Phenotypic Determinants inChronic 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 potentialfor reversibility

Obstructive bronchitis- airway remodelling with no reversiblecomponent

Emphysema –irreversible breakdown of pulmonary elastictissue.

Differences in compensatory mechanisms within normal subjectsTranslated to patients

Interplay of these factors possibly determines the clinical presentationand 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 themaintenance of adequate gas exchange

CO2 balance designed to keep pCO2 about 40mmHg.O2 little function in normals but rugged in adverse hypoxic

situationsA 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 pathologiesbecause of anatomical destruction of capillary bed in poorlyventilated areas

But regional hypoxic vasoconstrictiojn will also preserve V/Q balance

Hypoxic subjects more likely to develop cor pulmonale because ofhypoxic 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 dwellersAcute mountain sicknessNormals 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 arterialpressure 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 smokeSERPINE2- on 2q, has been linked to FEV/VC%SFTPB- involved in normal surfactant synthesisGSTP1- binds electrophilic compounds to reduced glutathioneTGFB1- associated with experimental emphysema in animal modelsSingle nucleotide polymorphism examined and association analysis with hypoxaemia,hypercarbia and pulmonary hypertension carried out.

Postulated that certain genetic polymorphisms would be associatedwith 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 cohortSince 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” earlyIn 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.