739 results on '"Zabner, Joseph"'
Search Results
302. Transduction of Pig Small Airway Epithelial Cells and Distal Lung Progenitor Cells by AAV4.
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Chen, Oliver G., Mather, Steven E., Brommel, Christian M., Hamilton, Bradley A., Ehler, Annie, Villacreses, Raul, Girgis, Reda E., Abou Alaiwa, Mahmoud, Stoltz, David A., Zabner, Joseph, Li, Xiaopeng, and Gray, Michael
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PROGENITOR cells ,ADENOVIRUS diseases ,CYSTIC fibrosis ,GENETIC mutation ,AIRWAY (Anatomy) ,GENETIC transduction ,EPITHELIAL cells - Abstract
Cystic fibrosis (CF) is caused by genetic mutations of the CF transmembrane conductance regulator (CFTR), leading to disrupted transport of Cl
− and bicarbonate and CF lung disease featuring bacterial colonization and chronic infection in conducting airways. CF pigs engineered by mutating CFTR develop lung disease that mimics human CF, and are well-suited for investigating CF lung disease therapeutics. Clinical data suggest small airways play a key role in the early pathogenesis of CF lung disease, but few preclinical studies have focused on small airways. Efficient targeted delivery of CFTR cDNA to small airway epithelium may correct the CFTR defect and prevent lung infections. Adeno-associated virus 4 (AAV4) is a natural AAV serotype and a safe vector with lower immunogenicity than other gene therapy vectors such as adenovirus. Our analysis of AAV natural serotypes using cultured primary pig airway epithelia showed that AAV4 has high tropism for airway epithelia and higher transduction efficiency for small airways compared with large airways. AAV4 mediated the delivery of CFTR, and corrected Cl− transport in cultured primary small airway epithelia from CF pigs. Moreover, AAV4 was superior to all other natural AAV serotypes in transducing ITGα6β4+ pig distal lung progenitor cells. In addition, AAV4 encoding eGFP can infect pig distal lung epithelia in vivo. This study demonstrates AAV4 tropism in small airway progenitor cells, which it efficiently transduces. AAV4 offers a novel tool for mechanistical study of the role of small airway in CF lung pathogenesis in a preclinical large animal model. [ABSTRACT FROM AUTHOR]- Published
- 2021
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303. Efficient killing of inhaled bacteria in ...F508 mice: Role of airway surface liquid composition.
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McCray Jr., Paul B. and Zabner, Joseph
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PULMONARY surfactant , *BACTERIOLYSIS , *TRACHEA physiology , *MICE physiology - Abstract
Examines the role of airway surface liquid composition in the efficient killing of inhaled bacteria in mice. Bronchoalveolar lavage (BAL) profiles of naive animals; Salt-sensitive antimicrobial activity of murine BAL fluid; Role of low-molecular weight peptides in human pulmonary defenses.
- Published
- 1999
304. Functional activation of the cystic fibrosis trafficking mutant ΔF508-CFTR by overexpression.
- Author
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CHENG, SENG H., FANG, SHAONA L., ZABNER, JOSEPH, MARSHALL, JOHN, PIRAINO, SUSAN, SCHIAVI, SUSAN C., JEFFERSON, DOUGLAS M., WELSH, MICHAEL J., and SMITH, ALAN E.
- Published
- 1995
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305. Keratinocyte growth factor induced epithelial proliferation facilitates retroviralmediated gene transfer to distal lung epithelia in vivo
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Wang, Guoshun, Slepushkin, Vladimir A., Bodner, Mordechai, Zabner, Joseph, Es, Helmuth H. G. van, Thomas, Patricia, Jolly, Doug J., Davidson, Beverly L., and McCray, Paul B.
- Abstract
Cell proliferation, vector titer and accessibility of target cells represent hurdles for efficient gene transfer to lung epithelia in vivo using recombinant murine leukemia (MuLV)-based retroviruses. We tested the hypothesis that the pulmonary epithelium is susceptible to retroviral-mediated gene transfer when stimulated to proliferate by a mitogen, keratinocyte growth factor (KGF). Rats received keratinocyte growth factor (KGF, 2.5 µg/g×4 doses, two consecutive days) intratracheally followed by high titer amphotropic retrovirus expressing β-galactosidase. Gene transfer was assessed five days later. KGF stimulated transient proliferation in the bronchiolar and alveolar epithelia (3040% PCNA positive cells at peak) which decreased to background levels seven days after administration. Gene transfer to epithelia (X-Gal positive cells) occurred more frequently in KGF treated rats, but proliferation exceeded the level of gene transfer. X-gal positive cells were noted in the alveolar epithelium and occasionally in the bronchiolar epithelium. In order to understand the discrepancy between the number of proliferating and transduced cells, primary rat tracheal epithelium cultured at the air-liquid interface was infected from either the apical or basolateral side. Gene transfer was achieved only through basolateral application of vector, suggesting that epithelial polarity represents a barrier to MuLV-based lung gene transfer in vivo. KGF transiently stimulates epithelial proliferation in vivo, facilitating MuLV-based gene transfer. Retroviral vectors may encounter multiple barriers which have evolved to defend the lung from infections. Copyright © 1999 John Wiley & Sons, Ltd.
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- 1999
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306. Seasonal Antimicrobial Activity of the Airway: Post-Hoc Analysis of a Randomized Placebo-Controlled Double-Blind Trial.
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Vargas Buonfiglio, Luis G., Vanegas Calderon, Oriana G., Cano, Marlene, Simmering, Jacob E., Polgreen, Philip M., Zabner, Joseph, Gerke, Alicia K., and Comellas, Alejandro P.
- Abstract
Background: It is widely unknown why respiratory infections follow a seasonal pattern. Variations in ultraviolet B (UVB) light during seasons affects cutaneous synthesis of vitamin D
3 . Serum vitamin D concentration influences the expression of airway surface liquid (ASL) antimicrobial peptides such as LL-37. Objective: We sought to determine the effect of seasons on serum vitamin D levels and ASL antimicrobial activity. Methods: Forty participants, 18–60 years old, were randomized 1:1 to receive 90 days of 1000 IU vitamin D3 or placebo. We collected ASL via bronchoscopy and measured serum 25(OH) vitamin D from participants before and after intervention across seasons. We measured ASL antimicrobial activity by challenging samples with bioluminescent Staphylococcus aureus and measured relative light units (RLUs) after four minutes. We also investigated the role of LL-37 using a monoclonal neutralizing antibody. Results: We found that participants, prior to any intervention, during summer–fall (n = 20) compared to winter–spring (n = 20) had (1) decreased live bacteria after challenge (5542 ± 175.2 vs. 6585 ± 279 RLU, p = 0.003) and (2) higher serum vitamin D (88.25 ± 24.25 vs. 67.5 ± 45.25 nmol/L, p = 0.026). Supplementation with vitamin D3 increased vitamin D levels and restored ASL antimicrobial activity only during the winter–spring. The increased ASL antimicrobial activity seen during the summer–fall was abrogated by adding the LL-37 neutralizing antibody. Conclusion: ASL kills bacteria more effectively during the summer–fall compared to the winter–spring. Supplementation of vitamin D during winter–spring restores ASL antimicrobial activity by increasing the expression of antimicrobial peptides including LL-37. [ABSTRACT FROM AUTHOR]- Published
- 2020
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307. Cystic Fibrosis Gene Therapy Using an Adenovirus Vector: In VivoSafety and Efficacy in Nasal Epithelium. Howard Hughes Medical Institute, Iowa City, IA
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Welsh, Michael J., Smith, Alan E., Zabner, Joseph, Rich, Devra P., Graham, Scott M., Gregory, Richard J., Pratt, Bruce M., and Moscicki, Richard A.
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- 1994
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308. Complexes of Adenovirus with Polycationic Polymers and Cationic Lipids Increase the Efficiency of Gene Transfer in Vitroand in Vivo*
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Fasbender, Al, Zabner, Joseph, Chillón, Miguel, Moninger, Thomas O., Puga, Aurita P., Davidson, Beverly L., and Welsh, Michael J.
- Abstract
Improving the efficiency of gene transfer remains an important goal in developing new treatments for cystic fibrosis and other diseases. Adenovirus vectors and nonviral vectors each have specific advantages, but they also have limitations. Adenovirus vectors efficiently escape from the endosome and enter the nucleus, but the virus shows limited binding to airway epithelia. Nonviral cationic vectors bind efficiently to the negatively charged cell surface, but they do not catalyze subsequent steps in gene transfer. To take advantage of the unique features of the two different vector systems, we noncovalently complexed cationic molecules with recombinant adenovirus encoding a transgene. Complexes of cationic polymers and cationic lipids with adenovirus increased adenovirus uptake and transgene expression in cells that were inefficiently infected by adenovirus alone. Infection by both complexes was independent of adenovirus fiber and its receptor and occurred via a different cellular pathway than adenovirus alone. Complexes of cationic molecules and adenovirus also enhanced gene transfer to differentiated human airway epithelia in vitroand to the nasal epithelium of cystic fibrosis mice in vivoThese data show that complexes of adenovirus and cationic molecules increase the efficiency of gene transfer, which may enhance the development of gene therapy.
