Browsing by Subject "Chronic obstructive pulmonary disease"
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Item Extracellular vesicles: novel communicators in lung diseases(BMC, 2020-07-08) Mohan, Aradhana; Agarwal, Stuti; Clauss, Matthias; Britt, Nicholas S.; Dhillon, Navneet K.; Medicine, School of MedicineThe lung is the organ with the highest vascular density in the human body. It is therefore perceivable that the endothelium of the lung contributes significantly to the circulation of extracellular vesicles (EVs), which include exosomes, microvesicles, and apoptotic bodies. In addition to the endothelium, EVs may arise from alveolar macrophages, fibroblasts and epithelial cells. Because EVs harbor cargo molecules, such as miRNA, mRNA, and proteins, these intercellular communicators provide important insight into the health and disease condition of donor cells and may serve as useful biomarkers of lung disease processes. This comprehensive review focuses on what is currently known about the role of EVs as markers and mediators of lung pathologies including COPD, pulmonary hypertension, asthma, lung cancer and ALI/ARDS. We also explore the role EVs can potentially serve as therapeutics for these lung diseases when released from healthy progenitor cells, such as mesenchymal stem cells.Item Identification of potential key genes associated with severe pneumonia using mRNA-seq(Spandidos, 2018-08) Feng, Cong; Huang, He; Huang, Sai; Zhai, Yong-Zhi; Dong, Jing; Chen, Li; Huang, Zhi; Zhou, Xuan; Li, Bei; Wang, Li-Li; Chen, Wei; Lv, Fa-Qin; Li, Tan-Shi; Electrical and Computer Engineering, School of Engineering and TechnologyThis study aimed to identify the potential key genes associated with severe pneumonia using mRNA-seq. Nine peripheral blood samples from patients with severe pneumonia alone (SP group, n=3) and severe pneumonia accompanied with chronic obstructive pulmonary disease (COPD; CSP group, n=3), as well as volunteers without pneumonia (control group, n=3) underwent mRNA-seq. Based on the sequencing data, differentially expressed genes (DEGs) were identified by Limma package. Following the pathway enrichment analysis of DEGs, the genes that were differentially expressed in the SP and CSP groups were selected for pathway enrichment analysis and coexpression analysis. In addition, potential genes related to pneumonia were identified based on the information in the Comparative Toxicogenomics Database. In total, 645 and 528 DEGs were identified in the SP and CSP groups, respectively, compared with the normal controls. Among these DEGs, 88 upregulated genes and 80 downregulated genes were common between the two groups. The functions of the common DEGs were similar to those of the DEGs in the SP group. In the coexpression network, the commonly downregulated genes (including ND1, ND3, ND4L, and ND6) and the commonly upregulated genes (including TSPY6P and CDY10P) exhibited a higher degree. In addition, 131 DEGs (including ND1, ND3, ND6, MIR449A and TAS2R43) were predicted to be potential pneumonia-related genes. In conclusion, the present study demonstrated that the common DEGs may be associated with the progression of severe pneumonia.Item Impact of COPD on clinical and CT characteristics of COVID-19-associated pneumonia: single tertiary center experience(Springer, 2022-11-29) Filippenko, Yevgeniya; Zagurovskaya, Marianna; Abdrakhmanova, Aigul; Kassenova, Saule; Zhakenova, Zhanar; Aimakhanova, Aizat; Zholdybay, Zhamilya; Radiology and Imaging Sciences, School of MedicineBackground The severe acute respiratory syndrome-related coronavirus 2 pandemic continues to this day worldwide. Individuals with COPD are at increased risk of contracting SARS-CoV-2. Most of the conducted studies are based on the clinical assessment of COVID-19 infection with different comorbidities. The specific contribution of COPD to the severity of the disease and outcome still remains the point of