Novel mechanisms regulating endothelial barrier function in the pulmonary microcirculation

Abstract

The pulmonary epithelial and vascular endothelial cell layers provide two sequential physical and immunological barriers that together form a semi-permeable interface and prevent alveolar and interstitial oedema formation. In this review, we focus specifically on the continuous endothelium of the pulmonary microvascular bed that warrants strict control of the exchange of gases, fluid, solutes and circulating cells between the plasma and the interstitial space. The present review provides an overview of emerging molecular mechanisms that permit constant transcellular exchange between the vascular and interstitial compartment, and cause, prevent or reverse lung endothelial barrier failure under experimental conditions, yet with a clinical perspective. Based on recent findings and at times seemingly conflicting results we discuss emerging paradigms of permeability regulation by altered ion transport as well as shifts in the homeostasis of sphingolipids, angiopoietins and prostaglandins.

TRPV4 channels are essential for alveolar epithelial barrier function as protection from lung edema

“…As TRPV4 is highly expressed in lung endothelium, and its activation results in an increase of endothelial permeability (reviewed in ref. 38 ), we focused on its possible functions in the epithelium. Epithelial cells represent the second natural barrier regulating edema formation.…”

“…Activation of TRPV4 in endothelial cells by mechanical stress, for example, stretching ( 27 , 28 , 43 ), as well as oxidative stress by exposure to H 2 O 2 ( 44 ) resulted in an increased Ca 2+ influx mediated by the channel and an increase in endothelial permeability conducive to lung edema (reviewed in ref. 38 ). Along these lines, pharmacological blockade of TRPV4, for example, by the specific blocker HC-067047, decreased intracellular Ca 2+ levels in endothelial cells and protected mice from vascular leakage and lung injury ( 28 ).…”

“…However, as outlined above, endothelial permeability is also increased by TRPV4 activation (summarized in ref. 38 ). Along these lines, we analyzed I/R-induced edema formation in a TRPV4-deficient (TRPV4 –/– ) mouse model.…”

The role of CD36 in endothelial albumin transcytosis

“…The process is initiated by endocytosis on one side of the cell (e.g., luminal or apical), followed by vesicular traffic and subsequent exocytosis on the opposite side (e.g., abluminal or basolateral) in a uni-or bidirectional manner. Generally, the initial endocytic step may be receptor-mediated and thus substrate-specific and clathrin-or caveolae-driven depending on the cell type, or it may be nonspecific in case of macropinocytosis (9,12,14). One of the molecules that have been extensively studied as a cargo in the context of transcytosis is albumin.…”

Overview: pulmonary vascular function in health and disease

“…In this issue, Simmons et al . () describe recent advances in uncovering the molecular mechanisms that cause, or promote recovery from, pulmonary endothelial barrier disruption and highlight promising targets for clinical trials.…”