Regulators of endothelial and epithelial barrier integrity and function in acute lung injury

doi:10.1016/j.bcp.2009.01.014

Biochemical Pharmacology

Volume 77, Issue 12, 15 June 2009, Pages 1763-1772

https://doi.org/10.1016/j.bcp.2009.01.014 Get rights and content

Abstract

Permeability edema is a life-threatening complication accompanying acute lung injury (ALI), severe pneumonia and the acute respiratory distress syndrome (ARDS), which can be associated with a reduced alveolar liquid clearance (ALC) capacity, a disruption of the alveolar epithelial barrier, and an increased capillary endothelial permeability. Bacterial and viral infections can directly promote pulmonary endothelial hyperpermeability and indirectly decrease the function and/or expression of ion transporters regulating ALC in type II alveolar epithelial cells, by means of inducing a strong inflammatory and oxidative stress response in the infected lungs. Apart from ventilation strategies, no standard treatment exists for permeability edema, making the search for novel regulators of endothelial and epithelial hyperpermeability and dysfunction important. Here, we present an overview of recently identified substances that inhibit and/or reverse endothelial barrier disruption and permeability or alveolar epithelial dysfunction: (1) zinc chelators, which were shown to attenuate the effects of oxidative stress on the pulmonary endothelium; (2) peroxisome proliferator activated receptor (PPAR) ligands, which have been shown to exert anti-inflammatory effects, by decreasing the expression of pro-inflammatory genes; (3) extracellular ATP, produced during inflammation, which induces a rapid and dose-dependent increase in transendothelial electrical resistance (TER) across pulmonary endothelial cells; (4) the lectin-like domain of TNF, which is spatially distinct from the receptor binding sites and which protects from hydrostatic and permeability edema and (5) Hsp90 inhibitors, which prevent and repair toxin-induced hyperpermeability. Unraveling the mechanism of action of these agents could contribute to the development of novel therapeutic strategies to combat permeability edema.

Graphical abstract

Introduction

Pulmonary permeability edema is a major complication of acute lung injury (ALI), severe pneumonia and ARDS. This pathology can be accompanied by (1) a reduction of alveolar liquid clearance capacity, caused by an inhibition of the expression of crucial sodium transporters, such as the epithelial sodium channel (ENaC) and the Na⁺-K⁺-ATPase, (2) an epithelial and endothelial hyperpermeability and (3) a disruption of the epithelial and endothelial barriers, caused by increased apoptosis or necrosis. Since, apart from ventilation strategies, no standard treatment exists for permeability edema, the following chapters will review a selection of novel approaches aiming to improve these parameters in the capillary endothelium and the alveolar epithelium.

Section snippets

Role of apoptotic pathways in the development of ALI/ARDS

Apoptosis is an essential physiological process for the selective elimination of cells. However, the dysregulation of apoptotic pathways is thought to play an important role in the pathogenesis of ALI. Both delayed neutrophil apoptosis and enhanced endothelial/epithelial cell apoptosis have been identified in ALI/ARDS. In the case of neutrophils, which contribute significantly to ALI/ARDS, studies in both animals and ARDS patients suggest that apoptosis is inhibited during the early stages (<2

Disruption of Zn²⁺ homeostasis in ALI/ARDS

Many physiological, nutritional, and biochemical functions have been attributed to Zn²⁺[9]. There is evidence that Zn²⁺ requirement of the vascular endothelium increase during inflammatory conditions, such as atherosclerosis, where apoptotic cell death is prevalent [9]. Further, zinc deficiency has been shown to increase the lung injury associated with hyperoxia [10], while the addition of exogenous Zn²⁺ can reduce the injury [11]. This has led to the suggestion that Zn²⁺ is a cytoprotective

Peroxisome proliferators activated receptor (PPAR) signaling in the lung

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily, that includes receptors for steroid hormones, thyroid hormones, retinoic acid, and fat-soluble vitamins. Since their discovery in 1990, increasing data has been published on the role of PPARs in diverse processes, including lipid and glucose metabolism, diabetes and obesity, atherosclerosis, cellular proliferation and differentiation, neurological

