The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders.

Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders

STAT3 regulates the onset of oxidant-induced senescence in lung fibroblasts

Copyright © 2019 by the American Thoracic Society. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause with a median survival of only 3 years. Other investigators and we have shown that fibroblasts derived from IPF lungs display characteristics of senescent cells, and that dysregulated activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) correlates with IPF progression. The question of whether STAT3 activation is involved in fibroblast senescence remains unanswered. We hypothesized that inhibiting STAT3 activation after oxidantinduced senescence would attenuate characteristics of the senescent phenotype. We aimed to characterize a model of oxidant-induced senescence in human lung fibroblasts and to determine the effect of inhibiting STAT3 activity on the development of senescence. Exposing human lung fibroblasts to 150 μM hydrogen peroxide (H2O2) resulted in increased senescence-associated β-galactosidase content and expression of p21 and IL-6, all of which are features of senescence. The shift into senescence was accompanied by an increase of STAT3 translocation to the nucleus and mitochondria. Additionally, Seahorse analysis provided evidence of increased mitochondrial respiration characterized by increased basal respiration, proton leak, and an associated increase in superoxide (O2-) production in senescent fibroblasts. Targeting STAT3 activity using the small-molecule inhibitor STA-21 attenuated IL-6 production, reduced p21 levels, decreased senescence-associated b-galactosidase accumulation, and restored normalmitochondrial function. The results of this study illustrate that stress-induced senescence in lung fibroblasts involves the activation of STAT3, which can be pharmacologically modulated

Spacetime Noncommutativity and Antisymmetric Tensor Dynamics in the Early Universe

This paper investigates the possible cosmological implications of the presence of an antisymmetric tensor field related to a lack of commutatitivity of spacetime coordinates at the Planck era. For this purpose, such a field is promoted to a dynamical variable, inspired by tensor formalism. By working to quadratic order in the antisymmetric tensor, we study the field equations in a Bianchi I universe in two models: an antisymmetric tensor plus scalar field coupled to gravity, or a cosmological constant and a free massless antisymmetric tensor. In the first scenario, numerical integration shows that, in the very early universe, the effects of the antisymmetric tensor can prevail on the scalar field, while at late times the former approaches zero and the latter drives the isotropization of the universe. In the second model, an approximate solution is obtained of a nonlinear ordinary differential equation which shows how the mean Hubble parameter and the difference between longitudinal and orthogonal Hubble parameter evolve in the early universe.Comment: 25 pages, Revtex file, 4 figures in attachmen

Stochastic Inflation:The Quantum Phase Space Approach

In this paper a quantum mechanical phase space picture is constructed for coarse-grained free quantum fields in an inflationary Universe. The appropriate stochastic quantum Liouville equation is derived. Explicit solutions for the phase space quantum distribution function are found for the cases of power law and exponential expansions. The expectation values of dynamical variables with respect to these solutions are compared to the corresponding cutoff regularized field theoretic results (we do not restrict ourselves only to \VEV{\F^2}). Fair agreement is found provided the coarse-graining scale is kept within certain limits. By focusing on the full phase space distribution function rather than a reduced distribution it is shown that the thermodynamic interpretation of the stochastic formalism faces several difficulties (e.g., there is no fluctuation-dissipation theorem). The coarse-graining does not guarantee an automatic classical limit as quantum correlations turn out to be crucial in order to get results consistent with standard quantum field theory. Therefore, the method does {\em not} by itself constitute an explanation of the quantum to classical transition in the early Universe. In particular, we argue that the stochastic equations do not lead to decoherence.Comment: 43 page

Vacuum fluctuations and topological Casimir effect in Friedmann-Robertson-Walker cosmologies with compact dimensions

We investigate the Wightman function, the vacuum expectation values of the field squared and the energy-momentum tensor for a massless scalar field with general curvature coupling parameter in spatially flat Friedmann-Robertson-Walker universes with an arbitrary number of toroidally compactified dimensions. The topological parts in the expectation values are explicitly extracted and in this way the renormalization is reduced to that for the model with trivial topology. In the limit when the comoving lengths of the compact dimensions are very short compared to the Hubble length, the topological parts coincide with those for a conformal coupling and they are related to the corresponding quantities in the flat spacetime by standard conformal transformation. In the opposite limit of large comoving lengths of the compact dimensions, in dependence of the curvature coupling parameter, two regimes are realized with monotonic or oscillatory behavior of the vacuum expectation values. In the monotonic regime and for nonconformally and nonminimally coupled fields the vacuum stresses are isotropic and the equation of state for the topological parts in the energy density and pressures is of barotropic type. In the oscillatory regime, the amplitude of the oscillations for the topological part in the expectation value of the field squared can be either decreasing or increasing with time, whereas for the energy-momentum tensor the oscillations are damping.Comment: 20 pages, 2 figure

Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1−/−) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect

Inflation and Preheating in NO models

We study inflationary models in which the effective potential of the inflaton field does not have a minimum, but rather gradually decreases at large $\phi$. In such models the inflaton field does not oscillate after inflation, and its effective mass becomes vanishingly small, so the standard theory of reheating based on the decay of the oscillating inflaton field does not apply. For a long time the only mechanism of reheating in such non-oscillatory (NO) models was based on gravitational particle production in an expanding universe. This mechanism is very inefficient. We will show that it may lead to cosmological problems associated with large isocurvature fluctuations and overproduction of dangerous relics such as gravitinos and moduli fields. We also note that the setting of initial conditions for the stage of reheating in these models should be reconsidered. All of these problems can be resolved in the context of the recently proposed scenario of instant preheating if there exists an interaction ${g^2} \phi^2\chi^2$ of the inflaton field $\phi$ with another scalar field $\chi$. We show that the mechanism of instant preheating in NO models is much more efficient than the usual mechanism of gravitational particle production even if the coupling constant $g^2$ is extremely small, $10^{-14} \ll g^2 \ll 1$.Comment: 10 pages, revte

On exact solutions for quantum particles with spin S= 0, 1/2, 1 and de Sitter event horizon

Exact wave solutions for particles with spin 0, 1/2 and 1 in the static coordinates of the de Sitter space-time model are examined in detail. Firstly, for a scalar particle, two pairs of linearly independent solutions are specified explicitly: running and standing waves. A known algorithm for calculation of the reflection coefficient $R_{\epsilon j}$ on the background of the de Sitter space-time model is analyzed. It is shown that the determination of R_{\epsilon j} requires an additional constrain on quantum numbers \epsilon \rho / \hbar c >> j, where \rho is a curvature radius. When taken into account of this condition, the R_{\epsilon j} vanishes identically. It is claimed that the calculation of the reflection coefficient R_{\epsilon j} is not required at all because there is no barrier in an effective potential curve on the background of the de Sitter space-time. The same conclusion holds for arbitrary particles with higher spins, it is demonstrated explicitly with the help of exact solutions for electromagnetic and Dirac fields.Comment: 30 pages. This paper is an updated and more comprehensive version of the old paper V.M. Red'kov. On Particle penetrating through de Sitter horizon. Minsk (1991) 22 pages Deposited in VINITI 30.09.91, 3842 - B9