investigation. The main goals of our study are to assess COPD’s influence on the severity of clinical and CT characteristics of COVID-19 pneumonia and associated in-hospital mortality. Results This is a retrospective study on 281 patients with RT-PCR-confirmed COVID-19 infection and CT spectrum of COVID-19 pneumonia. Fifty patients have COPD based on CT criteria. No significant difference was observed in the mean hospital length of stay, arterial oxygen saturation on admission or in-hospital mortality between COPD and non-COPD groups. Patients with COPD were two times less likely to have fever less than 37.9 °C (RR = 2.037; 95% CI 1.114–3.724, p = 0.016), but higher absolute neutrophil count (p = 0.033) and median level of neutrophil/lymphocyte ratio (p = 0.029). The COPD group was presented with milder CT severity score (especially CT1, less than 25% of lung involvement) (p = 0.022), less likely to have bilateral (RR = 2.601; 95% CI: 1.341–5.044, p = 0.023) or central (RR = 1.754; 95% CI 1.024–3.003, p = 0.046) distribution of ground-glass opacities, right lower lobe (RR = 2.887; 95% CI 1.574–5.293, p = 0.008) or left lung (RR = 2.627; 95% CI 1.448–4.765, p = 0.009) involvement, and “crazy-paving” pattern (RR = 2.208; 95% CI 1.292–3.774, p = 0.003). Both moderate positive and negative relationship was observed between CT1, CT4, hypoxia and in-hospital mortality in the COPD group (r = − 0.383, p = 0.033; r = 0.486, p = 0.007; r = − 0,354, p = 0,022, respectively). Conclusion The presence of COPD by imaging criteria in the settings of COVID-19-associated pneumonia did not significantly influence the clinical or imaging performance of the patients, nor was it linked to the increased in-hospital mortality.Item Pharmacological sphingosine-1 phosphate receptor 1 targeting in cigarette smoke-induced emphysema in mice(American Physiological Society, 2022) Goel, Khushboo; Schweitzer, Kelly S.; Serban, Karina A.; Bittman, Robert; Petrache, Irina; Medicine, School of MedicinePrimarily caused by chronic cigarette smoking (CS), emphysema is characterized by loss of alveolar cells comprising lung units involved in gas exchange and inflammation that culminate in airspace enlargement. Dysregulation of sphingolipid metabolism with increases of ceramide relative to sphingosine-1 phosphate (S1P) signaling has been shown to cause lung cell apoptosis and is emerging as a potential therapeutic target in emphysema. We sought to determine the impact of augmenting S1P signaling via S1P receptor 1 (S1P1) in a mouse model of CS-induced emphysema. DBA2 mice were exposed to CS for 4 or 6 mo and treated with pharmacological agonists of S1P1: phosphonated FTY720 (FTY720-1S and 2S analogs; 0.01–1.0 mg/kg) or GSK183303A (10 mg/kg). Pharmacological S1P1 agonists ameliorated CS-induced lung parenchymal apoptosis and airspace enlargement as well as loss of body weight. S1P1 agonists had modest inhibitory effects on CS-induced airspace inflammation and lung functional changes measured by Flexivent, improving lung tissue resistance. S1P1 abundance was reduced in chronic CS-conditions and remained decreased after CS-cessation or treatment with FTY720-1S. These results support an important role for S1P-S1P1 axis in maintaining the structural integrity of alveoli during chronic CS exposure and suggest that increasing both S1P1 signaling and abundance may be beneficial to counteract the effects of chronic CS exposure.Item Smoking exposure induces human lung endothelial cell adaptation to apoptotic stress(American Thoracic Society, 2014-03) Petrusca, Daniela N.; Van Demark, Mary; Gu, Yuan; Justice, Matthew J.; Rogozea, Adriana; Hubbard, Walter C.; Petrache, Irina; Medicine, School of MedicineProlonged exposure to cigarette smoking is the main risk factor for emphysema, a component of chronic obstructive pulmonary diseases (COPDs) characterized by destruction of alveolar walls. Moreover, smoking is associated with pulmonary