Novel mechanism of cyclic nucleotide crosstalk mediated by PKG-dependent proteasomal degradation of the Hsp90 client protein phosphodiesterase 3A.

Endothelial cAMP-specific phosphodiesterase PDE3A is one of the major negative regulators of the endothelial barrier function in acute lung injury models. However, the mechanisms underlying its regulation still need to be fully resolved. We show here that the PDE3A is a newly described client of the molecular chaperone heat shock protein 90 (hsp90).

The Pulmonary Endothelial Glycocalyx Modifications in Glypican 1 Knockout Mice Do Not Affect Lung Endothelial Function in Physiological Conditions.

The endothelial glycocalyx is a dynamic signaling surface layer that is involved in the maintenance of cellular homeostasis. The glycocalyx has a very diverse composition, with glycoproteins, proteoglycans, and glycosaminoglycans interacting with each other to form a mesh-like structure. Due to its highly interactive nature, little is known about the relative contribution of each glycocalyx constituent to its overall function.

Nitration-mediated activation of the small GTPase RhoA stimulates cellular glycolysis through enhanced mitochondrial fission.

Mitochondrial fission and a Warburg phenotype of increased cellular glycolysis are involved in the pathogenesis of pulmonary hypertension (PH). The purpose of this study was to determine whether increases in mitochondrial fission are involved in a glycolytic switch in pulmonary arterial endothelial cells (PAECs). Mitochondrial fission is increased in PAEC isolated from a sheep model of PH induced by pulmonary overcirculation (Shunt PAEC).

Loss of SOX18/CLAUDIN5 disrupts the pulmonary endothelial barrier in ventilator-induced lung injury.

Mechanical strain contributes to ventilator-induced lung injury (VILI) through multi-factorial and complex mechanisms that remain unresolved. Prevailing evidence suggests that the loss of pulmonary endothelial tight junctions (TJs) plays a critical role. TJs are dynamically regulated by physiologic and hemodynamic forces to stabilize the endothelial barrier.

NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury.

In acute lung injury (ALI), the NF-κB-mediated downregulation of Sox18 gene expression leads to the disruption of the pulmonary endothelial barrier. Previous studies have suggested that the action of NF-κB as a transcriptional repressor also requires the action of class I histone deacetylases (HDACs). Thus, the purpose of this study was to investigate and further delineate the mechanism of Sox18 repression during lipopolysaccharide (LPS) induced ALI.

Solitary pulses and periodic wave trains in a bistable FitzHugh-Nagumo model with cross diffusion and cross advection.

We describe analytically, and simulate numerically, traveling waves with oscillatory tails in a bistable, piecewise-linear reaction-diffusion-advection system of the FitzHugh-Nagumo type with linear cross-diffusion and cross-advection terms of opposite signs. We explore the dynamics of two wave types, namely, solitary pulses and their infinite sequences, i.e.

Nitration of protein kinase G-Iα modulates cyclic nucleotide crosstalk via phosphodiesterase 3A: Implications for acute lung injury.

Phosphodiesterase 3A (PDE3A) selectively cleaves the phosphodiester bond of cAMP and is inhibited by cGMP, making it an important regulator of cAMP-cGMP signaling crosstalk in the pulmonary vasculature. In addition, the nitric oxide-cGMP axis is known to play an important role in maintaining endothelial barrier function. However, the potential role of protein kinase G-Iα (PKG-Iα) in this protective process is unresolved and was the focus of our study.

Nonlinear waves in a quintic FitzHugh-Nagumo model with cross diffusion: Fronts, pulses, and wave trains.

We study a tristable piecewise-linear reaction-diffusion system, which approximates a quintic FitzHugh-Nagumo model, with linear cross-diffusion terms of opposite signs. Basic nonlinear waves with oscillatory tails, namely, fronts, pulses, and wave trains, are described. The analytical construction of these waves is based on the results for the bistable case [Zemskov et al.

The mitochondrial redistribution of eNOS is involved in lipopolysaccharide induced inflammasome activation during acute lung injury.

Acute lung injury (ALI) is a devastating clinical syndrome with no effective therapies. Inflammasome activation has been reported to play a critical role in the initiation and progression of ALI. The molecular mechanisms involved in regulating the activation of inflammasome in ALI remains unresolved, although increases in mitochondrial derived reactive oxygen species (mito-ROS) are involved.

Activation of the mechanosensitive Ca channel TRPV4 induces endothelial barrier permeability via the disruption of mitochondrial bioenergetics.

Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS), a refractory lung disease with an unacceptable high mortality rate. Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The specific mechanisms involved in VILI-induced pulmonary capillary leakage, a key pathologic feature of VILI are still far from resolved.

Complex interplay between autophagy and oxidative stress in the development of pulmonary disease.

The autophagic pathway involves the encapsulation of substrates in double-membraned vesicles, which are subsequently delivered to the lysosome for enzymatic degradation and recycling of metabolic precursors. Autophagy is a major cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins.

Oscillatory multipulsons: Dissipative soliton trains in bistable reaction-diffusion systems with cross diffusion of attractive-repulsive type.

One-dimensional localized sequences of bound (coupled) traveling pulses, wave trains with a finite number of pulses, are described in a piecewise-linear reaction-diffusion system of the FitzHugh-Nagumo type with linear cross-diffusion terms of opposite signs. The simplest case of two bound pulses, the paired-pulse waves (pulse pairs), is solved analytically. The solutions contain oscillatory tails in the wave profiles so that the pulse pairs consist of a double-peak core and wavy edges.

Multifront regime of a piecewise-linear FitzHugh-Nagumo model with cross diffusion.

