Fig. 1

Endothelial events leading to lung IRI. Reperfusion can increase fluid shear stress and activate mechanosensitive Piezo1 channels at the cell membrane. Piezo1 channels are a crucial Ca²⁺ entry pathway in endothelial cells. IR also increases extracellular ATP levels in the lung via Panx1 channels. Extracellular ATP can activate purinergic receptors, further increasing cytosolic Ca²⁺ levels. ATP activation of purinergic P2Y2 receptors (P2Y2R) leads to increased activity of TRPV4 channels, another mechanically activated Ca²⁺ entry pathway on endothelial cell membrane. FFA transporter CD36 elevates cytosolic FFA levels, in turn increasing Ca²⁺ influx and ROS production and triggering a cytokine storm. These pro-inflammatory intracellular signaling events dismantle intercellular junctions and promote neutrophil infiltration, increased capillary fluid extravasation, and lung edema formation. Glycocalyx masks the endothelial surface adhesion molecules (ICAM, VCAM, P- and L-selectin) and has a protective effect against IR-mediated deleterious events. Integrins at the cell surface are also involved in increased vascular permeability after IR. IEL, internal elastic lamina; FFA, Free fatty acid; CD36, Cluster of differentiation 36