artery remodeling and pulmonary hypertension, even in the absence of COPD, through as yet unexplained mechanisms. In murine models, elevations of intra- and paracellular ceramides in response to smoking have been implicated in the induction of lung endothelial cell apoptosis, but the role of ceramides in human cell counterparts is yet unknown. We modeled paracrine increases (outside-in) of palmitoyl ceramide (Cer16) in primary human lung microvascular cells. In naive cells, isolated from nonsmokers, Cer16 significantly reduced cellular proliferation and induced caspase-independent apoptosis via mitochondrial membrane depolarization, apoptosis-inducing factor translocation, and poly(ADP-ribose) polymerase cleavage. In these cells, caspase-3 was inhibited by ceramide-induced Akt phosphorylation, and by the induction of autophagic microtubule-associated protein-1 light-chain 3 lipidation. In contrast, cells isolated from smokers exhibited increased baseline proliferative features associated with lack of p16(INK4a) expression and Akt hyperphosphorylation. These cells were resistant to Cer16-induced apoptosis, despite presence of both endoplasmic reticulum stress response and mitochondrial membrane depolarization. In cells from smokers, the prominent up-regulation of Akt pathways inhibited ceramide-triggered apoptosis, and was associated with elevated sphingosine and high-mobility group box 1, skewing the cell's response toward autophagy and survival. In conclusion, the cell responses to ceramide are modulated by an intricate cross-talk between Akt signaling and sphingolipid metabolites, and profoundly modified by previous cigarette smoke exposure, which selects for an apoptosis-resistant phenotype.Item Sphingosine 1 Phosphate (S1P) Receptor 1 Is Decreased in Human Lung Microvascular Endothelial Cells of Smokers and Mediates S1P Effect on Autophagy(MDPI, 2021-05-14) Goel, Khushboo; Beatman, Erica L.; Egersdorf, Nicholas; Scruggs, April; Cao, Danting; Berdyshev, Evgeny V.; Schweitzer, Kelly S.; Petrache, Irina; Medicine, School of MedicineDestruction of alveoli by apoptosis induced by cigarette smoke (CS) is a major driver of emphysema pathogenesis. However, when compared to cells isolated from non-smokers, primary human lung microvascular endothelial cells (HLMVECs) isolated from chronic smokers are more resilient when exposed to apoptosis-inducing ceramide. Whether this adaptation restores homeostasis is unknown. To better understand the phenotype of HLMVEC in smokers, we interrogated a major pro-survival pathway supported by sphingosine-1-phosphate (S1P) signaling via S1P receptor 1 (S1P1). Primary HLMVECs from lungs of non-smoker or smoker donors were isolated and studied in culture for up to five passages. S1P1 mRNA and protein abundance were significantly decreased in HLMVECs from smokers compared to non-smokers. S1P1 was also decreased in situ in lungs of mice chronically exposed to CS. Levels of S1P1 expression tended to correlate with those of autophagy markers, and increasing S1P (via S1P lyase knockdown with siRNA) stimulated baseline macroautophagy with lysosomal degradation. In turn, loss of S1P1 (siRNA) inhibited these effects of S1P on HLMVECs autophagy. These findings suggest that the anti-apoptotic phenotype of HLMVECs from smokers may be maladaptive, since it is associated with decreased S1P1 expression that may impair their autophagic response to S1P.Item Stimulation of sphingosine 1-phosphate signaling as an alveolar cell survival strategy in emphysema(American Thoracic Society, 2010-02-15) Diab, Khalil J.; Adamowicz, Jeremy J.; Kamocki, Krzysztof; Rush, Natalia I.; Garrison, Jana; Gu, Yuan; Schweitzer, Kelly S.; Skobeleva, Anastasia; Rajashekhar, Gangaraju; Hubbard, Walter C.; Berdyshev, Evgeny V.; Petrache, Irina; Medicine, School of MedicineRATIONALE: Vascular endothelial growth factor receptor (VEGFR) inhibition increases ceramides in lung structural cells of the