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- 1997
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309. Effects of Tham Nasal Alkalinization on Airway Microbial Communities: A Pilot Study in Non-CF and CF Adults
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Holliday, Zachary M., Launspach, Janice L., Durairaj, Lakshmi, Singh, Pradeep K., Zabner, Joseph, and Stoltz, David A.
- Abstract
Objectives: In cystic fibrosis (CF), loss of CFTR-mediated bicarbonate secretion reduces the airway surface liquid (ASL) pH causing airway host defense defects. Aerosolized sodium bicarbonate can reverse these defects, but its effects are short-lived. Aerosolized tromethamine (THAM) also raises the ASL pH but its effects are much longer lasting. In this pilot study, we tested the hypothesis that nasally administered THAM would alter the nasal bacterial composition in adults with and without CF.Methods: Subjects (n = 32 total) received intranasally administered normal saline or THAM followed by a wash out period prior to receiving the other treatment. Nasal bacterial cultures were obtained prior to and after each treatment period.Results: At baseline, nasal swab bacterial counts were similar between non-CF and CF subjects, but CF subjects had reduced microbial diversity. Both nasal saline and THAM were well-tolerated. In non-CF subjects, nasal airway alkalinization decreased both the total bacterial density and the gram-positive bacterial species recovered. In both non-CF and CF subjects, THAM decreased the amount of Corynebacterium accolensdetected, but increased the amount of Corynebacterium pseudodiphtheriticumrecovered on nasal swabs. A reduction in Staphylococcus aureusnasal colonization was also found in subjects who grew C. pseudodiphtheriticum.Conclusions: This study shows that aerosolized THAM is safe and well-tolerated and that nasal airway alkalinization alters the composition of mucosal bacterial communities.Clinical Trial Registration: NCT00928135 (https://clinicaltrials.gov/ct2/show/NCT00928135).
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- 2021
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310. Additional file 8: Table S2. of Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility
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Bruse, Shannon, Moreau, Michael, Bromberg, Yana, Jang, Jun-Ho, Wang, Nan, Hongseok Ha, Picchi, Maria, Lin, Yong, Langley, Raymond, Qualls, Clifford, Klensney-Tait, Julia, Zabner, Joseph, Shuguang Leng, Mao, Jenny, Belinsky, Steven, Jinchuan Xing, and Nyunoya, Toru
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respiratory tract diseases ,3. Good health - Abstract
Table S2 siRNA sequences targeting 81 COPD candidate genes.
311. Additional file 7: Table S1. of Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility
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Bruse, Shannon, Moreau, Michael, Bromberg, Yana, Jang, Jun-Ho, Wang, Nan, Hongseok Ha, Picchi, Maria, Lin, Yong, Langley, Raymond, Qualls, Clifford, Klensney-Tait, Julia, Zabner, Joseph, Shuguang Leng, Mao, Jenny, Belinsky, Steven, Jinchuan Xing, and Nyunoya, Toru
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genetic processes ,information science ,natural sciences ,eye diseases ,3. Good health - Abstract
The information of Sanger sequencing validation for seven exonic variants of TACC2.
312. Additional file 8: Table S2. of Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility
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Bruse, Shannon, Moreau, Michael, Bromberg, Yana, Jang, Jun-Ho, Wang, Nan, Hongseok Ha, Picchi, Maria, Lin, Yong, Langley, Raymond, Qualls, Clifford, Klensney-Tait, Julia, Zabner, Joseph, Shuguang Leng, Mao, Jenny, Belinsky, Steven, Jinchuan Xing, and Nyunoya, Toru
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respiratory tract diseases ,3. Good health - Abstract
Table S2 siRNA sequences targeting 81 COPD candidate genes.
313. Effect of hypercapnia on fluid filtration rate during forward and reverse perfusion of isolated rabbit lungs
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DE LEN, ROBERTO SÁNCHEZ, primary, BRAJKOVICH, IMPERIA, additional, ZABNER, JOSEPH, additional, MARTINEZ-RUIZ, RICARDO, additional, and ANGELI, SIMN, additional
- Published
- 1986
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314. Airway surface liquid from smokers promotes bacterial growth and biofilm formation via iron-lactoferrin imbalance.
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Vargas Buonfiglio, Luis G., Borcherding, Jennifer A., Frommelt, Mark, Parker, Gavin J., Duchman, Bryce, Vanegas Calderón, Oriana G., Fernandez-Ruiz, Ruth, Noriega, Julio E., Stone, Elizabeth A., Gerke, Alicia K., Zabner, Joseph, Comellas, Alejandro P., and Vanegas Calderón, Oriana G
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RESPIRATORY infections ,HEALTH ,SMOKING ,CIGARETTE smokers ,HOMEOSTASIS ,BACTERIAL growth ,BRONCHOALVEOLAR lavage ,AIRWAY (Anatomy) - Abstract
Background: Smoking is a leading cause of respiratory infections worldwide. Tobacco particulate matter disrupts iron homeostasis in the lungs and increases the iron content in the airways of smokers. The airway epithelia secrete lactoferrin to quench iron required for bacteria to proliferate and cause lung infections. We hypothesized that smokers would have increased bacterial growth and biofilm formation via iron lactoferrin imbalance.Methods: We collected bronchoalveolar lavage (BAL) samples from non-smokers and smokers. We challenged these samples using a standard inoculum of Staphylococcus aureus and Pseudomonas aeruginosa and quantified bacterial growth and biofilm formation. We measured both iron and lactoferrin in the samples. We investigated the effect of supplementing non-smoker BAL with cigarette smoke extract (CSE) or ferric chloride and the effect of supplementing smoker BAL with lactoferrin on bacterial growth and biofilm formation.Results: BAL from smokers had increased bacterial growth and biofilm formation compared to non-smokers after both S. aureus and P. aeruginosa challenge. In addition, we found that samples from smokers had a higher iron to lactoferrin ratio. Supplementing the BAL of non-smokers with cigarette smoke extract and ferric chloride increased bacterial growth. Conversely, supplementing the BAL of smokers with lactoferrin had a concentration-dependent decrease in bacterial growth and biofilm formation.Conclusion: Cigarette smoking produces factors which increase bacterial growth and biofilm formation in the BAL. We propose that smoking disrupts the iron-to-lactoferrin in the airways. This finding offers a new avenue for potential therapeutic interventions to prevent respiratory infections in smokers. [ABSTRACT FROM AUTHOR]- Published
- 2018
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315. CFTR-rich ionocytes mediate chloride absorption across airway epithelia.
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Lei Lei, Traore, Soumba, Romano Ibarra, Guillermo S., Karp, Philip H., Rehman, Tayyab, Meyerholz, David K., Zabner, Joseph, Stoltz, David A., Sinn, Patrick L., Welsh, Michael J., McCray Jr., Paul B., and Thornell, Ian M.
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CYSTIC fibrosis transmembrane conductance regulator , *EPITHELIUM - Abstract
The volume and composition of a thin layer of liquid covering the airway surface defend the lung from inhaled pathogens and debris. Airway epithelia secrete Cl- into the airway surface liquid through cystic fibrosis transmembrane conductance regulator (CFTR) channels, thereby increasing the volume of airway surface liquid. The discovery that pulmonary ionocytes contain high levels of CFTR led us to predict that ionocytes drive secretion. However, we found the opposite. Elevating ionocyte abundance increased liquid absorption, whereas reducing ionocyte abundance increased secretion. In contrast to other airway epithelial cells, ionocytes contained barttin/Cl- channels in their basolateral membrane. Disrupting barttin/Cl-channel function impaired liquid absorption, and overexpressing barttin/Cl- channels increased absorption. Together, apical CFTR and basolateral barttin/Cl- channels provide an electrically conductive pathway for Cl- flow through ionocytes, and the transepithelial voltage generated by apical Na+ channels drives absorption. These findings indicate that ionocytes mediate liquid absorption, and secretory cells mediate liquid secretion. Segregating these counteracting activities to distinct cell types enables epithelia to precisely control the airway surface. Moreover, the divergent role of CFTR in ionocytes and secretory cells suggests that cystic fibrosis disrupts both liquid secretion and absorption. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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316. Disruption of the circadian rhythm of melatonin: A biomarker of critical illness severity.
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Melone, Marie-Anne, Becker, Taylor C., Wendt, Linder H., Ten Eyck, Patrick, Patel, Shruti B., Poston, Jason, Pohlman, Anne S., Pohlman, Mark, Miller, Annette, Nedeltcheva, Arlet, Hall, Jesse B., Van Cauter, Eve, Zabner, Joseph, and Gehlbach, Brian K.
