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.