In a recent stereotactic body radiation therapy animal model, radiation pneumonitis and radiation pulmonary fibrosis were observed at around 2 and 6 weeks, respectively. However, the molecular ...signature of this model remains unclear. This study aimed to examine the molecular characteristics at these two stages using RNA-seq analysis. Transcriptomic profiling revealed distinct transcriptional patterns for each stage. Inflammatory response and immune cell activation were involved in both stages. Cell cycle processes and response to type II interferons were observed during the inflammation stage. Extracellular matrix organization and immunoglobulin production were noted during the fibrosis stage. To investigate the impact of a 10 Gy difference on fibrosis progression, doses of 45, 55, and 65 Gy were tested. A dose of 65 Gy was selected and compared with 75 Gy. The 65 Gy dose induced inflammation and fibrosis as well as the 75 Gy dose, but with reduced lung damage, fewer inflammatory cells, and decreased collagen deposition, particularly during the inflammation stage. Transcriptomic analysis revealed significant overlap, but differences were observed and clarified in Gene Ontology and KEGG pathway analysis, potentially influenced by changes in interferon-gamma-mediated lipid metabolism. This suggests the suitability of 65 Gy for future preclinical basic and pharmaceutical research connected with radiation-induced lung injury.
Radiation-induced lung fibrosis (RILF) is a common complication of radiotherapy in lung cancer. However, to date no effective treatment has been developed for this condition. NXC736 is a novel ...small-molecule compound that inhibits NLRP3, but its effect on RILF is unknown. NLRP3 activation is an important trigger for the development of RILF. Thus, we aimed to evaluate the therapeutic effect of NXC736 on lung fibrosis inhibition using a RILF animal model and to elucidate its molecular signaling pathway. The left lungs of mice were irradiated with a single dose of 75 Gy. We observed that NXC736 treatment inhibited collagen deposition and inflammatory cell infiltration in irradiated mouse lung tissues. The damaged lung volume, evaluated by magnetic resonance imaging, was lower in NXC736-treated mice than in irradiated mice. NXC736-treated mice exhibited significant changes in lung function parameters. NXC736 inhibited inflammasome activation by interfering with the NLRP3-ASC-cleaved caspase-1 interaction, thereby reducing the expression of IL-1β and blocking the fibrotic pathway. In addition, NXC736 treatment reduced the expression of epithelial–mesenchymal transition markers such as α-SMA, vimentin, and twist by blocking the Smad 2,3,4 signaling pathway. These data suggested that NXC736 is a potent therapeutic agent against RILF.
Peroxiredoxins (Prxs) are a family of peroxidases that reduce hydroperoxides. The cysteine residue in the active site of certain eukaryotic Prx enzymes undergoes reversible oxidation to sulfinic acid ...(Cys-SO2H) during catalysis, and sulfiredoxin (Srx) has been identified as responsible for reversal of the resulting enzyme inactivation in yeast. We have now characterized mammalian orthologs of yeast Srx with an assay based on monitoring of the reduction of sulfinic Prx by immunoblot analysis with antibodies specific for the sulfinic state. Sulfinic reduction by mammalian Srx was found to be a slow process (kcat = 0.18/min) that requires ATP hydrolysis. ATP could be efficiently replaced by GTP, dATP, or dGTP but not by CTP, UTP, dCTP, or dTTP. Both glutathione and thioredoxin are potential physiological electron donors for the Srx reaction, given that their Km values (1.8 mm and 1.2 μm, respectively) are in the range of their intracellular concentrations, and the Vmax values obtained with the two reductants were similar. Although its pKa is relatively low (∼7.3), the active site cysteine of Srx remained reduced even when the active site cysteine of most Prx molecules became oxidized. Finally, depletion of human Srx by RNA interference suggested that Srx is largely responsible for reduction of the Cys-SO2H of Prx in A549 human cells.
