Explore the vast range of titles available.

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin–expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 (TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF. Objectives We aimed to define an association between mtDNA and fibroblast responses in IPF. Methods We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-β1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects. Measurements and Main Results Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-β1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival. Conclusions These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.

Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium. miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRAS /Trp (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.

Infection, especially with opportunistic microbes, is a prominent feature of pulmonary alveolar proteinosis; extrapulmonary infection suggests a systemic susceptibility. The authors show that neutrophil functions (phagocytosis, adhesion, oxidative burst, and bactericidal activity) are depressed in patients with pulmonary alveolar proteinosis and that the cause is autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). These findings clearly demonstrate the essential role of GM-CSF in the antimicrobial activities of neutrophils. The authors show that neutrophil functions are depressed in patients with pulmonary alveolar proteinosis and that the cause is autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). Pulmonary alveolar proteinosis 1 is a rare disorder in which surfactant accumulates within pulmonary alveoli, causing respiratory insufficiency. 2 , 3 The disease is specifically associated with high levels of autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF) in blood and tissues, including pulmonary alveoli. 4 These autoantibodies neutralize the biologic activity of GM-CSF. 5 In mice, GM-CSF stimulates the terminal differentiation of alveolar macrophages, primarily through the action of the transcription factor PU.1. 6 The homozygous deletion of GM-CSF genes causes pulmonary alveolar proteinosis in mice 7 , 8 by impairing the clearance of pulmonary surfactant by alveolar macrophages that are dependent on GM-CSF. 9 In patients with pulmonary alveolar . . .

Cigarette smoke (CS) creates a “cancer field” in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial growth factor-driven pathway. Applying a multi-step molecular screen, we identified angiogenic genes regulated by miR-1 in the lungs of smokers. Knockdown of one of these genes, Notch homolog protein 3, simulates the anti-angiogenic effects of miR-1. These findings suggest that miR-1 can be used as an indicator of malignant transformation. Exposure to cigarette smoke induces the angiogenic activation of the endothelial cells in the cancer field by selective degradation of mature microRNA-1. This change can be detected in the lungs of non-small cell lung cancer patients and correlates with their smoking burden.

Thoracentesis is commonly performed to evaluate pleural effusions. Many medications (warfarin, heparin, clopidogrel) or physiological factors (elevated International Normalized Ratio [INR], thrombocytopenia, uremia) increase the risk for bleeding. Frequently these medications are withheld or transfusions are performed to normalize physiological parameters before a procedure. The safety of performing thoracentesis without correction of these bleeding risks has not been prospectively evaluated. This prospective observational cohort study enrolled 312 patients who underwent thoracentesis. All patients were evaluated for the presence of risk factors for bleeding. Hematocrit levels were obtained pre- and postprocedure, and the occurrence of postprocedural hemothorax was evaluated. Thoracenteses were performed in 312 patients, 42% of whom had a risk for bleeding. Elevated INR, secondary to liver disease or warfarin, and renal disease were the two most common etiologies for bleeding risk, although many patients had multiple potential bleeding risks. There was no significant difference in pre- and postprocedural hematocrit levels in patients with a bleeding risk when compared with patients with no bleeding risk. No patient developed a hemothorax as a result of the thoracentesis. This single-center, observational study suggests that thoracentesis may be safely performed without prior correction of coagulopathy, thrombocytopenia, or medication-induced bleeding risk. This may reduce the morbidity associated with transfusions or withholding of medications.