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.

Keywords: Sphingosine-1-phosphate; TRP channels; ceramide; cystic fibrosis transmembrane conductance regulator; endothelial barrier; prostaglandin; pulmonary microvessels; transcytosis.

Figure 1. Regulated albumin transcytosis

Thrombin stimulation of lung microvascular endothelial cells activates acid sphingomyelinase (ASM) which hydrolyses sphingomyelin from the outer leaflet of the plasma membrane into ceramide. Caveolin‐1 is recruited into ceramide‐rich lipid domains resulting in increased formation and/or budding of caveolae, and enhanced transendothelial albumin transport.

Figure 2. Sphingolipids and their contrasting effects on lung barrier integrity

While ceramide promotes the disruption of intercellular interactions and oedema formation, S1P and LPA stabilize the endothelial barrier function.

Figure 3. Schematic representation of ion channels expressed in lung endothelial cells and their respective signalling that regulates the endothelial barrier

AA, arachidonic acid; ADPR, adenosine diphosphate ribose; ASM, acid sphingomyelinase; CFTR, cystic fibrosis transmembrane conductance regulator; DAG, diacylglycerol; EET, epoxyeicosatrienoic acid; MLCK, myosin light chain kinase; NA, nicotinamide; NAD⁺, nicotinamide adenine dinucleotide; NKCC1, Na⁺–K⁺–2Cl⁻ cotransporter; PAF, platelet activating factor; PAF‐R, PAF receptor; PLCγ, phospholipase C γ; PARP‐1, poly(ADP‐ribose)‐polymerase 1; TRPC6, transient receptor protein canonical 6; TRPM2, transient receptor protein melastatin 2; TRPV4, transient receptor protein vanilloid 4; PLA, phospholipase A; ROS, reactive oxygen species; S1P, sphingosine 1‐phosphate.

Figure 4. Receptor–agonist interactions and potential therapeutic implications for the improvement of endothelial barrier integrity

Physiological prostaglandins PGE₂, PGA₂ and PGI₂ and angiopoietin‐1 as well as synthetic agonists OxPAPC, ILO, ILO‐PC and vasculotide increase endothelial barrier integrity. MSCs produce and secrete both Ang‐1 and PGE₂, but also release barrier promoting miRNA by EVs. Ang, angiopoietin; EP4, prostaglandin receptor 4; ILO, iloprost; ILO‐PC, phosphatidyl choline attached to iloprost; IP, prostacyclin receptor; miRNA, micro RNA; MSC, mesenchymal stem cell; MSC‐EV, mesenchymal stem cell‐derived extracellular vesicles; OxPAPC, oxidized 1‐palmitoyl‐2‐arachidonoyl‐sn‐glycero‐3‐phosphorylcholine; PGA₂, prostaglandin A₂; PGE₂, prostaglandin E₂; PGI₂, prostaglandin I₂/prostacyclin; Tie‐2, angiopoietin receptor‐2.