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CRITICALLY ill , *CIRCADIAN rhythms , *NONLINEAR regression , *MELATONIN , *BIOMARKERS - Abstract
Circadian dysrhythmias occur commonly in critically ill patients reflecting variable effects of underlying illness, ICU environment, and treatments. We retrospectively analyzed the relationship between clinical outcomes and 24-h urinary 6-sulfatoxymelatonin (aMT6s) excretion profiles in 37 critically ill patients with shock and/or respiratory failure. Nonlinear regression was used to fit a 24-h cosine curve to each patient's aMT6s profile, with rhythmicity determined by the zero-amplitude test. From these curves we determined acrophase, amplitude, phase, and night/day ratio. After assessing unadjusted relationships, we identified the optimal multivariate models for hospital survival and for discharge to home (vs. death or transfer to another facility). Normalized aMT6s rhythm amplitude was greater (p = 0.005) in patients discharged home than in those who were not, while both groups exhibited a phase delay. Patients with rhythmic aMT6s excretion were more likely to survive (OR 5.25) and be discharged home (OR 8.89; p < 0.05 for both) than patients with arrhythmic profiles, associations that persisted in multivariate modelling. In critically ill patients with shock and/or respiratory failure, arrhythmic and/or low amplitude 24-h aMT6s rhythms were associated with worse clinical outcomes, suggesting a role for the melatonin-based rhythm as a novel biomarker of critical illness severity. [Display omitted] • Among ICU patients, 24-h urinary melatonin rhythms are frequently phase delayed. • The amplitude of the aMT6s rhythm is significantly greater in ICU patients discharged home than not. • Patients with rhythmic aMT6s profiles are more likely to survive critical illness. • Arrhythmic 24-h aMT6s rhythms in ICU patients are associated with worse clinical outcomes. • Melatonin rhythm dysregulation may be a novel biomarker of critical illness severity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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317. Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility
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Bruse, Shannon, Moreau, Michael, Bromberg, Yana, Jang, Jun-Ho, Wang, Nan, Ha, Hongseok, Picchi, Maria, Lin, Yong, Langley, Raymond J., Qualls, Clifford, Klesney-Tait, Julia, Zabner, Joseph, Leng, Shuguang, Mao, Jenny, Belinsky, Steven A., Xing, Jinchuan, and Nyunoya, Toru
- Abstract
Background: Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible airflow limitation in response to inhalation of noxious stimuli, such as cigarette smoke. However, only 15–20 % smokers manifest COPD, suggesting a role for genetic predisposition. Although genome-wide association studies have identified common genetic variants that are associated with susceptibility to COPD, effect sizes of the identified variants are modest, as is the total heritability accounted for by these variants. In this study, an extreme phenotype exome sequencing study was combined with in vitro modeling to identify COPD candidate genes. Results: We performed whole exome sequencing of 62 highly susceptible smokers and 30 exceptionally resistant smokers to identify rare variants that may contribute to disease risk or resistance to COPD. This was a cross-sectional case-control study without therapeutic intervention or longitudinal follow-up information. We identified candidate genes based on rare variant analyses and evaluated exonic variants to pinpoint individual genes whose function was computationally established to be significantly different between susceptible and resistant smokers. Top scoring candidate genes from these analyses were further filtered by requiring that each gene be expressed in human bronchial epithelial cells (HBECs). A total of 81 candidate genes were thus selected for in vitro functional testing in cigarette smoke extract (CSE)-exposed HBECs. Using small interfering RNA (siRNA)-mediated gene silencing experiments, we showed that silencing of several candidate genes augmented CSE-induced cytotoxicity in vitro. Conclusions: Our integrative analysis through both genetic and functional approaches identified two candidate genes (TACC2and MYO1E) that augment cigarette smoke (CS)-induced cytotoxicity and, potentially, COPD susceptibility.
- Published
- 2016
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318. Role of CFTR on Sinus Development and Disease in the CF Pig
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Stoltz, David, Pezzulo, Alejandro, and Zabner, Joseph
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- 2010
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319. FXYD3 facilitates Na+ and liquid absorption across human airway epithelia by increasing the transport capacity of the Na/K ATPase.
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Portillo, Camilo Cano, Villacreses, Raul, Thurman, Andrew L., Pezzulo, Alejandro A., Zabner, Joseph, and Thornell, Ian M.
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ADENOSINE triphosphatase , *SHORT-circuit currents , *ION transport (Biology) , *EPITHELIAL cells , *ABSORPTION , *EPITHELIUM - Abstract
Na/K ATPase activity is essential for ion transport across epithelia. FXYD3, a γ subunit of the Na/K ATPase, is expressed in the airway, but its function remains undetermined. Single-cell RNA sequencing and immunohistochemistry revealed that FXYD3 localizes within the basolateral membrane of all airway epithelial cells. To study FXYD3 function, we reduced FXYD3 expression using siRNA. After permeabilizing the apical membrane with nystatin, epithelia pretreated with FXYD3-targeting siRNA had lower ouabain-sensitive short-circuit currents than control epithelia. FXYD3-targeting siRNA also reduced amiloride-sensitive short-circuit currents and liquid absorption across intact epithelia. These data are consistent with FXYD3 facilitating Na+ and liquid absorption. FXYD3 may be needed to maintain the high rates of Na+ and fluid absorption observed for airway and other FXYD3-expressing epithelia. [ABSTRACT FROM AUTHOR]
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- 2022
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320. The ΔF508Mutation Causes CFTR Misprocessing and Cystic Fibrosis–Like Disease in Pigs
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Ostedgaard, Lynda S., Meyerholz, David K., Chen, Jeng-Haur, Pezzulo, Alejandro A., Karp, Philip H., Rokhlina, Tatiana, Ernst, Sarah E., Hanfland, Robert A., Reznikov, Leah R., Ludwig, Paula S., Rogan, Mark P., Davis, Greg J., Dohrn, Cassie L., Wohlford-Lenane, Christine, Taft, Peter J., Rector, Michael V., Hornick, Emma, Nassar, Boulos S., Samuel, Melissa, Zhang, Yuping, Richter, Sandra S., Uc, Aliye, Shilyansky, Joel, Prather, Randall S., McCray, Paul B., Zabner, Joseph, Welsh, Michael J., and Stoltz, David A.
- Abstract
A common mutation in human cystic fibrosis, CFTR-ΔF508, results in misprocessed CFTR and a cystic fibrosis–like clinical phenotype in pigs.
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- 2011
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321. Effects of Tham Nasal Alkalinization on Airway Microbial Communities: A Pilot Study in Non-CF and CF Adults.
- Author
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Holliday, Zachary M., Launspach, Janice L., Durairaj, Lakshmi, Singh, Pradeep K., Zabner, Joseph, and Stoltz, David A.
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TROMETHAMINE , *SODIUM bicarbonate , *PILOT projects , *HOST-bacteria relationships , *CORYNEBACTERIUM , *CYSTIC fibrosis , *HUMAN microbiota , *STAPHYLOCOCCUS aureus , *GRAM-positive bacteria , *ADULTS - Abstract
Objectives: In cystic fibrosis (CF), loss of CFTR-mediated bicarbonate secretion reduces the airway surface liquid (ASL) pH causing airway host defense defects. Aerosolized sodium bicarbonate can reverse these defects, but its effects are short-lived. Aerosolized tromethamine (THAM) also raises the ASL pH but its effects are much longer lasting. In this pilot study, we tested the hypothesis that nasally administered THAM would alter the nasal bacterial composition in adults with and without CF. Methods: Subjects (n = 32 total) received intranasally administered normal saline or THAM followed by a wash out period prior to receiving the other treatment. Nasal bacterial cultures were obtained prior to and after each treatment period. Results: At baseline, nasal swab bacterial counts were similar between non-CF and CF subjects, but CF subjects had reduced microbial diversity. Both nasal saline and THAM were well-tolerated. In non-CF subjects, nasal airway alkalinization decreased both the total bacterial density and the gram-positive bacterial species recovered. In both non-CF and CF subjects, THAM decreased the amount of Corynebacterium accolens detected, but increased the amount of Corynebacterium pseudodiphtheriticum recovered on nasal swabs. A reduction in Staphylococcus aureus nasal colonization was also found in subjects who grew C. pseudodiphtheriticum. Conclusions: This study shows that aerosolized THAM is safe and well-tolerated and that nasal airway alkalinization alters the composition of mucosal bacterial communities. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
322. Tromethamine improves mucociliary clearance in cystic fibrosis pigs.
- Author
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Ash, Jamison J., Hilkin, Brieanna M., Gansemer, Nicholas D., Hoffman, Eric A., Zabner, Joseph, Stoltz, David A., and Abou Alaiwa, Mahmoud H.
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CYSTIC fibrosis transmembrane conductance regulator , *MUCOCILIARY system , *CYSTIC fibrosis , *SWINE , *HYPERTONIC saline solutions - Abstract
In cystic fibrosis (CF), the loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated Cl− and HCO3− secretion across the epithelium acidifies the airway surface liquid (ASL). Acidic ASL alters two key host defense mechanisms: Rapid ASL bacterial killing and mucociliary transport (MCT). Aerosolized tromethamine (Tham) increases ASL pH and restores the ability of ASL to rapidly kill bacteria in CF pigs. In CF pigs, clearance of insufflated microdisks is interrupted due to abnormal mucus causing microdisks to abruptly recoil. Aerosolizing a reducing agent to break disulfide bonds that link mucins improves MCT. Here, we are interested in restoring MCT in CF by aerosolizing Tham, a buffer with a pH of 8.4. Because Tham is hypertonic to serum, we use an acidified formulation as a control. We measure MCT by tracking the caudal movement of individual tantalum microdisks with serial chest computed tomography scans. Alkaline Tham improves microdisk clearance to within the range of that seen in non‐CF pigs. It also partially reverses MCT defects, including reduced microdisk recoil and elapse time until they start moving after methacholine stimulation in CF pig airways. The effect is not due to hypertonicity, as it is not seen with acidified Tham or hypertonic saline. This finding indicates acidic ASL impairs CF MCT and suggests that alkalinization of ASL pH with inhaled Tham may improve CF airway disease. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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323. Vitamin D-mediated effects on airway innate immunity in vitro.
