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Title: The pulmonary endothelium contributes to inflammation in chronic heart failure : the role of mechanical strain and bone morphogenetic protein-9
Author: Park, John E. S.
ISNI:       0000 0004 2710 3253
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Chronic heart failure (CHF) is a debilitating condition with a poor prognosis. Remodelling of the alveolar capillary membrane (ACM) protects against pulmonary oedema, but also results in dyspnoea and a worsened prognosis. Systemic inflammation associated with CHF contributes to the pathophysiology and mortality of the syndrome. Monocyte chemoattractant protein (MCP)-1, a CC chemokine, is elevated in patients with CHF and associated with increased mortality. Also, deficiencies in the bone morphogentic protein receptor (BMPR) signalling contribute to the pathophysiology of vascular remodelling in pulmonary arterial hypertension (PAH), and similar changes are seen in CHF. The mechanisms underlying lung remodelling and inflammation in CHF are not known. This thesis investigated the contribution of the pulmonary endothelium to inflammation and ACM remodelling in CHF. We hypothesised that pulmonary venous hypertension (PVH) in CHF imparts mechanical strain at the ACM stimulating the release of mediators, contributing to lung remodelling. To model PVH cyclic mechanical strain (CMS) was applied to monolayers of human lung microvascular endothelial cells (HLMVEC) and to an endothelial cell line (EaHy 926). MCP-1 was identified as a stretch-induced inflammatory mediator whose induction was dependent on activation of the extracellular signal-related kinase (ERK 1/2) pathway. Supernatants from stretched compared to non-stretched cells increased fibroblast and pulmonary smooth muscle cell proliferation, and fibroblast differentiation. Bone morphogenetic protein (BMP)-9 stimulated pulmonary arterial endothelial cells to release endothelin-1 (ET-1) in a Smad-independent, p38MAPK-dependent, manner. In a rodent heart failure model, animals subjected to left coronary artery ligation had increased levels of MCP-1 in whole lung, serum and bronchoalveolar lavage. Animals treated with gene therapy (SERCA2a) demonstrated functional rescue with attenuated release of MCP-1 and ET-1. These data support a role for pulmonary ECs in inflammation and remodelling in CHF. Increased understanding of lung remodelling may lead to improved management of dyspnoea for CHF sufferers.
Supervisor: Griffiths, Mark ; Wort, John Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral