American journal of respiratory cell and molecular biology
-
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.
-
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.
-
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.