Research Topic

Multiscale Vascular and Ventricular Mechanics Associated with Pulmonary Vascular Disease and Lung Dysfunction

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Pulmonary diseases such as pulmonary hypertension (PH), acute respiratory distress syndrome (ARDS), and lung fibrosis are associated with high mortality rates. A common feature among these diseases is mechanical dysfunction at the molecular, cellular, and whole organ level but it is unknown how these altered ...

Pulmonary diseases such as pulmonary hypertension (PH), acute respiratory distress syndrome (ARDS), and lung fibrosis are associated with high mortality rates. A common feature among these diseases is mechanical dysfunction at the molecular, cellular, and whole organ level but it is unknown how these altered mechanical properties contribute to the development and progression of lung disease. Currently no therapeutic strategies specifically target mechanical stiffness in lung disease.

Pulmonary arterial compliance, a measure of global pulmonary vascular stiffness, is strongly associated with mortality in pulmonary arterial hypertension. In addition to decreased pulmonary arterial compliance, there is increased afterload on the right ventricle that leads to ventricular remodeling and changes in the mechanical stiffness of the ventricle. Increased pulmonary vascular vasoconstriction, remodeling and chronic thrombosis all contribute to increased pulmonary vascular stiffness. Investigations in the molecular mechanism of altered composition, amount and organization of the extracellular matrix (ECM) have identified the transforming growth factor-β (TGF-β) superfamily of receptors, bone morphogenetic protein receptor 2 [BMPR2], altered serotonin signaling dynamics, and inflammation as significant contributors to altered vascular stiffness. An upregulation of mechanosensitive calcium channels induced by mechanical stimuli contributes to enhanced concentrations of cytosolic Ca2+ in pulmonary arterial smooth muscle cells (PASMC) from idiopathic pulmonary arterial hypertension (IPAH) patients.

Lung injuries, including those induced during therapeutic treatment such as ventilator-induced lung injury (VILI), lead to cytoskeletal remodeling of endothelial cells, resulting in altered cellular stiffness. Cell stiffness is highly sensitive of structural rearrangements of cytoskeletal filaments. Most significantly, rearrangement of cytoskeletal filaments in endothelial cells also produces the paracellular gaps responsible for increased permeability of the lung endothelial barrier, a common pathophysiological mechanism in numerous lung disorders, including ARDS, PH and chronic obstructive pulmonary disease (COPD). A number of experimental techniques have proved to be particularly valuable in the measurement of important mechanical properties.

This Research Topic focuses on the pathophysiological mechanisms across multiple length-scales (whole organ down to the molecular level) that lead to mechanical dysfunction in lung diseases (pulmonary hypertension, acute lung injury, etc…) and ventricular dysfunction.


Keywords: Pulmonary Hypertension, Acute Lung Injury, endothelial barrier permeability, cellular and tissue stiffness, cellular viscoelasticity


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