American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Jun 2014
Prevention of ventilator-induced lung edema by inhalation of nanoparticles releasing ruthenium red.
The acute respiratory distress syndrome (ARDS), a devastating lung disease that has no cure, is exacerbated by life-supportive mechanical ventilation that worsens lung edema and inflammation through the syndrome of ventilator-induced lung injury. Recently, the membrane ion channel transient receptor potential vanilloid 4 (TRPV4) on alveolar macrophages was shown to mediate murine lung vascular permeability induced by high-pressure mechanical ventilation. The objective of this study was to determine whether inhalation of nanoparticles (NPs) containing the TRPV4 inhibitor ruthenium red (RR) prevents ventilator-induced lung edema in mice. ⋯ Poly-lactic-co-glycolic acid NPs (300 nm) released RR for 150 hours in vitro, and blocked TRPV4-mediated calcium signaling in cells up to 7 days after phagocytosis. Inhaled NPs deposited in alveoli of spontaneously breathing mice were rapidly phagocytosed by alveolar macrophages, and blocked increased vascular permeability from high-pressure mechanical ventilation for 72 hours in ex vivo ventilation perfusion experiments. These data offer proof of principle that inhalation of NPs containing a TRPV4 inhibitor prevents ventilator damage for several days, and imply that this novel drug delivery strategy could be used to target alveolar macrophages in patients at risk of ventilator-induced lung injury before initiating mechanical ventilation.
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Am. J. Respir. Cell Mol. Biol. · Jun 2014
Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension.
Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic of pulmonary arterial hypertension (PAH). Although a phenotypic switch in pulmonary endothelial cells (ECs) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal of this study was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. ⋯ Moreover, we identified breast cancer 1 (BRCA1) as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.
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Am. J. Respir. Cell Mol. Biol. · May 2014
ReviewImmunotherapy for malignant pleural mesothelioma. Current status and future prospects.
Malignant pleural mesothelioma (MPM) is a rare malignancy of the pleura that is frequently resistant to conventional therapies. Immunotherapy is a promising investigational approach for MPM that has shown some evidence of clinical benefit in select patients. However, tumor-induced immunosuppression is likely a major impediment to achieving optimal clinical responses to immunotherapeutic intervention. ⋯ Additional immunosuppressive factors identified in other human tumor types, such as tumor-associated programmed death ligand-1 expression, may be relevant for investigation in MPM. Conventional cytoreductive therapies, such as radiation, chemotherapy, and surgery, may play a critical role in successful immunotherapeutic strategies by ablating intratumoral and/or systemic immunosuppressive factors, thus creating a host environment more amenable to immunotherapy. This article reviews the immunotherapeutic approaches being evaluated in patients with MPM and discusses how immunotherapy might be rationally combined with conventional tumor cytoreductive therapies for this disease.
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Am. J. Respir. Cell Mol. Biol. · May 2014
Novel mechanism of attenuation of LPS-induced NF-κB activation by the heat shock protein 90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, in human lung microvascular endothelial cells.
Heat shock protein (hsp) 90 inhibition attenuates NF-κB activation and blocks inflammation. However, the precise mechanism of NF-κB regulation by hsp90 in the endothelium is not clear. We investigated the mechanisms of hsp90 inhibition by 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) on NF-κB activation by LPS in primary human lung microvascular endothelial cells. ⋯ The effect of LPS on IKBα mRNA expression was associated with rapid deacetylation of histone-H3(Lys9) and a dramatic down-regulation of core histone H3 binding. Even though treatment with an HDAC inhibitor produced the same effect as hsp90 inhibition, the effect of 17-AAG was independent of HDAC. We conclude that hsp90 inhibition attenuates NF-κB transcriptional activation by preventing coactivator recruitment and nucleosome eviction from the target promoter in human lung endothelial cells.
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Am. J. Respir. Cell Mol. Biol. · May 2014
DNA methylation is globally disrupted and associated with expression changes in chronic obstructive pulmonary disease small airways.
DNA methylation is an epigenetic modification that is highly disrupted in response to cigarette smoke and involved in a wide spectrum of malignant and nonmalignant diseases, but surprisingly not previously assessed in small airways of patients with chronic obstructive pulmonary disease (COPD). Small airways are the primary sites of airflow obstruction in COPD. We sought to determine whether DNA methylation patterns are disrupted in small airway epithelia of patients with COPD, and evaluate whether changes in gene expression are associated with these disruptions. ⋯ Our results indicate that aberrant DNA methylation is (1) a genome-wide phenomenon in small airways of patients with COPD, and (2) associated with altered expression of genes and pathways important to COPD, such as the NF-E2-related factor 2 oxidative response pathway. DNA methylation is likely an important mechanism contributing to modulation of genes important to COPD pathology. Because these methylation events may underlie disease-specific gene expression changes, their characterization is a critical first step toward the development of epigenetic markers and an opportunity for developing novel epigenetic therapeutic interventions for COPD.