Various proapoptotic stimuli increase the production of superoxide and H 2 O 2 by mitochondria. Whereas superoxide impairs mitochondrial function and is removed by Mn 2+ -dependent superoxide ...dismutase, the role and metabolism of mitochondrial H 2 O 2 during apoptosis have remained unclear. The effects on apoptotic signaling of depletion of peroxiredoxin (Prx) III, a mitochondrion-specific
H 2 O 2 -scavenging enzyme, have now been investigated by RNA interference in HeLa cells. Depletion of Prx III resulted in increased
intracellular levels of H 2 O 2 and sensitized cells to induction of apoptosis by staurosporine or TNF-α. The rates of mitochondrial membrane potential collapse,
cytochrome c release, and caspase activation were increased in Prx III-depleted cells, and these effects were reversed by ectopic expression
of Prx III or mitochondrion-targeted catalase. Depletion of Prx III also exacerbated damage to mitochondrial macromolecules
induced by the proapoptotic stimuli. Our results suggest that Prx III is a critical regulator of the abundance of mitochondrial
H 2 O 2 , which itself promotes apoptosis in cooperation with other mediators of apoptotic signaling.
Recruitment and activation of dendritic cells (DCs) in the lungs are critical for Th2 responses in asthma, and CCL20 secreted from bronchial epithelial cells (BECs) is known to influence the ...recruitment of DCs. Because asthma is a disease that is closely associated with oxidative stress, we hypothesized that clusterin, an oxidative stress regulatory molecule, may have a role in the development of allergic airway inflammation. The aim of this study was to examine whether clusterin regulates CCL20 production from the BECs and the subsequent DC recruitment in the lungs. To verify the idea, clusterin knockout (Clu(-/-)), clusterin heterogeneous (Clu(+/-)), and wild-type mice were exposed intranasally to house dust mite (HDM) extract to induce allergic airway inflammation. We found that the total number of immune cells in bronchoalveolar lavage fluid and the lung was increased in Clu(-/-) and Clu(+/-) mice. Of these immune cells, inflammatory DCs (CD11b(+)CD11c(+)) and Ly6C(high) monocyte populations in the lung were significantly increased, which was accompanied by increased levels of various chemokines, including CCL20 in bronchoalveolar lavage fluid, and increased oxidative stress markers in the lung. Moreover, HDM-stimulated human BECs with either up- or downregulated clusterin expression showed that CCL20 secretion was negatively associated with clusterin expression. Interestingly, clusterin also reduced the level of intracellular reactive oxygen species, which is related to induction of CCL20 expression after HDM stimulation. Thus, the antioxidant property of clusterin is suggested to regulate the expression of CCL20 in BECs and the subsequent recruitment of inflammatory DCs in the airway.
Since the 1990s, state governments in the United States have diversified policy instruments to encourage the electric power industry to deploy renewable sources for electricity generation. This study ...identifies the trends and variations in renewable energy (RE) policy governance among states and examines the effectiveness of policy instruments in the deployment of RE sources for electricity production. This study explores 18 state legislative, RE‐related regulations, programs, or financial incentives existing between 2001 and 2010 in 48 states in the United States. Renewable energy policies were classified into three types of policy approaches: command‐and‐control, market‐based, and information instruments. Results suggest that authoritative approaches are more likely to be effective in the governmental intervention toward a pre‐existing market, and information instruments and citizen participation became important in the power industry in the 2000s. In addition, it gives us some evidence that federal assistance under the American Recovery and Reinvestment Act of 2009 influenced the overall growth of the renewable electricity industry, in addition to state government–led policy designs.
ABSTRACT
Background and objective
Emphysema is characterized by irreversible destruction of alveolar walls with distal air space enlargement. Cigarette smoke (CS) is considered a major risk factor ...for emphysematous changes in COPD. Progranulin (PGRN), a glycoprotein induced by CS, has been reported to participate in apoptosis. However, the precise role of PGRN in emphysema is currently unknown. This study aimed to evaluate the role of PGRN in human alveolar epithelial cells (AECs) in response to CS.
Methods
First, PGRN expression was assessed in a mouse model of CS‐induced emphysema and in AECs after exposure to CS extract (CSE). Then, the effect of PGRN on CSE‐mediated apoptosis was determined under PGRN silencing or overexpressing conditions. To investigate the functional mechanism of PGRN, endoplasmic reticulum (ER) stress markers and the mitogen‐activated protein kinase (MAPK) pathway were also evaluated in the CSE‐exposed cells. Finally, PGRN expression levels in sera and peripheral blood mononuclear cells (PBMCs) were measured and compared between patients with COPD and healthy subjects.
