Review
Molecular mechanisms in lipopolysaccharide-induced pulmonary endothelial barrier dysfunction

https://doi.org/10.1016/j.intimp.2015.10.010Get rights and content

Highlights

  • Pulmonary endothelial barrier dysfunction is involved in a variety of high mortality diseases.

  • MLCK, RhoA, calcium, tyrosine kinases, apoptosis are major barrier-disruptive factors.

  • Rac1, Cdc42, S1P, cAMP, ARs, PAR1, FoxM1 are major barrier-protective factors.

Abstract

The confluent pulmonary endothelium plays an important role as a semi-permeable barrier between the vascular space of blood vessels and the underlying tissues, and it contributes to the maintenance of circulatory fluid homeostasis. Pulmonary endothelial barrier dysfunction is a pivotal early step in the development of a variety of high mortality diseases, such as acute lung injury (ALI). Endothelium barrier dysfunction in response to inflammatory or infectious mediators, including lipopolysaccharide (LPS), is accompanied by invertible cell deformation and interendothelial gap formation. However, specific pharmacological therapies aiming at ameliorating pulmonary endothelial barrier function in patients are still lacking. A full understanding of the fundamental mechanisms that are involved in the regulation of pulmonary endothelial permeability is essential for the development of barrier protective therapeutic strategies. Therefore, this review summarizes several important molecular mechanisms involved in LPS-induced changes in pulmonary endothelial barrier function. As for barrier-disruption, the activation of myosin light chain kinase (MLCK), RhoA and tyrosine kinases; increase of calcium influx; and apoptosis of the endothelium lead to an elevation of lung endothelial permeability. Additionally, the activation of Rac1, Cdc42, protease activated receptor 1 (PAR1) and adenosine receptors (ARs), as well as the increase of cyclic AMP and sphingosine-1-phosphate (S1P) content, protect against LPS-induced lung endothelial barrier dysfunction. Furthermore, current regulatory factors and strategies against the development of LPS-induced lung endothelial hyper-permeability are discussed.

Introduction

Acute lung injury (ALI) is a clinical syndrome characterized by impairment in gas exchange and/or lung mechanics that causes hypoxemia and increased work to breathe [1]. Lung injuries caused by inflammatory mediators can lead to pathophysiological syndromes such as ALI and severe pneumonia. Despite recent therapeutic advances, these conditions still have high (30–40%) rates of patient mortality [2], [3], [4]. Dysfunction of the endothelial barrier results in increased permeability, protein-rich fluid extravasation and lung edema, which is a common feature of ALI and acute respiratory distress syndrome (ARDS; a more severe form of ALI) [5].

Among the endogenous and exogenous agents that cause endothelial barrier dysfunction, lipopolysaccharide (LPS, endotoxin) is widely studied [6]. The majority of studies are focusing on pulmonary endothelial permeability use with LPS to stimulate the dysfunction. It comprises the majority of the outer wall of Gram-negative bacteria, binds to Toll-like receptor 4 (TLR4) and activates a variety of signaling pathways [7], [8]. In addition, it activates macrophages, neutrophils, dendritic cells and other cell types that induce inflammation, oxidative stress and endothelial damage [9]. Exposure to LPS leads to endothelial barrier dysfunction and increased endothelial permeability.

For patients with ALI or ARDS, mechanical ventilation is a necessary and life-saving treatment but may also delay the inflammatory response and further enhance pulmonary endothelial barrier dysfunction. Specific pharmacological therapies that aim to improve pulmonary endothelial barrier function in patients with severe lung edema are absent [10]. Developing therapies that protect the integrity of the barrier and stabilize the gas exchange is a real matter of concern.

The knowledge of the mechanisms of pulmonary endothelial barrier dysfunction has greatly increased; the vast amount of new information has not yet been well summarized. Elucidating how pulmonary endothelial barrier permeability changes, is vital for researchers to understand the mechanisms of action. Importantly, no single mechanism explains all endothelial hyper-permeability. The selective control of barrier dysfunction requires either the inhibition of factors that increase endothelial permeability or the interference with intracellular activation mechanisms in endothelial cells leading to vascular hyper-permeability. Therefore, we attempted to provide an overview of recent insights into the molecular mechanisms in LPS-induced pulmonary endothelial barrier dysfunction. With this expectation, new insights in the mechanisms underlying hyper-permeability could offer potential novel targets and strategies for pharmacological intervention.

Section snippets

Pulmonary endothelial barrier

The inner walls of pulmonary microvessels are covered with a confluent endothelial cell (EC) monolayer. This delicate monolayer ensures effective and rapid gas exchange between alveolar and vascular lumens [7], [10]. An important physiological function of this vascular barrier is to minimize the leakage of plasma proteins and blood cells into the pulmonary interstitium and prevent life-threatening alveolar flooding at normal vascular pressures [11]. Stability of the barrier is highly dependent

Pulmonary endothelial barrier-disruptive mechanisms

Different mechanisms involved in LPS-induced pulmonary barrier dysfunction lead to diverse effects on endothelial cells. As shown in Fig. 1, the increase in EC cytoskeleton contraction, disruption of EC junctions and decrease in the number of EC are the main three causes of LPS-induced barrier disruption.

Pulmonary endothelial barrier-protective mechanisms

As shown in the Fig. 2, under LPS challenged models, the increase in cortex actin, inhibition of inflammatory signaling pathways and increase in number of EC are the main three ways for barrier enhancing mechanisms and mediators to protect the endothelial barrier.

Summary

Currently, the amount of studies analyzing molecular mechanisms of LPS-induced pulmonary endothelial barrier dysfunction is rather limited and offers only fragmented knowledge, which limits pharmacological approaches for its management.

In this review, we emphasized the role of several major molecular mechanisms in regulating LPS-induced pulmonary endothelial barrier dysfunction. In general, the activation of MLCK and RhoA (and consequent activation of ROCK), increase in Src phosphorylation,

Acknowledgments

The present research was supported by the National Natural Science Foundation of China (No. 81274131), 2011' Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education, a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors declared no disclosures.

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