Browsing by Subject "Emphysema"

Now showing 1 - 4 of 4
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    Ceramide and sphingosine-1 phosphate in COPD lungs
    (BMJ, 2021-01-29) Berdyshev, Evgeny V.; Serban, Karina A.; Schweitzer, Kelly S.; Bronova, Irina A.; Mikosz, Andrew; Petrache, Irina; Medicine, School of Medicine
    Studies of chronic obstructive pulmonary disease (COPD) using animal models and patient plasma indicate dysregulation of sphingolipid metabolism, but data in COPD lungs are sparse. Mass spectrometric and immunostaining measurements of lungs from 69 COPD, 16 smokers without COPD and 13 subjects with interstitial lung disease identified decoupling of lung ceramide and sphingosine-1 phosphate (S1P) levels and decreased sphingosine kinase-1 (SphK1) activity in COPD. The correlation of ceramide abundance in distal COPD lungs with apoptosis and the inverse correlation between SphK1 activity and presence of emphysema suggest that disruption of ceramide-to-S1P metabolism is an important determinant of emphysema phenotype in COPD.
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    EFFECTS OF TYPE VI COLLAGEN ON MACROPHAGES
    (Office of the Vice Chancellor for Research, 2011-04-08) Voiles, Larry; Han, Ling; Lupov, Ivan P.; Anderson, Bailey; Melnikov, Lonya; Pottratz, Sarah Marie; Chang, Hua-Chen
    Emphysema is an abnormal inflammatory response of the alveoli that lose their elasticity due to destruction of alveolar septi. Collagen, an extracellular matrix protein (ECM), is expressed in the lung, which is important in maintaining the integrity of the tissue. Destruction of the ECM components in the alveolar structure contributes to the development of emphysema. We have found that the gene expression of type VI collagen (COL6A1) is higher in the lungs of emphysema patients as compared to that from normal controls. Type VI collagen (COL6) is found in the pulmonary interstitial compartment where massive macrophages are infiltrated in the inflammatory environment. The hypothesis is that excessive COL6 activates macrophages to mediate inflammatory responses, which may contribute to the pathogenesis of emphysema. The goal is to define the effects of type VI collagen on macrophages. Results from murine bone marrow derived macrophages showed a marked increase in the numbers of CD86-positive cells after soluble COL6 stimulation. To further support the stimulatory function of COL6, human THP-1 cells as well as primary monocytes produced inflammatory cytokines IL-12 and IFNγ following COL6 stimulation. Taken together, our data has demonstrated the stimulatory effects on macrophages by COL6 stimulation, which may mediate the inflammatory responses in the pathogenesis of emphysema.
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    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 Medicine
    Primarily 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.
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    Targeted Induction of Lung Endothelial Cell Apoptosis Causes Emphysema-like Changes in the Mouse
    (American Society for Biochemistry and Molecular Biology, 2008-08-21) Giordano, Ricardo J.; Lahdenranta, Johanna; Zhen, Lijie; Chukwueke, Ugonma; Petrache, Irina; Langley, Robert R.; Fidler, Isaiah J.; Pasqualini, Renata; Tuder, Rubin M.; Arap, Wadih; Biochemistry and Molecular Biology, School of Medicine
    Pulmonary gas exchange relies on a rich capillary network, which, together with alveolar epithelial type I and II cells, form alveolar septa, the functional units in the lung. Alveolar capillary endothelial cells are critical in maintaining alveolar structure, because disruption of endothelial cell integrity underlies several lung diseases. Here we show that targeted ablation of lung capillary endothelial cells recapitulates the cellular events involved in cigarette smoke-induced emphysema, one of the most prevalent nonneoplastic lung diseases. Based on phage library screening on an immortalized lung endothelial cell line, we identified a lung endothelial cell-binding peptide, which preferentially homes to lung blood vessels. This peptide fused to a proapoptotic motif specifically induced programmed cell death of lung endothelial cells in vitro as well as targeted apoptosis of the lung microcirculation in vivo. As early as 4 days following peptide administration, mice developed air space enlargement associated with enhanced oxidative stress, influx of macrophages, and up-regulation of ceramide. Given that these are all critical elements of the corresponding human emphysema caused by cigarette smoke, these data provide evidence for a central role for the alveolar endothelial cells in the maintenance of lung structure and of endothelial cell apoptosis in the pathogenesis of emphysema-like changes. Thus, our data enable the generation of a convenient mouse model of human emphysema. Finally, combinatorial screenings on immortalized cells followed by in vivo targeting establishes an experimental framework for discovery and validation of additional ligand-directed pharmacodelivery systems.