Anti-Inflammatory effects of PPAR signaling

A role for PPARs in the control of inflammation was first evidenced for PPARα, where mice deficient in PPARα exhibited an increased duration of ear-swelling in response to the pro-inflammatory mediator, LTB4 [17]. More recently, a number of studies in mice and in humans have shown that PPAR agonists exhibit anti-inflammatory effects under a wide range of conditions. There are two main mechanisms by which PPARs exert their anti-inflammatory effect. The first involves complex formation, and the

PPAR agonists and ALI

Recent studies have shown that PPAR signaling can attenuate the airway inflammation induced by LPS in the mouse. It was shown that mice treated with the PPARα agonist, fenofibrate, had decreases in both inflammatory cell infiltration and inflammatory mediators [19]. Conversely, PPARα^−/− mice have been shown to have a greater number of neutrophils and macrophages, and increased levels of inflammatory mediators in bronchoalveolar lavage fluids (BALF) [20]. Other PPAR agonists, such as

Regulation of endothelial permeability

Permeability edema is characterized by a reduced alveolar liquid clearance capacity, combined with an endothelial hyperpermeability. Various signaling pathways, such as those involving reactive oxygen species (ROS), Rho GTPases and tyrosine phosphorylation of junctional proteins, converge to regulate junctional permeability, either by affecting the stability of junctional proteins or by modulating their interactions [23]. The regulation of junctional permeability is mainly mediated by dynamic

Regulation of endothelial permeability by extracellular purines

Extracellular purines (adenosine, ADP, and ATP) function as intercellular signaling molecules when released to extracellular compartments from different sources in the body and subsequently reach the target organs. Extracellular ATP has been detected in most tissues, including the epithelium and endothelium and the smooth muscles. Normally, the level of extracellular ATP is low (1–10 nM), due to the activity of ectonucleotidases. However, under pathological conditions, like during vascular

Dichotomous activities of TNF during ALI

During the course of ALI, the alveolar space, as well as the interstitium, are sites of intense inflammation, leading to the local production of pro-inflammatory cytokines, such as IL-1β, TGF-β and TNF. The latter pleiotropic cytokine is a 51 kDa homotrimeric protein, binding to two types of receptors, i.e. TNF-R1 and TNF-R2 and which is mainly produced by activated macrophages and T cells. Soluble TNF, as well as the soluble TNF receptors 1 and 2, are generated upon cleavage of membrane TNF or

The lectin-like domain of TNF reduces pulmonary edema formation

In order to explain the apparently contradictory effects of TNF in models of pulmonary edema, as discussed in the previous paragraph, we propose that functionally distinct domains of the cytokine, i.e. the receptor binding sites versus the lectin-like domain, account for the cytokine's dichotomous activity during pulmonary edema [58]. Spatially distinct from its receptor binding sites, TNF carries a lectin-like domain, recognizing specific oligosaccharides, such as N,N′-diacetylchitobiose and

Anti-inflammatory and barrier-protective effects of hsp90 inhibitors

Inflammation is a causative factor in most major cardiovascular diseases, including acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS). Single-target anti-inflammatory agents (e.g. COX inhibitors) lack serious side effects but are void of broad-spectrum anti-inflammatory activity. Clearly, the availability of multi-targeted, strong anti-inflammatory agents with limited side effects would be of great significance in the prevention and management of

Conclusion

Permeability edema represents a life-threatening complication of acute lung injury, severe pneumonia and ARDS, characterized by a combined dysregulation of pulmonary epithelial and endothelial apoptosis, endothelial barrier integrity and alveolar liquid clearance capacity. As such, it is likely that several of these parameters have to be targeted in order to obtain a successful therapy. This review focuses on a selection of recently discovered substances and mechanisms that might improve ALI

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CommentaryRegulators of endothelial and epithelial barrier integrity and function in acute lung injury