- Author
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Stapleton, Emma M., Keck, Kathy, Windisch, Robert, Stroik, Mallory R., Thurman, Andrew L., Zabner, Joseph, Thornell, Ian M., Pezzulo, Alejandro A., Klesney-Tait, Julia, and Comellas, Alejandro P.
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NATURAL immunity , *VITAMINS , *DIETARY supplements , *VITAMIN D , *AIRWAY (Anatomy) , *CALCITRIOL - Abstract
Introduction: Vitamin D supplementation has been suggested to enhance immunity during respiratory infection season. We tested the effect of active vitamin D (calcitriol) supplementation on key airway innate immune mechanisms in vitro. Methods: Primary human airway epithelial cells (hAECs) grown at the air liquid interface were supplemented with 10−7 M calcitriol for 24 hours (or a time course) and their antimicrobial airway surface liquid (ASL) was tested for pH, viscoscity, and antibacterial and antiviral properties. We also tested hAEC ciliary beat frequency (CBF). Next, we assessed alterations to hAEC gene expression using RNA sequencing, and based on results, we measured neutrophil migration across hAECs. Results: Calcitriol supplementation enhanced ASL bacterial killing of Staphylococcus aureus (p = 0.02) but did not enhance its antiviral activity against 229E-CoV. It had no effect on ASL pH or viscosity at three timepoints. Lastly, it did not affect hAEC CBF or neutrophil migration, although there was a trend of enhanced migration in the presence of a neutrophil chemokine (p = 0.09). Supplementation significantly altered hAEC gene expression, primarily of AMP-related genes including CAMP and TREM1. Conclusion: While vitamin D supplementation did not have effects on many airway innate immune mechanisms, it may provide a useful tool to resolve respiratory bacterial infections. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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324. Urban Particulate Matter Impairment of Airway Surface Liquid-Mediated Coronavirus Inactivation.
- Author
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Stapleton, Emma M, Welch, Jennifer L, Ubeda, Erika A, Xiang, Jinhua, Zabner, Joseph, Thornell, Ian M, Nonnenmann, Matthew W, Stapleton, Jack T, and Comellas, Alejandro P
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PARTICULATE matter , *INDOOR air pollution , *COVID-19 , *COMMON cold , *VOLCANIC ash, tuff, etc. - Abstract
Air pollution particulate matter (PM) is associated with SARS-CoV-2 infection and severity, although mechanistic studies are lacking. We tested whether airway surface liquid (ASL) from primary human airway epithelial cells is antiviral against SARS-CoV-2 and human alphacoronavirus 229E (CoV-229E) (responsible for common colds), and whether PM (urban, indoor air pollution [IAP], volcanic ash) affected ASL antiviral activity. ASL inactivated SARS-CoV-2 and CoV-229E. Independently, urban PM also decreased SARS-CoV-2 and CoV-229E infection, and IAP PM decreased CoV-229E infection. However, in combination, urban PM impaired ASL's antiviral activity against both viruses, and the same effect occurred for IAP PM and ash against SARS-CoV-2, suggesting that PM may enhance SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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325. The Coxsackie B Virus and Adenovirus Receptor Resides in a Distinct Membrane Microdomain.
- Author
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Excoffon, Katherine J.D. Ashbourne, Moninger, Thomas, and Zabner, Joseph
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COXSACKIEVIRUSES , *ADENOVIRUSES - Abstract
The coxsackie B virus and adenovirus receptor (CAR) is a member of the immunoglobulin superfamily. In addition to activity as a viral receptor, it may play a role in cellular adhesion. We asked what determines the cell membrane microdomain of CAR. We found that CAR is localized to a novel lipid-rich microdomain similar to that of the low-density lipoprotein receptor (LDLR) but distinct from that of a CAR variant that exhibited traditional lipid raft localization via fusion to a glycosylphosphatidylinositoi (GPI) tail. The cytoplasmic tail determines its membrane localization, since deletion of this domain resulted in mislocalization. Results indicate that CAR, CAR-LDLR, and LDLR reside in a novel lipid raft that is distinct from caveolin-1containing caveolae and GPI-linked proteins. Residence in a lipid-rich domain provides a mechanism that allows CAR to interact with other cell adhesion proteins and yet function as an adenovirus receptor. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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326. Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions.
- Author
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Miller, Aaron C., Comellas, Alejandro P., Hornick, Douglas B., Stoltz, David A., Cavanaugh, Joseph E., Gerke, Alicia K., Welsh, Michael J., Zabner, Joseph, and Polgreen, Philip M.
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CYSTIC fibrosis , *MALE infertility , *SHORT stature , *GENETIC testing - Abstract
Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CFrelated diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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327. Randomized controlled study of aerosolized hypertonic xylitol versus hypertonic saline in hospitalized patients with pulmonary exacerbation of cystic fibrosis.
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Singh, Sachinkumar, Hornick, Douglas, Fedler, Janel, Launspach, Janice L., Teresi, Mary E., Santacroce, Thomas R., Cavanaugh, Joseph E., Horan, Rebecca, Nelson, George, Starner, Timothy D., Zabner, Joseph, and Durairaj, Lakshmi
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HYPERTONIC saline solutions , *CYSTIC fibrosis , *XYLITOL , *CLINICAL trial registries , *HOSPITAL patients , *SPUTUM examination , *BRONCHIECTASIS - Abstract
Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and recurrent pulmonary exacerbations. Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration and augment innate immunity. We examined the safety and efficacy of aerosolized xylitol use for 2 weeks in subjects hospitalized with a pulmonary exacerbation of CF. In a 2-week study, 60 subjects with cystic fibrosis and FEV 1 > 30% predicted were enrolled to receive aerosolized 7% hypertonic saline (4 ml) or 15% xylitol (5 ml) twice a day for 14 days. Outcomes assessed included change from baseline in FEV 1 % predicted, change in sputum microbial density, revised CF quality of life questionnaire including the respiratory symptom score, time to next hospitalization for a pulmonary exacerbation, and frequency of adverse events. 59 subjects completed the study (one subject in the saline group withdrew before any study product administration). No significant differences were noted between the 2 arms in mean changes in lung function, sputum microbial density for Pseudomonas aeruginosa and Staphylococcus aureus , body weight, quality of life, and frequency of adverse events. Aerosolized hypertonic xylitol was well-tolerated among subjects hospitalized for CF pulmonary exacerbation. Future studies examining efficacy for long term use in patients with CF lung disease would be worthwhile. The clinical trial registration number for this study is NCT00928135. • The mean change in lung function was not different between the treatment groups. • Improvement in FEV 1 and FVC, BMI and WBC at treatment completion in both groups. • No difference in the median time to next exacerbation between the groups. • No difference in the incidence of adverse events between the groups. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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328. HSP90 inhibitor geldanamycin reverts IL-13- and IL-17-induced airway goblet cell metaplasia.
- Author
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Pezzulo, Alejandro A., Tudas, Rosarie A., Stewart, Carley G., Buonfiglio, Luis G. Vargas, Lindsay, Brian D., Taft, Peter J., Gansemer, Nicholas D., and Zabner, Joseph
- Abstract
Goblet cell metaplasia, a disabling hallmark of chronic lung disease, lacks curative treatments at present. To identify novel therapeutic targets for goblet cell metaplasia, we studied the transcriptional response profile of IL-13-exposed primary human airway epithelia in vitro and asthmatic airway epithelia in vivo. A perturbation-response profile connectivity approach identified geldanamycin, an inhibitor of heat shock protein 90 (HSP90) as a candidate therapeutic target. Our experiments confirmed that geldanamycin and other HSP90 inhibitors prevented IL-13-induced goblet cell metaplasia in vitro and in vivo. Geldanamycin also reverted established goblet cell metaplasia. Geldanamycin did not induce goblet cell death, nor did it solely block mucin synthesis or IL-13 receptor-proximal signaling. Geldanamycin affected the transcriptome of airway cells when exposed to IL-13, but not when exposed to vehicle. We hypothesized that the mechanism of action probably involves TGF-β, ERBB, or EHF, which would predict that geldanamycin would also revert IL-17-induced goblet cell metaplasia, a prediction confirmed by our experiments. Our findings suggest that persistent airway goblet cell metaplasia requires HSP90 activity and that HSP90 inhibitors will revert goblet cell metaplasia, despite active upstream inflammatory signaling. Moreover, HSP90 inhibitors may be a therapeutic option for airway diseases with goblet cell metaplasia of unknown mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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329. Effects of Coal Fly Ash Particulate Matter on the Antimicrobial Activity of Airway Surface Liquid.
