1. Phenotypic Determinants in Chronic airflow limitation M.C.F.Pain

2. 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.

3. 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.

6. 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

11. 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

12. 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.

13. 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?

14. V.Faoro et al.Chest 2009.135;1215-1222

15. 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.

16. Postulated that certain genetic polymorphisms would be associated with these factors independent of severity of airflow obstruction. Subjects with mean PASP >35mmHg,PaO2 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.

19. 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.