Results
Our results revealed that PGRN expression was elevated in CS‐exposed mouse lungs and CSE‐treated AECs. CSE‐induced cellular apoptosis was significantly increased in PGRN‐knockdown AECs and decreased in PGRN‐overexpression cells. The activation of ER stress‐associated molecules correlated with PGRN expression levels. Compared with healthy controls, COPD patients exhibited significantly lower PGRN serum levels and higher PBMC intracellular PGRN levels.
Conclusion
PGRN in airway epithelial cells may regulate CS‐induced AEC apoptosis and may be involved in the development of COPD.
In a previous study, it was shown that progranulin (PGRN) inhibits apoptosis. However, the precise role of PGRN and whether it attenuates apoptosis in alveolar epithelial cells (AECs) has not been clarified. Here, we demonstrate that PGRN protects AECs from apoptosis induced by cigarette smoke.
Progranulin, a protein secreted from the airway epithelium, is known to attenuate the downstream cascade of neutrophilic inflammation in particular. We hypothesized that progranulin may have a role ...in inflammatory regulation in asthma.
To investigate the association between serum progranulin levels and various clinical features in patients with asthma.
Serum samples and clinical data of 475 patients with asthma and 35 healthy controls at a tertiary referral hospital and its affiliated health promotion center were collected. Serum progranulin levels were compared between patients with asthma and healthy controls and then were compared within the patients with asthma in terms of pulmonary function and measures of inflammatory status. Univariate and multivariate analyses were performed to identify factors associated with severity of asthma.
Serum progranulin levels were significantly lower in the asthma group than in healthy group and were positively correlated with prebronchodilator forced expiratory volume in 1 second predicted within patients with asthma. We found a negative correlation between serum progranulin levels and blood neutrophil counts. Multivariate analysis revealed that higher serum progranulin levels were associated with a lower risk of severe asthma (odds ratio, 0.888; 95% confidence interval, 0.846-0.932; P < .001) after adjustment for other variables, such as age, sex, smoking status, blood neutrophil count, and current use of systemic corticosteroids.
Although the exact mechanism of the anti-inflammatory action of progranulin remains unknown, we suggest that serum progranulin may be an indicator of severe asthma with airflow limitation. Future studies with comprehensive airway sampling strategies are warranted to clarify its role, particularly in neutrophilic asthma.
With the institutionalization of reducing emissions from deforestation and forest degradation, and the role of conservation, sustainable management of forests, and enhancement of forest carbon stocks ...in developing countries (REDD+), the global REDD+ financial network has been formed to support the implementation of REDD+ in developing countries. Although the rapid expansion of the network made it decentralized, it is still a highly centralized network in terms of the distribution of financial resources, revolving around only a few major actors. While the source of financing was diversified due to an increase in influential donors, the majority of financing still came from a few constant major donors, and a few constant major developing countries received most of the financial support. Although increases in donor numbers and the amount of finance received can provide more chances to support developing countries, it may cause inefficiency due to overlaps and duplications. Also, over-centralization of financial resources can be ineffective in terms of achieving maximum greenhouse gas (GHG) reduction, and can broaden gaps between developing countries’ ability to cope with climate change and deforestation. Lack of coordination among donors and the differing capacity of developing countries may have caused centralization of financial resources in the global REDD+ financial network. To minimize this problem, a comprehensive monitoring system and platforms for information sharing are needed.
•Solid waste management presents a policy venue of “green economic development.”•There is a 0.4% SWMR employment growth upon a 1% point recycling rate increase.•Presence of strong environmental ...groups influences SWMR employment growth.•Labor force and unemployment rate result in scrap materials business growth.•Popular tourist destinations attract more recycling processing jobs in Florida.
Recycling solid waste not only produces environmental and health benefits, but also generates economic benefit. This paper empirically evaluates the employment impact of Florida county recycling programs from 2000 through 2011, applying a fixed effects regression model. The results indicate that a one percentage point increase of county recycling rate leads to a 0.4% job growth in overall solid waste and recycling industry. However, the impact of recycling programs on green jobs are not uniform across the recycling subsectors: the effect is concentrated in the recycling processing sector while the solid waste collection sector and scrap materials businesses are unlikely to be influenced by county’s recycling performance.
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