Pulmonary Endothelial Mechanical Sensing and Signaling, a Story of Focal Adhesions and Integrins in Ventilator Induced Lung Injury

Abstract

Patients with critical illness such as acute lung injury often undergo mechanical ventilation in the intensive care unit. Though lifesaving in many instances, mechanical ventilation often results in ventilator induced lung injury (VILI), characterized by overdistension of lung tissue leading to release of edemagenic agents, which further damage the lung and contribute to the mortality and progression of pulmonary inflammation. The endothelium is particularly sensitive, as VILI associated mechanical stress results in endothelial cytoskeletal rearrangement, stress fiber formation, and integrity loss. At the heart of these changes are integrin tethered focal adhesions (FAs) which participate in mechanosensing, structure, and signaling. Here, we present the known roles of FA proteins including c-Src, talin, FAK, paxillin, vinculin, and integrins in the sensing and response to cyclic stretch and VILI associated stress. Attention is given to how stretch is propagated from the extracellular matrix through integrins to talin and other FA proteins, as well as signaling cascades that include FA proteins, leading to stress fiber formation and other cellular responses. This unifying picture of FAs aids our understanding in an effort to prevent and treat VILI.

Keywords: ARDS; VILI; cyclic stretch; focal adhesion; integrin β4; mechanical stress.

FIGURE 1

Endothelial focal adhesion in cyclic stretch. Integrins, heterodimers consisting of α and β subunits, serve as the key physical link between FAs and the ECM. During VILI, mechanical stress (cyclic stretch) causes calcium release from intracellular stores and c-Src activation via dephosphorylation. It then localizes to patches along the cytoskeleton and FAs where it targets and phosphorylates FA proteins including integrin β, paxillin, and FAK. Phosphorylated and activated FAK facilitates the formation of stress fibers. Talin is an adaptor protein essential for integrin connection to the cytoskeleton. In its activated form, talin dimers are bound to actin and likely assume a Y-shape with exposed vinculin binding sites. Vinculin is a cytosolic actin-binding protein that exists in a circular configuration localized close to integrins and binds paxillin. Upon activation, vinculin assumes an extended form and moves further toward actin fibers. Paxillin, another adaptor FA protein activated by c-Src mediated phosphorylation following stretch, allows for protein networking and signal transduction. Zyxin, a LIM protein, resides at unstretched FAs but dissociates and moves away from FAs and toward stress fibers during stretch. -P, phosphorylated.

FIGURE 2

Integrin pairing. Integrins are heterodimeric cell-surface receptors for ECM proteins. Each heterodimer consists of an α and a β subunit. The eighteen α integrins and eight β integrins are shown with lines connecting pairs that are able to heterodimerize with each other. They are also clustered by their major ligand. Integrins that can enter endothelial focal adhesions are outlined in red.