Abstract

Graphical abstract

Introduction

Section snippets

Role of apoptotic pathways in the development of ALI/ARDS

Disruption of Zn2+ homeostasis in ALI/ARDS

Peroxisome proliferators activated receptor (PPAR) signaling in the lung

Anti-Inflammatory effects of PPAR signaling

PPAR agonists and ALI

Regulation of endothelial permeability

Regulation of endothelial permeability by extracellular purines

Dichotomous activities of TNF during ALI

The lectin-like domain of TNF reduces pulmonary edema formation

Anti-inflammatory and barrier-protective effects of hsp90 inhibitors

Conclusion

Am J Pathol

Toxicology

Free Radic Biol Med

Free Radic Biol Med

Hum Pathol

J Biol Chem

J Pharmacol Sci

Cancer Cell

Mol Cell

Biochem Biophys Res Commun

J Biol Chem

Trends Biochem Sci

J Biol Chem

Biochem Biophys Res Commun

Roles of iNOS and nNOS in sepsis-induced pulmonary apoptosis

Am J Physiol Lung Cell Mol Physiol

Overview of ventilator-induced lung injury mechanisms

Current opinion in critical care

Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, reduces acute lung injury in endotoxemic rats

Crit Care Med

Novel action of indoleamine 2,3-dioxygenase attenuating acute lung allograft injury

Am J Respir Crit Care Med

Alterations in zinc homeostasis underlie endothelial cell death induced by oxidative stress from acute exposure to hydrogen peroxide

Am J Physiol Lung Cell Mol Physiol

Endothelial response to stress from exogenous Zn2+ resembles that of NO-mediated nitrosative stress, and is protected by MT-1 overexpression

Am J Physiol Cell Physiol

Is zinc deficiency a risk factor for atherosclerosis?

Br J Nutr

Excessive zinc intake elevates systemic blood pressure levels in normotensive rats—potential role of superoxide-induced oxidative stress

J Hypertens

Pulmonary and systemic effects of zinc-containing emission particles in three rat strains: multiple exposure scenarios

Toxicol Sci

Zinc and inflammatory/immune response in aging

Ann N Y Acad Sci

Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth

Circ Res

The PPARalpha-leukotriene B4 pathway to inflammation control

Nature

PPAR gamma ligands, 15-deoxy-delta12,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms

Br J Pharmacol

PPARalpha downregulates airway inflammation induced by lipopolysaccharide in the mouse

Resp Res

Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces pulmonary inflammatory response in a rat model of endotoxemia

Inflamm Res

Peroxisome proliferator-activated receptor-g as a regulator of lung inflammation and repair

Proc Am Thoracic Soc

Regulation of endothelial junctional permeability

Ann N Y Acad Sci

The role of the microtubules in tumor necrosis factor-alpha-induced endothelial cell permeability

Am J Respir Cell Mol Biol

Increased release of ATP from endothelial cells during acute inflammation

Inflamm Res

Cell surface measurements of ATP release from single pancreatic beta cells using a novel biosensor technique

Pflugers Arch

Extracellular ATP signaling and P2X nucleotide receptors in monolayers of primary human vascular endothelial cells

Am J Physiol Cell Physiol

ATP-stimulated release of ATP by human endothelial cells

J Cardiovasc Pharmacol

Vascular endothelial and smooth muscle cells in culture selectively release adenine nucleotides

Nature

Purinergic axis in cardiac blood vessels. Agonist-mediated release of ATP from cardiac endothelial cells

Circ Res

Physiology and pathophysiology of purinergic neurotransmission

Physiol Rev

Commentary
Regulators of endothelial and epithelial barrier integrity and function in acute lung injury

Disruption of Zn²⁺ homeostasis in ALI/ARDS

ATP reduces macromolecule permeability of endothelial monolayers despite increasing [Ca²⁺]_i

Differential actions of cAMP on endothelial [Ca²⁺]_i and permeability in microvessels exposed to ATP