Chronic obstructive pulmonary disease (COPD) is a non-communicable chronic disease that is top-ranking with respect to mortality and morbidity rates, posing an enormous burden on patients, caregivers ...and societies at large ....
Oxidative stress in an important hallmark of asthma and much research has therefore focused on the predominant antioxidant in the lungs, namely the tripeptide glutathione.
In lung samples of patients ...with asthma increased levels of glutathione are typically observed, which appear to relate to the level of pulmonary inflammation and are therefore regarded as an adaptive response to the associated oxidative stress. Also in blood samples increased total GSH levels have been reported, representing the systemic inflammatory component of the disease. In addition, a number of the antioxidant enzymes involved in the maintenance of the GSH/GSSG ratio as well as enzymes that utilize GSH have been found to be altered in the lungs and blood of asthmatics and will be summarized in this review. Very few studies have however linked enzymatic alterations to GSH levels or found that either of these correlated with disease severity. Some animal studies have started to investigate the pathophysiological role of GSH biochemistry in asthma and have yielded surprising results. Important in this respect is the physiological role of the GSH redox equilibrium in determining the outcome of immune responses, which could be deregulated in asthmatics and contribute to the disease.
Clinical data as well as animal and cell culture studies regarding these aspects of GSH in the context of asthma will be summarized and discussed in this review. This article is part of a Special Issue entitled: Biochemistry of Asthma.
►Glutathione levels are increased in lungs and blood of patients with asthma. ►This can be seen as part of the adaptive response to oxidative stress. ►Most enzymes involved in maintaining reduced glutathione are altered. ►However, glutathione and enzyme levels are rarely examined in conjunction. ►Interesting new studies on the influence of glutathione redox homeostasis on immune responses.
Age-related, non-communicable chronic inflammatory diseases represent the major 21st century health problem. Especially in Western countries, the prevalence of non-communicable diseases like chronic ...obstructive pulmonary disease, cardiovascular disease, type 2 diabetes and osteoporosis are exponentially rising as the population ages. These diseases are determined by common risk factors and share an age-related onset. The affected organs display evidence of accelerated ageing, and are hallmarked by chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) has been implicated in a number of inflammatory diseases and plays a central role in amplifying inflammatory responses. Advanced glycation end product (AGE) formation and accumulation is accelerated under these conditions. Advanced glycation end products are not only linked to RAGE signaling and inflammation, but to various hallmarks of the ageing process. In addition to these biological functions, circulating levels of the soluble form of RAGE and of advanced glycation end products are candidate biomarkers for many age-related inflammatory diseases. The purpose of this review is to provide an overview of the mechanistic connections between RAGE and advanced glycation end products and the processes of inflammation and ageing. Furthermore, through the presented overview of AGE-RAGE alterations that have been described in clinical studies in chronic obstructive pulmonary disease, cardiovascular disease, type 2 diabetes and osteoporosis, and insight obtained from mechanistic in vitro and animal studies, it can be concluded that these AGE-RAGE disturbances are a common contributing factor to the inflammatory state and pathogenesis of these various conditions.
Asthma is a chronic disorder characterized by inflammation, mucus metaplasia, airway remodeling, and hyperresponsiveness. We recently showed that IL-1-induced glycolytic reprogramming contributes to ...allergic airway disease using a murine house dust mite model. Moreover, levels of pyruvate kinase M2 (PKM2) were increased in this model as well as in nasal epithelial cells from asthmatics as compared with healthy controls. Although the tetramer form of PKM2 converts phosphoenolpyruvate to pyruvate, the dimeric form of PKM2 has alternative, nonglycolysis functions as a transcriptional coactivator to enhance the transcription of several proinflammatory cytokines. In the current study, we examined the impact of PKM2 on the pathogenesis of house dust mite-induced allergic airways disease in C57BL/6NJ mice. We report, in this study, that activation of PKM2, using the small molecule activator, TEPP46, augmented PKM activity in lung tissues and attenuated airway eosinophils, mucus metaplasia, and subepithelial collagen. TEPP46 attenuated IL-1β-mediated airway inflammation and expression of proinflammatory mediators. Exposure to TEPP46 strongly decreased the IL-1β-mediated increases in thymic stromal lymphopoietin (TSLP) and GM-CSF in primary tracheal epithelial cells isolated from C57BL/6NJ mice. We also demonstrate that IL-1β-mediated increases in nuclear phospho-STAT3 were decreased by TEPP46. Finally, STAT3 inhibition attenuated the IL-1β-induced release of TSLP and GM-CSF, suggesting that the ability of PKM2 to phosphorylate STAT3 contributes to its proinflammatory function. Collectively, these results demonstrate that the glycolysis-inactive form of PKM2 plays a crucial role in the pathogenesis of allergic airways disease by increasing IL-1β-induced proinflammatory signaling, in part, through phosphorylation of STAT3.
In myeloid cells the inflammasome plays a crucial role in innate immune defenses against pathogen- and danger-associated patterns such as crystalline silica. Respirable mineral particles impinge upon ...the lung epithelium causing irreversible damage, sustained inflammation and silicosis. In this study we investigated lung epithelial cells as a target for silica-induced inflammasome activation.
