Injured lung endothelium: mechanisms of self-repair and agonist-assisted recovery (2017 Grover Conference Series)

Abstract

The lung endothelium is vulnerable to both exogenous and endogenous insults, so a properly coordinated efficient repair system is essential for the timely recovery of the lung after injury. The agents that cause endothelial injury and dysfunction fall into a broad range from mechanical forces such as pathological cyclic stretch and shear stress to bacterial pathogens and their virulent components, vasoactive agonists including thrombin and histamine, metabolic causes including high glucose and oxidized low-density lipoprotein (OxLDL), circulating microparticles, and inflammatory cytokines. The repair mechanisms employed by endothelial cells (EC) can be broadly categorized into three groups: (1) intrinsic mechanism of recovery regulated by the cross-talk between small GTPases as exemplified by Rap1-mediated EC barrier recovery from Rho-mediated thrombin-induced EC hyperpermeability; (2) agonist-assisted recovery facilitated by the activation of Rac and Rap1 with subsequent inhibition of Rho signaling as observed with many barrier protective agonists including oxidized phospholipids, sphingosine 1-phosphate, prostacyclins, and hepatocyte growth factor; and (3) self-recovery of EC by the secretion of growth factors and other pro-survival bioactive compounds including anti-inflammatory molecules such as lipoxins during the resolution of inflammation. In this review, we will discuss the molecular and cellular mechanisms of pulmonary endothelium repair that is critical for the recovery from various forms of lung injuries.

Keywords: barrier recovery and repair; endothelial cells; growth factors; lung injury; small GTPases.

Fig. 1.

Mechanism of EC barrier auto-recovery after thrombin challenge. In parallel with rapid activation of the Rho pathway leading to increased EC permeability, thrombin causes activation of Src kinase, which stimulates the Rap1-specific GEF C3G and, via Rap1-Tiam1, turns on the Rac1 signaling. Activation of the Rap1–Rac1 signaling axis downregulates the Rho pathway of barrier disruption and promotes reassembly of AJ complexes and endothelial monolayer barrier restoration.

Fig. 2.

Summary of signaling mechanisms activated by barrier-protective oxidized phospholipids.

Fig. 3.

Balance of EC-disruptive and EC-protective mechanisms in the course of lung injury and resolution phase. Lung injurious factors (bacterial pathogens, excessive mechanical stretch, cytokines, disruptive bioactive molecules) trigger pathologic signaling (i.e. oxidative stress, RhoA pathway, signaling kinases, secreted factors) leading to endothelial hyperpermeability, inflammation, and lung dysfunction. However, pathologic stimuli also activate mechanisms of auto-recovery such as secretion of pro-survival growth factors and anti-inflammatory lipid mediators which suppress inflammation, downregulate pro-inflammatory and disruptive RhoA GTPase-mediated pathways, and stimulate Rap1 and Rac1 GTPase-mediated cytoskeletal remodeling leading to EC barrier recovery.