S58 MECHANICAL STIMULATION OF HUMAN LUNG MICROVASCULAR ENDOTHELIAL CELLS CAUSES REMODELLING OF THE ALVEOLAR-CAPILLARY MEMBRANE AND DYSPNOEA IN CHRONIC HEART FAILURE

¹JES Park, ²AR Lyon, ²SE Harding, ¹MJD Griffiths. ¹Unit of Critical Care, NHLI, Imperial College, London, UK, ²Department of Cardiac Medicine, NHLI, Imperial College, London, UK

Introduction: Dyspnoea is a common and debilitating symptom of chronic heart failure (CHF). Patients with CHF have reduced pulmonary microvascular permeability and gas transfer that persists after effective treatment of pulmonary oedema, suggesting a structural abnormality of the alveolar-capillary membrane (ACM). Structural remodelling of the lungs in CHF is characterised by proliferation of myofibroblasts with excess matrix deposition in alveolar septae. Endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, binding endothelin A receptor and endothelin B receptor on human fibroblasts stimulates collagen 1 synthesis. The plasma ET-1 concentration in CHF correlates with the degree of haemodynamic disturbance, dyspnoea and mortality. We propose that in CHF, pulmonary venous hypertension and resultant mechanical strain on the pulmonary microvasculature stimulates the release by endothelial cells of “fibrogenic” mediators including ET-1. This process contributes to ACM remodelling and dyspnoea in patients.

Methods: The expression of message for components of the ET-1 pathway was investigated in strained (static mechanical strain 20% elongation for 4 h, Flexercell 4000) monolayers of human lung microvascular endothelial cells (HLMVEC; Lonza, UK) and in whole lungs of rats with or without heart failure 16 weeks after myocardial infarction (MI) or a sham procedure.¹ Supernatants from HLMVEC strained in the presence phosphoramidon (0–5 mmol), an endothelial converting enzyme inhibitor were added to serum starved human fetal lung fibroblasts (HFL-1) to assess cellular proliferation (CyQUANT assay).

Results: Expression of ppET-1 by HLMVEC increased after SMS and in whole lungs of rats after MI, with a decrease in endothelin B receptor message also seen in lungs post-MI (fig). Supernatants from HLMVEC stretched in the absence but not in the presence of …