A human bronchial epithelial cell line (BEAS-2B) and primary normal human bronchial epithelial cells (NHBE) were exposed to toxic but nonlethal doses of crystalline silica over time to perform functional characterization of NLRP3, caspase-1, IL-1β, bFGF and HMGB1. Quantitative RT-PCR, caspase-1 enzyme activity assay, Western blot techniques, cytokine-specific ELISA and fibroblast (MRC-5 cells) proliferation assays were performed.
We were able to show transcriptional and translational upregulation of the components of the NLRP3 intracellular platform, as well as activation of caspase-1. NLRP3 activation led to maturation of pro-IL-1β to secreted IL-1β, and a significant increase in the unconventional release of the alarmins bFGF and HMGB1. Moreover, release of bFGF and HMGB1 was shown to be dependent on particle uptake. Small interfering RNA experiments using siNLRP3 revealed the pivotal role of the inflammasome in diminished release of pro-inflammatory cytokines, danger molecules and growth factors, and fibroblast proliferation.
Our novel data indicate the presence and functional activation of the NLRP3 inflammasome by crystalline silica in human lung epithelial cells, which prolongs an inflammatory signal and affects fibroblast proliferation, mediating a cadre of lung diseases.
The airway epithelium plays a critical role in innate responses to airborne allergens by secreting IL-1 family cytokines such as IL-1α and IL-33 as alarmins that subsequently orchestrate appropriate ...immune responses. Previous studies revealed that epithelial IL-33 secretion by allergens such as
or house dust mite involves Ca
-dependent signaling, via initial activation of ATP-stimulated P2YR2 (type 2 purinoceptor) and subsequent activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase DUOX1. We sought to identify proximal mechanisms by which epithelial cells sense these allergens and here highlight the importance of PAR2 (protease-activated receptor 2) and TRP (transient receptor potential) Ca
channels such as TRPV1 (TRP vanilloid 1) in these responses. Combined studies of primary human nasal and mouse tracheal epithelial cells, as well as immortalized human bronchial epithelial cells, indicated the importance of both PAR2 and TRPV1 in IL-33 secretion by both
and house dust mite, based on both pharmacological and genetic approaches. TRPV1 was also critically involved in allergen-induced ATP release, activation of DUOX1, and redox-dependent activation of EGFR (epidermal growth factor receptor). Moreover, genetic deletion of TRPV1 dramatically attenuated allergen-induced IL-33 secretion and subsequent type 2 responses in mice
. TRPV1 not only contributed to ATP release and P2YR2 signaling but also was critical in downstream innate responses to ATP, indicating potentiating effects of P2YR2 on TRPV1 activation. In aggregate, our studies illustrate a complex relationship between various receptor types, including PAR2 and P2YR2, in epithelial responses to asthma-relevant airborne allergens and highlight the central importance of TRPV1 in such responses.
The transcription factor NF-κB, a central regulator of immunity, is subject to regulation by redox changes. We now report that cysteine-179 of the inhibitory κB kinase (IKK) β-subunit of the IKK ...signalosome is a central target for oxidative inactivation by means of S-glutathionylation. S-glutathionylation of IKK-β Cys-179 is reversed by glutaredoxin (GRX), which restores kinase activity. Conversely, GRX1 knockdown sensitizes cells to oxidative inactivation of IKK-β and dampens TNF-α-induced IKK and NF-κB activation. Primary tracheal epithelial cells from Glrx1-deficient mice display reduced NF-κB DNA binding, RelA nuclear translocation, and MIP-2 (macrophage inflammatory protein 2) and keratinocytederived chemokine production in response to LPS. Collectively, these findings demonstrate the physiological relevance of the S-glutathionylation-GRX redox module in controlling the magnitude of activation of the NF-κB pathway.
The prenatal and perinatal environments can have profound effects on the development of chronic inflammatory diseases. However, mechanistic insight into how the early-life microenvironment can impact ...upon development of the lung and immune system and consequent initiation and progression of respiratory diseases is still emerging. Recent studies investigating the developmental origins of lung diseases have started to delineate the effects of early-life changes in the lung, environmental exposures and immune maturation on the development of childhood and adult lung diseases. While the influencing factors have been described and studied in mostly animal models, it remains challenging to pinpoint exactly which factors and at which time point are detrimental in lung development leading to respiratory disease later in life. To advance our understanding of early origins of chronic lung disease and to allow for proper dissemination and application of this knowledge, we propose four major focus areas: 1) policy and education; 2) clinical assessment; 3) basic and translational research; and 4) infrastructure and tools, and discuss future directions for advancement. This review is a follow-up of the discussions at the European Respiratory Society Research Seminar “Early origins of lung disease: towards an interdisciplinary approach” (Lisbon, Portugal, November 2019).
The Translational Science Working Group at the European Respiratory Society (ERS) aims to bridge the gap between basic and clinical science by providing a platform where scientists, clinicians and ...experts in the respiratory field can actively shape translational research. For the 2023 Congress, dedicated translational science sessions were created and sessions of interest to many assemblies from the clinical and the scientific point of view were tagged as translational sessions, attracting clinical and scientific experts to the same room to discuss relevant topics and strengthening translational efforts among all ERS assemblies.
PDF