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Buonfiglio, Luis G. Vargas, Mudunkotuwa, Imali A., Alaiwa, Mahmoud H. Abou, Calderón, Oriana G. Vanegas, Borcherding, Jennifer A., Gerke, Alicia K., Zabner, Joseph, Grassian, Vicki H., and Comellas, Alejandro P.
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AIR pollution , *ANALYSIS of variance , *ANIMAL experimentation , *ANTI-infective agents , *BRONCHOSCOPY , *CELL culture , *FLUIDS , *FLUORESCENCE spectroscopy , *FOSSIL fuels , *IMMUNOASSAY , *PEPTIDES , *PROTEINS , *RESEARCH funding , *RESPIRATORY organ physiology , *SWINE , *T-test (Statistics) , *PARTICULATE matter , *DATA analysis software , *DESCRIPTIVE statistics , *IN vitro studies , *MANN Whitney U Test , *KRUSKAL-Wallis Test - Abstract
BACKGROUND: Sustained exposure to ambient particulate matter (PM) is a global cause of mortality. Coal fly ash (CFA) is a byproduct of coal combustion and is a source of anthropogenic PM with worldwide health relevance. The airway epithelia are lined with fluid called airway surface liquid (ASL), which contains antimicrobial proteins and peptides (AMPs). Cationic AMPs bind negatively charged bacteria to exert their antimicrobial activity. PM arriving in the airways could potentially interact with AMPs in the ASL to affect their antimicrobial activity. OBJECTIVES: We hypothesized that PM can interact with ASL AMPs to impair their antimicrobial activity. METHODS: We exposed pig and human airway explants, pig and human ASL, and the human cationic AMPs b-defensin-3, LL-37, and lysozyme to CFA or control. Thereafter, we assessed the antimicrobial activity of exposed airway samples using both bioluminescence and standard colonyforming unit assays. We investigated PM-AMP electrostatic interaction by attenuated total reflection Fourier-transform infrared spectroscopy and measuring the zeta potential. We also studied the adsorption of AMPs on PM. METHODS: We exposed pig and human airway explants, pig and human ASL, and the human cationic AMPs b-defensin-3, LL-37, and lysozyme to CFA or control. Thereafter, we assessed the antimicrobial activity of exposed airway samples using both bioluminescence and standard colonyforming unit assays. We investigated PM-AMP electrostatic interaction by attenuated total reflection Fourier-transform infrared spectroscopy and measuring the zeta potential. We also studied the adsorption of AMPs on PM. METHODS: We exposed pig and human airway explants, pig and human ASL, and the human cationic AMPs b-defensin-3, LL-37, and lysozyme to CFA or control. Thereafter, we assessed the antimicrobial activity of exposed airway samples using both bioluminescence and standard colonyforming unit assays. We investigated PM-AMP electrostatic interaction by attenuated total reflection Fourier-transform infrared spectroscopy and measuring the zeta potential. We also studied the adsorption of AMPs on PM. RESULTS: We found increased bacterial survival in CFA-exposed airway explants, ASL, and AMPs. In addition, we report that PM with a negative surface charge can adsorb cationic AMPs and form negative particle-protein complexes. CONCLUSION: We propose that when CFA arrives at the airway, it rapidly adsorbs AMPs and creates negative complexes, thereby decreasing the functional amount of AMPs capable of killing pathogens. These results provide a novel translational insight into an early mechanism for how ambient PM increases the susceptibility of the airways to bacterial infection. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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330. Airway acidification initiates host defense abnormalities in cystic fibrosis mice.
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Shah, Viral S., Meyerholz, David K., Xiao Xiao Tang, Reznikov, Leah, Alaiwa, Mahmoud Abou, Ernst, Sarah E., Karp, Philip H., Wohlford-Lenane, Christine L., Heilmann, Kristopher P., Leidinger, Mariah R., Allen, Patrick D., Zabner, Joseph, McCray Jr, Paul B., Ostedgaard, Lynda S., Stoltz, David A., Randak, Christoph O., and Welsh, Michael J.
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ACIDIFICATION , *CYSTIC fibrosis , *LABORATORY mice , *BICARBONATE ions , *GENETIC mutation - Abstract
Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H+ secretion by the nongastric H+/K+ adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H+; consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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331. Aggregates of mutant CFTR fragments in airway epithelial cells of CF lungs: New pathologic observations.
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Du, Kai, Karp, Philip H., Ackerley, Cameron, Zabner, Joseph, Keshavjee, Shaf, Cutz, Ernest, and Yeger, Herman
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CYSTIC fibrosis transmembrane conductance regulator , *GENETIC mutation , *EPITHELIAL cells , *HOMEOSTASIS , *LYSOSOMES - Abstract
Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene resulting in a loss of Cl − channel function, disrupting ion and fluid homeostasis, leading to severe lung disease with airway obstruction due to mucus plugging and inflammation. The most common CFTR mutation, F508del, occurs in 90% of patients causing the mutant CFTR protein to misfold and trigger an endoplasmic reticulum based recycling response. Despite extensive research into the pathobiology of CF lung disease, little attention has been paid to the cellular changes accounting for the pathogenesis of CF lung disease. Here we report a novel finding of intracellular retention and accumulation of a cleaved fragment of F508del CFTR in concert with autophagic like phagolysosomes in the airway epithelium of patients with F508del CFTR. Aggregates consisting of poly-ubiquitinylated fragments of only the N-terminal domain of F508del CFTR but not the full-length molecule accumulate to appreciable levels. Importantly, these undegraded intracytoplasmic aggregates representing the NT-NBD1 domain of F508del CFTR were found in ciliated, in basal, and in pulmonary neuroendocrine cells. Aggregates were found in both native lung tissues and ex-vivo primary cultures of bronchial epithelial cells from CF donors, but not in normal control lungs. Our findings present a new, heretofore, unrecognized innate CF gene related cell defect and a potential contributing factor to the pathogenesis of CF lung disease. Mutant CFTR intracytoplasmic aggregates could be analogous to the accumulation of misfolded proteins in other degenerative disorders and in pulmonary “conformational protein-associated” diseases. Consequently, potential alterations to the functional integrity of airway epithelium and regenerative capacity may represent a critical new element in the pathogenesis of CF lung disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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332. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis.
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Hoegger, Mark J., Fischer, Anthony J., McMenimen, James D., Ostedgaard, Lynda S., Tucker, Alex J., Awadalla, Maged A., Moninger, Thomas O., Michalski, Andrew S., Hoffman, Eric A., Zabner, Joseph, Stoltz, David A., and Welsh, Michael J.
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CYSTIC fibrosis , *LUNG diseases , *BACTERIAL diseases , *MUCOCILIARY system , *CHOLINERGIC mechanisms , *MUCUS , *PHYSIOLOGY - Abstract
Lung disease in people with cystic fibrosis (CF) is initiated by defective host defense that predisposes airways to bacterial infection. Advanced CF is characterized by a deficit in mucociliary transport (MCT), a process that traps and propels bacteria out of the lungs, but whether this deficit occurs first or is secondary to airway remodeling has been unclear. To assess MCT, we tracked movement of radiodense microdisks in airways of newborn piglets with CF. Cholinergic stimulation, which elicits mucus secretion, substantially reduced microdisk movement. Impaired MCT was not due to periciliary liquid depletion; rather, CF submucosal glands secreted mucus strands that remained tethered to gland ducts. Inhibiting anion secretion in non-CF airways replicated CF abnormalities. Thus, impaired MCT is a primary defect in CF, suggesting that submucosal glands and tethered mucus may be targets for early CF treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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333. Abundant DNase I-Sensitive Bacterial DNA in Healthy Porcine Lungs and Its Implications for the Lung Microbiome.
- Author
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PezzuIo, Alejandro A., Kelly, Patrick H., Nassar, Boulos S., Rutland, Cedric J., Gansemer, Nicholas D., Dohrn, Cassie L., Costello, Andrew J., Stoltz, David A., and Zabner, Joseph
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LUNG microbiology , *NUCLEOTIDE sequence , *BACTERIAL diversity , *BRONCHOALVEOLAR lavage , *HOMOGENEITY - Abstract
Human lungs are constantly exposed to bacteria in the environment, yet the prevailing dogma is that healthy lungs are sterile. DNA sequencing-based studies of pulmonary bacterial diversity challenge this notion. However, DNA-based microbial analysis currently fails to distinguish between DNA from live bacteria and that from bacteria that have been killed by lung immune mechanisms, potentially causing overestimation of bacterial abundance and diversity. We investigated whether bacterial DNA recovered from lungs represents live or dead bacteria in bronchoalveolar lavage (BAL) fluid and lung samples in young healthy pigs. Live bacterial DNA was DNase I resistant and became DNase I sensitive upon human antimicrobial-mediated killing in vitro. We determined live and total bacterial DNA loads in porcine BAL fluid and lung tissue by comparing DNase I-treated versus untreated samples. In contrast to the case for BAL fluid, we were unable to culture bacteria from most lung homogenates. Surprisingly, total bacterial DNA was abundant in both BAL fluid and lung homogenates. In BAL fluid, 63% was DNase I sensitive. In 6 out of 11 lung homogenates, all bacterial DNA was DNase I sensitive, suggesting a predominance of dead bacteria; in the remaining homogenates, 94% was DNase I sensitive, and bacterial diversity determined by 16S rRNA gene sequencing was similar in DNase I-treated and untreated samples. Healthy pig lungs are mostly sterile yet contain abundant DNase I-sensitive DNA from inhaled and aspirated bacteria killed by pulmonary host defense mechanisms. This approach and conceptual frame- work will improve analysis of the lung microbiome in disease. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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334. Transepithelial migration of neutrophils into the lung requires TREM-1.
