American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Jan 2019
Identification of a Novel Inhibitor of Human Rhinovirus Replication and Inflammation in Airway Epithelial Cells.
Human rhinovirus (RV), the major cause of the common cold, triggers the majority of acute airway exacerbations in patients with asthma and chronic obstructive pulmonary disease. Nitric oxide, and the related metabolite S-nitrosoglutathione, are produced in the airway epithelium via nitric oxide synthase (NOS) 2 and have been shown to function in host defense against RV infection. We hypothesized that inhibitors of the S-nitrosoglutathione-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), might potentiate the antiviral properties of airway-derived NOS2. ⋯ Moreover, a structurally dissimilar GSNOR inhibitor (N6022) did not alter RV replication, suggesting that the properties of C3m may be specific to rhinovirus owing to an off-target effect. Consistent with this, C3m antiviral effects were not blocked by either NOS inhibition or GSNOR knockdown but appeared to be mediated by reduced intercellular adhesion molecule 1 transcription and increased shedding of soluble intercellular adhesion molecule 1 protein. Collectively these data show that C3m has novel antirhinoviral properties that may synergize with, but are unrelated to, its GSNOR inhibitor activity.
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Am. J. Respir. Cell Mol. Biol. · Dec 2018
Chronic Cigarette Smoke Exposure Subdues PP2A Activity by Enhancing Expression of the Oncogene CIP2A.
Phosphatase activity of the major serine threonine phosphatase, protein phosphatase 2A (PP2A), is blunted in the airways of individuals with chronic obstructive pulmonary disease (COPD), which results in heightened inflammation and proteolytic responses. The objective of this study was to investigate how PP2A activity is modulated in COPD airways. PP2A activity and endogenous inhibitors of PP2A were investigated in animal and cell models of COPD. ⋯ Enhanced epithelial growth factor receptor responses in cells from subjects with COPD were observed to modulate CIP2A expression levels. Our study indicates that chronic cigarette smoke induction of epithelial growth factor receptor signaling and CIP2A expression can impair PP2A responses that are associated with loss of lung function and enhancement of proteolytic responses. Augmenting PP2A activity by manipulating CIP2A expression may represent a feasible therapeutic approach to counter smoke-induced lung disease.
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Am. J. Respir. Cell Mol. Biol. · Dec 2018
Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells.
Human rhinovirus (RV) infections are a significant risk factor for exacerbations of asthma and chronic obstructive pulmonary disease. Thus, approaches to prevent RV infection in such patients would give significant benefit. Through RNA interference library screening, we identified lanosterol synthase (LSS), a component of the cholesterol biosynthetic pathway, as a novel regulator of RV replication in primary normal human bronchial epithelial cells. ⋯ We also demonstrated that LSS inhibition led to a profound increase in expression of the innate antiviral defense protein, IFN-β. We found LSS to be a novel regulator of RV replication and innate antiviral immunity and identified a potential molecular mechanism for this effect, via induction of 24(S),25 epoxycholesterol. Inhibition of LSS could therefore be a novel therapeutic target for prevention of RV-induced exacerbations.
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Am. J. Respir. Cell Mol. Biol. · Dec 2018
EditorialAlveolar Micromechanics in Bleomycin-induced Lung Injury.
Lung injury results in intratidal alveolar recruitment and derecruitment and alveolar collapse, creating stress concentrators that increase strain and aggravate injury. In this work, we sought to describe alveolar micromechanics during mechanical ventilation in bleomycin-induced lung injury and surfactant replacement therapy. Structure and function were assessed in rats 1 day and 3 days after intratracheal bleomycin instillation and after surfactant replacement therapy. ⋯ However, the simulations also predicted a dramatic increase in alveolar strain with injury that we attribute to alveolar interdependence. These findings suggest that in progressive lung injury, alveolar collapse with increased distension of patent (open) alveoli dominates alveolar micromechanics. PEEP and surfactant substitution reduce alveolar collapse and dynamic strain but increase static strain.
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Am. J. Respir. Cell Mol. Biol. · Nov 2018
Whole-Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease.
Genome-wide association studies have identified common variants associated with chronic obstructive pulmonary disease (COPD). Whole-genome sequencing (WGS) offers comprehensive coverage of the entire genome, as compared with genotyping arrays or exome sequencing. We hypothesized that WGS in subjects with severe COPD and smoking control subjects with normal pulmonary function would allow us to identify novel genetic determinants of COPD. ⋯ With WGS, we identified more than 20 million new variants, not seen with imputation, including more than 10,000 of potential importance in previously identified COPD genome-wide association study regions. WGS in severe COPD identifies a large number of potentially important functional variants, with the strongest associations being in known COPD risk loci, including HHIP and SERPINA1. Larger sample sizes will be needed to identify associated variants in novel regions of the genome.