Vascular permeability in the fibrotic lung

Abstract

Idiopathic pulmonary fibrosis (IPF) is thought to result from aberrant tissue repair processes in response to chronic or repetitive lung injury. The origin and nature of the injury, as well as its cellular and molecular targets, are likely heterogeneous, which complicates accurate pre-clinical modelling of the disease and makes therapeutic targeting a challenge. Efforts are underway to identify central pathways in fibrogenesis which may allow targeting of aberrant repair processes regardless of the initial injury stimulus. Dysregulated endothelial permeability and vascular leak have long been studied for their role in acute lung injury and repair. Evidence that these processes are of importance to the pathogenesis of fibrotic lung disease is growing. Endothelial permeability is increased in non-fibrosing lung diseases, but it resolves in a self-limited fashion in conditions such as bacterial pneumonia and acute respiratory distress syndrome. In progressive fibrosing diseases such as IPF, permeability appears to persist, however, and may also predict mortality. In this hypothesis-generating review, we summarise available data on the role of endothelial permeability in IPF and focus on the deleterious consequences of sustained endothelial hyperpermeability in response to and during pulmonary inflammation and fibrosis. We propose that persistent permeability and vascular leak in the lung have the potential to establish and amplify the pro-fibrotic environment. Therapeutic interventions aimed at recognising and "plugging" the leak may therefore be of significant benefit for preventing the transition from lung injury to fibrosis and should be areas for future research.

FIGURE 1

Integration of dysregulated vascular permeability into the paradigm of idiopathic pulmonary fibrosis (IPF) pathogenesis. Fibrosis is believed to develop as an aberrant response to repetitive tissue injury, which appears to primarily target alveolar epithelial cells (AECs) and the adjacent endothelium. Upon AEC injury, the adjacent endothelium becomes activated in response to inflammatory stimuli and increases its permeability as part of the normal repair response. With ongoing injury and increased vascular leak, abnormal angiogenesis is seen in addition to extravascular coagulation, provisional matrix deposition and vascular and airway remodelling as part of the fibrotic process.

FIGURE 2

Cytoskeletal regulation of endothelial barrier function within an endothelial cell (EC). Under inflammatory conditions, mediators such as the bioactive lipid LPA, thrombin, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)β, angiotensin 1 and 2, and multiple cytokines including interleukin (IL)-8 and IL-10 are increased. These ligands interact with EC surface receptors to induce changes in the cellular cytoskeleton. One of the effects of injury on the EC are increased contractile forces generated via the formation of actin stress fibres, predominate and lead to paracellular gap formation and loss of barrier integrity.