- Author
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Klesney-Tait, Julia, Keck, Kathy, Li, Xiaopeng, Gilfillan, Susan, Otero, Karel, Baruah, Sankar, Meyerholz, David K., Varga, Steven M., Knudson, Cory J., Moninger, Thomas O., Moreland, Jessica, Zabner, Joseph, and Colonna, Marco
- Subjects
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EPITHELIAL cells , *CELL migration , *NEUTROPHILS , *RESPIRATORY infections , *MORTALITY , *IMMUNE response , *ANTI-infective agents - Abstract
Acute respiratory infections are responsible for more than 4 million deaths each year. Neutrophils play an essential role in the innate immune response to lung infection. These cells have an armamentarium of pattern recognition molecules and antimicrobial agents that identify and eliminate pathogens. In the setting of infec-tion, neutrophil triggering receptor expressed on myeloid cells 1 (TREM-1) amplifies inflammatory signaling. Here we demonstrate for the first time that TREM-1 also plays an important role in transepithelial migra-tion of neutrophils into the airspace. We developed a TREM-l/3-deficient mouse model of pneumonia and found that absence of TREM-1/3 markedly increased mortality following Pseudomonas aeruginosa challenge. Unexpectedly, TREM-1 /3 deficiency resulted in increased local and systemic cytokine production. TREM-1/3-deficient neutrophils demonstrated intact bacterial killing, phagocytosis, and Chemotaxis; however, histo-logic examination of TREM-l/3-deficient lungs revealed decreased neutrophil infiltration of the airways. TREM-l/3-deficient neutrophils effectively migrated across primary endothelial cell monolayers but failed to migrate across primary airway epithelia grown at the air-liquid interface. These data define a new function for TREM-1 in neutrophil migration across airway epithelial cells and suggest that it amplifies inflammation through targeted neutrophil migration into the lung. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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335. Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions
- Author
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Lorentzen, Daniel, Durairaj, Lakshmi, Pezzulo, Alejandro A., Nakano, Yoko, Launspach, Janice, Stoltz, David A., Zamba, Gideon, McCray, Paul B., Zabner, Joseph, Welsh, Michael J., Nauseef, William M., and Bánfi, Botond
- Subjects
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ANTIBACTERIAL agents , *THIOCYANATES , *CYSTIC fibrosis , *FREE radicals , *PEROXIDASE , *GENETIC mutation , *AIRWAY (Anatomy) , *SECRETION - Abstract
Abstract: A recently discovered enzyme system produces antibacterial hypothiocyanite (OSCN−) in the airway lumen by oxidizing the secreted precursor thiocyanate (SCN−). Airway epithelial cultures have been shown to secrete SCN− in a CFTR-dependent manner. Thus, reduced SCN− availability in the airway might contribute to the pathogenesis of cystic fibrosis (CF), a disease caused by mutations in the CFTR gene and characterized by an airway host defense defect. We tested this hypothesis by analyzing the SCN− concentration in the nasal airway surface liquid (ASL) of CF patients and non-CF subjects and in the tracheobronchial ASL of CFTR-ΔF508 homozygous pigs and control littermates. In the nasal ASL, the SCN− concentration was ~30-fold higher than in serum independent of the CFTR mutation status of the human subject. In the tracheobronchial ASL of CF pigs, the SCN− concentration was somewhat reduced. Among human subjects, SCN− concentrations in the ASL varied from person to person independent of CFTR expression, and CF patients with high SCN− levels had better lung function than those with low SCN− levels. Thus, although CFTR can contribute to SCN− transport, it is not indispensable for the high SCN− concentration in ASL. The correlation between lung function and SCN− concentration in CF patients may reflect a beneficial role for SCN−. [Copyright &y& Elsevier]
- Published
- 2011
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336. Drosophila are protected from Pseudomonas aeruginosa lethality by transgenic expression of paraoxonase-1.
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Stoltz, David A., Ozer, Egon A., Taft, Peter J., Barry, Marilyn, Lei Liu, Kiss, Peter J., Moninger, Thomas O., Parsek, Matthew R., Zabner, Joseph, and Liu, Lei
- Subjects
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DROSOPHILA , *PSEUDOMONAS aeruginosa , *INTERNAL medicine , *DROSOPHILA melanogaster , *PARAOXONASE , *CARDIOVASCULAR diseases , *PSEUDOMONAS metabolism , *ANIMAL experimentation , *BIOLOGICAL models , *COMPARATIVE studies , *ESTERASES , *GENES , *IMMUNITY , *INFLAMMATION , *INSECTS , *RESEARCH methodology , *MEDICAL cooperation , *GENETIC mutation , *PSEUDOMONAS diseases , *RESEARCH , *TIME , *TRANSGENIC animals , *MICROBIAL virulence , *EVALUATION research , *PREVENTION - Abstract
Pseudomonas aeruginosa uses quorum sensing, an interbacterial communication system, to regulate gene expression. The signaling molecule N-3-oxododecanoyl homoserine lactone (3OC12-HSL) is thought to play a central role in quorum sensing. Since 3OC12-HSL can be degraded by paraoxonase (PON) family members, we hypothesized that PONs regulate P. aeruginosa virulence in vivo. We chose Drosophila melanogaster as our model organism because it has been shown to be a tractable model for investigating host-pathogen interactions and lacks PONs. By using quorum-sensing-deficient P. aeruginosa, synthetic acyl-HSLs, and transgenic expression of human PON1, we investigated the role of 3OC12-HSL and PON1 on P. aeruginosa virulence. We found that P. aeruginosa virulence in flies was dependent upon 3OC12-HSL. PON1 transgenic flies expressed enzymatically active PON1 and thereby exhibited arylesterase activity and resistance to organophosphate toxicity. Moreover, PON1 flies were protected from P. aeruginosa lethality, and protection was dependent on the lactonase activity of PON1. Our findings show that PON1 can interfere with quorum sensing in vivo and provide insight into what we believe is a novel role for PON1 in the innate immune response to quorum-sensing-dependent pathogens. These results raise intriguing possibilities about human-pathogen interactions, including potential roles for PON1 as a modifier gene and for PON1 protein as a regulator of normal bacterial florae, a link between infection/inflammation and cardiovascular disease, and a potential therapeutic modality. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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337. Safety assessment of inhaled xylitol in subjects with cystic fibrosis
- Author
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Durairaj, Lakshmi, Launspach, Janice, Watt, Janet L., Mohamad, Zeinab, Kline, Joel, and Zabner, Joseph
- Subjects
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XYLITOL , *CYSTIC fibrosis , *SAFETY , *SPIROMETRY , *SPUTUM , *PATIENTS - Abstract
Abstract: Background: Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration, thus enhancing innate immunity. We tested the safety and tolerability of aerosolized iso-osmotic xylitol in subjects with cystic fibrosis. Methods: In this pilot study, 6 subjects with cystic fibrosis and an FEV1 >60% predicted underwent a baseline spirometry followed by exposures to aerosolized saline (10 ml) and 5% xylitol (10 ml). Serum osmolarity and electrolytes were measured at baseline and after xylitol exposure. Spirometry, oxygen saturation and respiratory symptom questionnaire using visual analog scale were tested at baseline and after each exposure. Sputum for cytokine analysis was collected after saline and xylitol nebulizations. Results: There was no change in FEV1 after xylitol exposure compared with baseline or normal saline exposure (p =0.19). Laboratory values and respiratory symptoms were not affected by xylitol inhalation. The mean IL-8 level in the sputum was similar with saline and xylitol exposures (3.5±0.5 vs. 3.5±0.6 ng/ml). Conclusions: A single dose inhalation of aerosolized iso-osmotic xylitol was well tolerated by subjects with cystic fibrosis. Future studies of long term safety are required. [Copyright &y& Elsevier]
- Published
- 2007
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338. The Coxsackievirus and Adenovirus Receptor: A new adhesion protein in cochlear development
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Excoffon, Katherine J.D.A., Avenarius, Matthew R., Hansen, Marlan R., Kimberling, William J., Najmabadi, Hossein, Smith, Richard J.H., and Zabner, Joseph
- Subjects
- *
EAR diseases , *HEARING , *HEARING disorders , *COCHLEA - Abstract
Abstract: The Coxsackievirus and Adenovirus Receptor (CAR) is an essential regulator of cell growth and adhesion during development. The gene for CAR, CXADR, is located within the genomic locus for Usher syndrome type 1E (USH1E). Based on this and a physical interaction with harmonin, the protein responsible for USH1C, we hypothesized that CAR may be involved in cochlear development and that mutations in CXADR may be responsible for USH1E. The expression of CAR in the cochlea was determined by PCR and immunofluorescence microscopy. We found that CAR expression is highly regulated during development. In neonatal mice, CAR is localized to the junctions of most cochlear cell types but is restricted to the supporting and strial cells in adult cochlea. A screen of two populations consisting of non-syndromic deaf and Usher 1 patients for mutations in CXADR revealed one haploid mutation (P356S). Cell surface expression, viral receptor activity, and localization of the mutant form of CAR were indistinguishable from wild-type CAR. Although we were unable to confirm a role for CAR in autosomal recessive, non-syndromic deafness, or Usher syndrome type 1, based on its regulation, localization, and molecular interactions, CAR remains an attractive candidate for genetic deafness. [Copyright &y& Elsevier]
- Published
- 2006
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339. The indirect effect of Tityus discrepans on rabbit pulmonary vasculature
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Novoa, Eva, D'Suze, Gina, Winter, Michael, Crespo, Astrid, Tortoledo, Maria A., Marcano, Héctor, Friedman, Eliot, Sevcik, Carlos, Zabner, Joseph, and Sánchez de León, Roberto
- Subjects
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SERUM , *RABBITS , *VENOM , *PULMONARY artery , *LUNGS , *SCORPION venom , *UMBILICAL cord , *EPITHELIUM , *VASCULAR endothelium - Abstract
Serum (IS) was obtained 0.5, 2, 4 or 6 h after inoculating s.c. six rabbits (≈2 kg) in each time period with 1 mg/kg of Tityus discrepans (Td) venom; the control was serum obtained from four rabbits 4 h after injecting them 1 ml s.c. of 0.9% NaCl. IS produced a transient (<25 min) rise in pulmonary artery pressure of isolated and perfused rabbit lungs, other lung parameters were not altered. We found that both scorpion venom and IS produced a ≈50% transient increase of transendothelial electric resistance in cultured tissue human umbilical cord vein. Neither venom nor IS changed the transepithelial electrical resistance of tissue cultured human airway epithelia. The experiments suggest that humoral factors contained in the inoculated serum modify vascular endothelium in a much more effective manner than the venom by itself. These experiments also make it unlikely that vascular endothelium is the source of the humoral factors contained in inflammatory serum. [Copyright &y& Elsevier]
- Published
- 2003
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340. Adenovirus Fiber Disrupts CAR-Mediated Intercellular Adhesion Allowing Virus Escape.
