex and multifactorial, it is
unlikely that a single gene polymorphism is a major player.
A genetic factor in the hypoxic vasoconstrictive response remains an
intriguing probability.
Now possible to assess the extent of “compensatory factors” early
In the disease.
Study a cohort of middle aged smokers with early spirometric changes
Determine 1.methacholine reactivity
2.ventilatory response to hypercapnia and hypoxia
3.hypoxic vasoconstrictive response
4.presence of emphysematous changes
Predict likely phenotype over next 25 years.