Oscillatory reaction-diffusion fronts are described analytically in a piecewise-linear approximation of the FitzHugh-Nagumo equations with linear cross-diffusion terms, which correspond to a pursuit-evasion situation. Fundamental dynamical regimes of front propagation into a stable and into an unstable state are studied, and the shape of the waves for both regimes is explored in detail. We find that oscillations in the wave profile may either be negligible due to rapid attenuation or noticeable if the damping is slow or vanishes.

Biomechanical Forces and Oxidative Stress: Implications for Pulmonary Vascular Disease.

Oxidative stress in the cell is characterized by excessive generation of reactive oxygen species (ROS). Superoxide (O) and hydrogen peroxide (HO) are the main ROS involved in the regulation of cellular metabolism. As our fundamental understanding of the underlying causes of lung disease has increased it has become evident that oxidative stress plays a critical role.

Oscillatory pulse-front waves in a reaction-diffusion system with cross diffusion.

We explore traveling waves with oscillatory tails in a bistable piecewise linear reaction-diffusion system of the FitzHugh-Nagumo type with linear cross diffusion. These waves differ fundamentally from the standard simple fronts of the kink type. In contrast to kinks, the waves studied here have a complex shape profile with a front-back-front (a pulse-front) pattern.

Hemolysis-induced Lung Vascular Leakage Contributes to the Development of Pulmonary Hypertension.

Although hemolytic anemia-associated pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are more common than the prevalence of idiopathic PAH alone, the role of hemolysis in the development of PAH is poorly characterized. We hypothesized that hemolysis independently contributes to PAH pathogenesis via endothelial barrier dysfunction with resulting perivascular edema and inflammation. Plasma samples from patients with and without PAH (both confirmed by right heart catheterization) were used to measure free hemoglobin (Hb) and its correlation with PAH severity.

LPS-induced Acute Lung Injury Involves NF-κB-mediated Downregulation of SOX18.

One of the early events in the progression of LPS-mediated acute lung injury in mice is the disruption of the pulmonary endothelial barrier resulting in lung edema. However, the molecular mechanisms by which the endothelial barrier becomes compromised remain unresolved. The SRY (sex-determining region on the Y chromosome)-related high-mobility group box (Sox) group F family member, SOX18, is a barrier-protective protein through its ability to increase the expression of the tight junction protein CLDN5.

ROS Signaling in the Pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS).

The generation of reactive oxygen species (ROS) plays an important role for the maintenance of cellular processes and functions in the body. However, the excessive generation of oxygen radicals under pathological conditions such as acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) leads to increased endothelial permeability. Within this hallmark of ALI and ARDS, vascular microvessels lose their junctional integrity and show increased myosin contractions that promote the migration of polymorphonuclear leukocytes (PMNs) and the transition of solutes and fluids in the alveolar lumen.

Oscillatory pulses and wave trains in a bistable reaction-diffusion system with cross diffusion.

We study waves with exponentially decaying oscillatory tails in a reaction-diffusion system with linear cross diffusion. To be specific, we consider a piecewise linear approximation of the FitzHugh-Nagumo model, also known as the Bonhoeffer-van der Pol model. We focus on two types of traveling waves, namely solitary pulses that correspond to a homoclinic solution, and sequences of pulses or wave trains, i.

Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets.

Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The pathobiology of VILI and ARDS shares many inflammatory features including increases in lung vascular permeability due to loss of endothelial cell barrier integrity resulting in alveolar flooding.

Hyper-activation of pp60 limits nitric oxide signaling by increasing asymmetric dimethylarginine levels during acute lung injury.

The molecular mechanisms by which the endothelial barrier becomes compromised during lipopolysaccharide (LPS) mediated acute lung injury (ALI) are still unresolved. We have previously reported that the disruption of the endothelial barrier is due, at least in part, to the uncoupling of endothelial nitric oxide synthase (eNOS) and increased peroxynitrite-mediated nitration of RhoA. The purpose of this study was to elucidate the molecular mechanisms by which LPS induces eNOS uncoupling during ALI.

Diffusive instabilities in hyperbolic reaction-diffusion equations.

We investigate two-variable reaction-diffusion systems of the hyperbolic type. A linear stability analysis is performed, and the conditions for diffusion-driven instabilities are derived. Two basic types of eigenvalues, real and complex, are described.

Wavy fronts in a hyperbolic FitzHugh-Nagumo system and the effects of cross diffusion.

We study a hyperbolic version of the FitzHugh-Nagumo (also known as the Bonhoeffer-van der Pol) reaction-diffusion system. To be able to obtain analytical results, we employ a piecewise linear approximation of the nonlinear kinetic term. The hyperbolic version is compared with the standard parabolic FitzHugh-Nagumo system.

Wave reflection in a reaction-diffusion system: breathing patterns and attenuation of the echo.

Formation and interaction of the one-dimensional excitation waves in a reaction-diffusion system with the piecewise linear reaction functions of the Tonnelier-Gerstner type are studied. We show that there exists a parameter region where the established regime of wave propagation depends on initial conditions. Wave phenomena with a complex behavior are found: (i) the reflection of waves at a growing distance (the remote reflection) upon their collision with each other or with no-flux boundaries and (ii) the periodic transformation of waves with the jumping from one regime of wave propagation to another (the periodic trigger wave).

Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner.

Acute lung injury and acute respiratory distress syndrome are accompanied by thrombin activation and fibrin deposition that enhance lung inflammation, activate endothelial cells and disrupt lung paracellular permeability. Heparin possesses anti-inflammatory properties but its clinical use is limited by hemorrhage and heparin induced thrombocytopenia. We studied the effects of heparin and low anticoagulant 2-O, 3-O desulfated heparin (ODSH) on thrombin-induced increases in paracellular permeability of cultured human pulmonary endothelial cells (ECs).