- Author
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Walters, Robert W., Freimuth, Paul, Moninger, Thomas O., Ganske, Ingrid, Zabner, Joseph, and Welsh, Michael J.
- Subjects
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CELL adhesion , *ADENOVIRUSES , *EPITHELIUM - Abstract
Investigates the mechanism of intercellular adhesion disruption by adenovirus fiber. Improvement of junction integrity at the basolateral membrane; Use of cell-cell adhesion molecules for epithelia-tropic virus; Role of human airway epithelia in the release of adenovirus to baselateral surface.
- Published
- 2002
- Full Text
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341. Residential urban tree canopy is associated with decreased mortality during tuberculosis treatment in California.
- Author
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Blount, Robert J., Pascopella, Lisa, Barry, Pennan, Zabner, Joseph, Stapleton, Emma M., Flood, Jennifer, Balmes, John, Nahid, Payam, and Catanzaro, Donald G.
- Abstract
• Tuberculosis is the leading cause of death from infection worldwide. • It is unknown if trees could mitigate the harmful effects of air pollution on tuberculosis patients. • Using Kaplan-Meier and Cox survival analyses, we determined the effects of trees on tuberculosis patient mortality. • Those living in neighborhoods with high percent tree cover were less likely to die during treatment. • Trees may provide health benefits to patients undergoing tuberculosis treatment. Trees can sequester air pollutants, and air pollution is associated with poor tuberculosis outcomes. However, the health impacts of urban trees on tuberculosis patients are unknown. To elucidate the effects of urban tree canopy on mortality during tuberculosis treatment, we evaluated patients diagnosed with active tuberculosis in California from 2000 through 2012, obtaining patient data from the California tuberculosis registry. Our primary outcome was all-cause mortality during tuberculosis treatment. We determined percent tree cover using 1 mresolution color infrared orthoimagery categorized into land cover classes, then linked tree cover to four circular buffer zones of 50–300 m radii around patient residential addresses. We used the Kaplan-Meier method to estimate survival probabilities and Cox regression models to determine mortality hazard ratios, adjusting for demographic, socioeconomic, and clinical covariates. Our cohort included 33,962 tuberculosis patients of median age 47, 59% male, 51% unemployed, and 4.9% HIV positive. Tuberculosis was microbiologically confirmed in 79%, and 1.17% were multi-drug resistant (MDR). Median tree cover was 7.9% (50 m buffer). Patients were followed for 23,280 person-years with 2370 deaths during tuberculosis treatment resulting in a crude mortality rate of 1018 deaths per 10,000 person-years. Increasing tree cover quintiles were associated with decreasing mortality risk during tuberculosis treatment in all buffers, and the magnitude of association decreased incrementally with increasing buffer radius: In the 50 m buffer, patients living in neighborhoods with the highest quintile tree cover experienced a 22% reduction in mortality (HR 0.78, 95%CI 0.68–0.90) compared to those living in lowest quintile tree cover; whereas for 100, 200, and 300 m buffers, a 21%, 13%, and 11% mortality risk reduction was evident. In conclusion, urban tree canopy was associated with decreased mortality during tuberculosis treatment even after adjusting for multiple demographic, socioeconomic, and clinical factors, suggesting that trees might play a role in improving tuberculosis outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
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342. 814. Adenovirus-Mediated Gene Transfer Demonstrates That Pirin, a Transcription Factor Up-Regulated in the Bronchial Epithelium by Cigarette Smoke, Mediates Bronchial Epithelial Cell Apoptosis
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Gelbman, Brian D., Heguy, Adriana, O'Connor, Timothy P., Zabner, Joseph, and Crystal, Ronald G.
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EPITHELIAL cells , *GENETIC transformation - Abstract
An abstract of the article "Adenovirus-Mediated Gene Transfer Demonstrates That Pirin, a Transcription Factor Up-Regulated in the Bronchial Epithelium by Cigarette Smoke, Mediates Bronchial Epithelial Cell Apoptosis," by Brian D. Gelbman and colleagues is presented.
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- 2005
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343. Functional Effects of Coxsackievirus and Adenovirus Receptor Glycosylation on Homophilic Adhesion and Adenoviral Infection.
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Ashbourne Excoffon, Katherine J. D., Gansemer, Nicholas, Traver, Geri, and Zabner, Joseph
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COXSACKIEVIRUSES , *ADENOVIRUSES , *VIRAL receptors , *INTEGRINS , *IMMUNOGLOBULINS , *GLYCOSYLATION - Abstract
The coxsackievirus and adenovirus receptor (CAR) is both a viral receptor and homophilic adhesion protein. The extracellular portion of CAR consists of two immunoglobulin (Ig)-like domains, each with a consensus sequence for N-glycosylation. We used chemical, genetic, and biochemical studies to show that both sites are glycosylated and contribute to the function of CAR. Although the glycosylation of CAR does not alter cell surface levels or junctional localization, it affects both adhesion and adenovirus infection in unique ways. CAR-mediated adhesion appears to require at least one site of glycosylation since cells expressing CAR without glycosylation do not cluster with each other. In contrast, glycosylation of the Ig-like domain proximal to the membrane is key to the cooperative behavior of adenovirus binding and infection. Contrary to the hypothesis that cooperativity improves viral infection, our data show that although glycosylation of the D2 domain is required for adenovirus cooperative binding, it has a negative consequence upon infection. This is the first report dissecting the adhesion and receptor activities of CAR, revealing that factors other than the binding interface play a significant role in the function of CAR. These data have important implications for both cancers with altered glycosylation states and cancer treatments using oncolytic adenovirus. [ABSTRACT FROM AUTHOR]
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- 2007
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344. 747. Identification and Characterization of Mutations within the Coxsackievirus and Adenovirus Receptor (CAR)
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Excoffon, Katherine J.D.A., Avenarius, Matthew, Smith, Richard, and Zabner, Joseph
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- *
COXSACKIEVIRUSES , *GENETIC mutation - Abstract
An abstract of the article "Identification and Characterization of Mutations within the Coxsackievirus and Adenovirus Receptor (CAR)," by Katherine J. D. A. Excoffon, Matthew Avenarius, Richard Smith and Joseph Zabner is presented.
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- 2005
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345. Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia.