alveolus, initiating apoptosis and alveolar destruction morphologically resembling emphysema. The effects of increased endogenous ceramides could be offset by sphingosine 1-phosphate (S1P), a prosurvival by-product of ceramide metabolism. OBJECTIVES: The aims of our work were to investigate the sphingosine-S1P-S1P receptor axis in the VEGFR inhibition model of emphysema and to determine whether stimulation of S1P signaling is sufficient to functionally antagonize alveolar space enlargement. METHODS: Concurrent to VEGFR blockade in mice, S1P signaling augmentation was achieved via treatment with the S1P precursor sphingosine, S1P agonist FTY720, or S1P receptor-1 (S1PR1) agonist SEW2871. Outcomes included sphingosine kinase-1 RNA expression and activity, sphingolipid measurements by combined liquid chromatography-tandem mass spectrometry, immunoblotting for prosurvival signaling pathways, caspase-3 activity and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays, and airspace morphometry. MEASUREMENTS AND MAIN RESULTS: Consistent with previously reported de novo activation of ceramide synthesis, VEGFR inhibition triggered increases in lung ceramides, dihydroceramides, and dihydrosphingosine, but did not alter sphingosine kinase activity or S1P levels. Administration of sphingosine decreased the ceramide-to-S1P ratio in the lung and inhibited alveolar space enlargement, along with activation of prosurvival signaling pathways and decreased lung parenchyma cell apoptosis. Sphingosine significantly opposed ceramide-induced apoptosis in cultured lung endothelial cells, but not epithelial cells. FTY720 or SEW2871 recapitulated the protective effects of sphingosine on airspace enlargement concomitant with attenuation of VEGFR inhibitor-induced lung apoptosis. CONCLUSIONS: Strategies aimed at augmenting the S1P-S1PR1 signaling may be effective in ameliorating the apoptotic mechanisms of emphysema development.Item Structural and functional characterization of endothelial microparticles released by cigarette smoke(SpringerNature, 2016-08-17) Serban, Karina A.; Rezania, Samin; Petrusca, Daniela N.; Poirier, Christophe; Cao, Danting; Justice, Matthew J.; Patel, Milan; Tsvetkova, Irina; Kamocki, Krzysztof; Mikosz, Andrew; Schweitzer, Kelly S.; Jacobson, Sean; Cardoso, Angelo; Carlesso, Nadia; Hubbard, Walter C.; Kechris, Katerina; Dragnea, Bogdan; Berdyshev, Evgeny V.; McClintock, Jeanette; Petrache, Irina; Department of Biochemistry & Molecular Biology, IU School of MedicineCirculating endothelial microparticles (EMPs) are emerging as biomarkers of chronic obstructive pulmonary disease (COPD) in individuals exposed to cigarette smoke (CS), but their mechanism of release and function remain unknown. We assessed biochemical and functional characteristics of EMPs and circulating microparticles (cMPs) released by CS. CS exposure was sufficient to increase microparticle levels in plasma of humans and mice, and in supernatants of primary human lung microvascular endothelial cells. CS-released EMPs contained predominantly exosomes that were significantly enriched in let-7d, miR-191; miR-126; and miR125a, microRNAs that reciprocally decreased intracellular in CS-exposed endothelium. CS-released EMPs and cMPs were ceramide-rich and required the ceramide-synthesis enzyme acid sphingomyelinase (aSMase) for their release, an enzyme which was found to exhibit significantly higher activity in plasma of COPD patients or of CS-exposed mice. The ex vivo or in vivo engulfment of EMPs or cMPs by peripheral blood monocytes-derived macrophages was associated with significant inhibition of efferocytosis. Our results indicate that CS, via aSMase, releases circulating EMPs with distinct microRNA cargo and that EMPs affect the clearance of apoptotic cells by specialized macrophages. These targetable effects may be important in the pathogenesis of diseases linked to endothelial injury and inflammation in smokers.