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Abou Alaiwa MA, Hilkin BM, Price MP, Gansemer ND, Rector MR, Stroik MR, Powers LS, Whitworth KM, Samuel MS, Jain A, Ostedgaard LS, Ernst SE, Philibert W, Boyken LD, Moninger TO, Karp PH, Hornick DB, Sinn PL, Fischer AJ, Pezzulo AA, McCray PB, Meyerholz DK, Zabner J, Prather RS, Welsh MJ, and Stoltz DA
- Abstract
Mutations in more than 50 different genes cause primary ciliary dyskinesia (PCD) by disrupting the activity of motile cilia that facilitate mucociliary transport (MCT). Knowledge of PCD has come from studies identifying disease-causing mutations, characterizing structural cilia abnormalities, finding genotype-phenotype relationships, and studying the cell biology of cilia. Despite these important findings, we still lack effective treatments and people with PCD have significant pulmonary impairment. As with many other diseases, a better understanding of pathogenic mechanisms may lead to effective treatments. To pursue disease mechanisms, we used CRISPR-Cas9 to develop a PCD pig with a disrupted DNAI1 gene. PCD pig airway cilia lacked the outer dynein arm and had impaired beating. MCT was impaired under both baseline conditions and after cholinergic stimulation in PCD pigs. Neonatal PCD pigs developed neonatal respiratory distress with evidence of atelectasis, air trapping, and airway mucus obstruction. Despite airway mucus accumulation, lung bacterial counts were similar between neonatal wild-type and PCD pigs. Sinonasal disease was present in all neonatal PCD pigs. Older PCD pigs developed worsening airway mucus obstruction, inflammation, and bacterial infection. This pig model closely mimics the disease phenotype seen in people with PCD and can be used to better understand the pathophysiology of PCD airway disease.
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- 2024
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346. Mucociliary Clearance is Impaired in Small Airways of Cystic Fibrosis Pigs.
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Stewart CG, Hilkin BM, Gansemer ND, Adam RJ, Dick DW, Sunderland JJ, Stoltz DA, Zabner J, and Abou Alaiwa MH
- Abstract
Cystic fibrosis is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance and progressive decline in lung function. The disease may start in the small airways; however, this is difficult to prove due to limited accessibility of the small airways with the current single photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of [
68 Ga] tagged macro-aggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down few minutes after delivery. Cystic fibrosis pig small airways cleared significantly less than non-CF pig small airways (non-CF 25.1±3.1% vs. CF 14.6±0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue UTP further impaired clearance (non-CF with UTP 20.9±0.3% vs. CF with UTP 13.0±1.8%). None of the cystic fibrosis pig treated with UTP (N = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.- Published
- 2024
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347. Long-COVID improves in 50% of patients after a year in a Midwestern cohort.
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Stalker G, Tudas R, Garg A, Graham L, Thurman AL, Wiblin RT, Hamzeh N, Blount RJ, Villacreses R, Zabner J, Comellas A, Cho JL, and Pezzulo A
- Abstract
Background: Many of those infected with COVID-19 experience long-term disability due to persistent symptoms known as Long-COVID, which include ongoing respiratory issues, loss of taste and smell, and impaired daily functioning., Research Question: This study aims to better understand the chronology of long-COVID symptoms., Study Design and Methods: We prospectively enrolled 403 adults from the University of Iowa long-COVID clinic (June 2020 to February 2022). Participants provided symptom data during acute illness, symptom progression, and other clinical characteristics. Patients in this registry received a survey containing questions including current symptoms and status since long-COVID diagnosis (sliding status scale, PHQ2, GAD2, MMRC). Those >12 months since acute-COVID diagnosis had chart review done to track their symptomology., Results: Of 403 participants contacted, 129 (32%) responded. The mean age (in years) was 50.17 +/-14.28, with 31.8% male and 68.2% female. Severity of acute covid treatment was stratified by treatment in the outpatient (70.5%), inpatient (16.3%), or ICU (13.2%) settings. 51.2% reported subjective improvement (sliding scale scores of 67-100) since long-COVID onset. Ages 18-29 reported significantly higher subjective status scores. Subjective status scores were unaffected by severity. 102 respondents were >12 months from their initial COVID-19 diagnosis and were tracked for longitudinal symptom persistence. All symptoms tracked had variance (mean fraction 0.58, range 0.34-0.75) in the reported symptoms at the time of long-COVID presentation when compared with patient survey report. 48 reported persistent dyspnea, 23 (48%) had resolved it at time of survey. For fatigue, 44 had persistence, 12 (27%) resolved., Interpretation: Overall, 51.2% respondents improved since their long-COVID began. Pulmonary symptoms were more persistent than neuromuscular symptoms (anosmia, dysgeusia, myalgias). Gender, time since acute COVID infection, and its severity didn't affect subjective status or symptoms. This study highlights recall bias that may be prevalent in other long-COVID research reliant on participant memory.
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- 2024
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348. Chronic obstructive pulmonary disease (COPD) and COPD-like phenotypes.
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Fortis S, Georgopoulos D, Tzanakis N, Sciurba F, Zabner J, and Comellas AP
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Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease. Historically, two COPD phenotypes have been described: chronic bronchitis and emphysema. Although these phenotypes may provide additional characterization of the pathophysiology of the disease, they are not extensive enough to reflect the heterogeneity of COPD and do not provide granular categorization that indicates specific treatment, perhaps with the exception of adding inhaled glucocorticoids (ICS) in patients with chronic bronchitis. In this review, we describe COPD phenotypes that provide prognostication and/or indicate specific treatment. We also describe COPD-like phenotypes that do not necessarily meet the current diagnostic criteria for COPD but provide additional prognostication and may be the targets for future clinical trials., Competing Interests: SF has received grants from American Thoracic Society and Fisher & Paykel and has served as a consultant for Society of Hospital Medicine (SHM). AC has consulted GSK, AstraZeneca, and VIDA Diagnostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fortis, Georgopoulos, Tzanakis, Sciurba, Zabner and Comellas.)
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- 2024
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349. FXYD3 facilitates Na + and liquid absorption across human airway epithelia by increasing the transport capacity of the Na/K ATPase.
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Cano Portillo C, Villacreses R, Thurman AL, Pezzulo AA, Zabner J, and Thornell IM
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- Humans, Membrane Proteins metabolism, Neoplasm Proteins metabolism, Nystatin, RNA, Small Interfering genetics, Sodium metabolism, Sodium-Potassium-Exchanging ATPase genetics, Sodium-Potassium-Exchanging ATPase metabolism, Amiloride, Ouabain
- Abstract
Na/K ATPase activity is essential for ion transport across epithelia. FXYD3, a γ subunit of the Na/K ATPase, is expressed in the airway, but its function remains undetermined. Single-cell RNA sequencing and immunohistochemistry revealed that FXYD3 localizes within the basolateral membrane of all airway epithelial cells. To study FXYD3 function, we reduced FXYD3 expression using siRNA. After permeabilizing the apical membrane with nystatin, epithelia pretreated with FXYD3 -targeting siRNA had lower ouabain-sensitive short-circuit currents than control epithelia. FXYD3 -targeting siRNA also reduced amiloride-sensitive short-circuit currents and liquid absorption across intact epithelia. These data are consistent with FXYD3 facilitating Na
+ and liquid absorption. FXYD3 may be needed to maintain the high rates of Na+ and fluid absorption observed for airway and other FXYD3-expressing epithelia.- Published
- 2022
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350. Quantitative Chest CT Assessment of Small Airways Disease in Post-Acute SARS-CoV-2 Infection.
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Cho JL, Villacreses R, Nagpal P, Guo J, Pezzulo AA, Thurman AL, Hamzeh NY, Blount RJ, Fortis S, Hoffman EA, Zabner J, and Comellas AP
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- COVID-19 diagnostic imaging, Female, Humans, Male, Middle Aged, Tomography, X-Ray Computed methods, Post-Acute COVID-19 Syndrome, COVID-19 complications, Lung Diseases diagnostic imaging, Lung Diseases virology
- Abstract
Background The long-term effects of SARS-CoV-2 infection on pulmonary structure and function remain incompletely characterized. Purpose To test whether SARS-CoV-2 infection leads to small airways disease in patients with persistent symptoms. Materials and Methods In this single-center study at a university teaching hospital, adults with confirmed COVID-19 who remained symptomatic more than 30 days following diagnosis were prospectively enrolled from June to December 2020 and compared with healthy participants (controls) prospectively enrolled from March to August 2018. Participants with post-acute sequelae of COVID-19 (PASC) were classified as ambulatory, hospitalized, or having required the intensive care unit (ICU) based on the highest level of care received during acute infection. Symptoms, pulmonary function tests, and chest CT images were collected. Quantitative CT analysis was performed using supervised machine learning to measure regional ground-glass opacity (GGO) and using inspiratory and expiratory image-matching to measure regional air trapping. Univariable analyses and multivariable linear regression were used to compare groups. Results Overall, 100 participants with PASC (median age, 48 years; 66 women) were evaluated and compared with 106 matched healthy controls; 67% (67 of 100) of the participants with PASC were classified as ambulatory, 17% (17 of 100) were hospitalized, and 16% (16 of 100) required the ICU. In the hospitalized and ICU groups, the mean percentage of total lung classified as GGO was 13.2% and 28.7%, respectively, and was higher than that in the ambulatory group (3.7%, P < .001 for both comparisons). The mean percentage of total lung affected by air trapping was 25.4%, 34.6%, and 27.3% in the ambulatory, hospitalized, and ICU groups, respectively, and 7.2% in healthy controls ( P < .001). Air trapping correlated with the residual volume-to-total lung capacity ratio (ρ = 0.6, P < .001). Conclusion In survivors of COVID-19, small airways disease occurred independently of initial infection severity. The long-term consequences are unknown. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Elicker in this issue.
- Published
- 2022
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