28 results on '"John T. Benjamin"'
Search Results
2. Alveolar repair following LPS-induced injury requires cell-ECM interactions
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Jennifer M.S. Sucre, Fabian Bock, Nicholas M. Negretti, John T. Benjamin, Peter M. Gulleman, Xinyu Dong, Kimberly T. Ferguson, Christopher S. Jetter, Wei Han, Yang Liu, Seunghyi Kook, Jason J. Gokey, Susan H. Guttentag, Jonathan A. Kropski, Timothy S. Blackwell, Roy Zent, and Erin J. Plosa
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Cell biology ,Pulmonology ,Medicine - Abstract
During alveolar repair, alveolar type 2 (AT2) epithelial cell progenitors rapidly proliferate and differentiate into flat AT1 epithelial cells. Failure of normal alveolar repair mechanisms can lead to loss of alveolar structure (emphysema) or development of fibrosis, depending on the type and severity of injury. To test if β1-containing integrins are required during repair following acute injury, we administered E. coli lipopolysaccharide (LPS) by intratracheal injection to mice with a postdevelopmental deletion of β1 integrin in AT2 cells. While control mice recovered from LPS injury without structural abnormalities, β1-deficient mice had more severe inflammation and developed emphysema. In addition, recovering alveoli were repopulated with an abundance of rounded epithelial cells coexpressing AT2 epithelial, AT1 epithelial, and mixed intermediate cell state markers, with few mature type 1 cells. AT2 cells deficient in β1 showed persistently increased proliferation after injury, which was blocked by inhibiting NF-κB activation in these cells. Lineage tracing experiments revealed that β1-deficient AT2 cells failed to differentiate into mature AT1 epithelial cells. Together, these findings demonstrate that functional alveolar repair after injury with terminal alveolar epithelial differentiation requires β1-containing integrins.
- Published
- 2023
- Full Text
- View/download PDF
3. Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice
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Sourav Panja, John T. Benjamin, and Bibhash C. Paria
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leukocytes ,chemokines ,cytokines ,lipopolysaccharide ,early pregnancy ,uterus ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Maternal infection-induced early pregnancy complications arise from perturbation of the immune environment at the uterine early blastocyst implantation site (EBIS), yet the underlying mechanisms remain unclear. Here, we demonstrated in a mouse model that the progression of normal pregnancy from days 4 to 6 induced steady migration of leukocytes away from the uterine decidual stromal zone (DSZ) that surrounds the implanted blastocyst. Uterine macrophages were found to be CD206+ M2-polarized. While monocytes were nearly absent in the DSZ, DSZ cells were found to express monocyte marker protein Ly6C. Systemic endotoxic lipopolysaccharide (LPS) exposure on day 5 of pregnancy led to: (1) rapid (at 2 h) induction of neutrophil chemoattractants that promoted huge neutrophil infiltrations at the EBISs by 24 h; (2) rapid (at 2 h) elevation of mRNA levels of MyD88, but not Trif, modulated cytokines at the EBISs; and (3) dose-dependent EBIS defects by day 7 of pregnancy. Yet, elimination of maternal neutrophils using anti-Ly6G antibody prior to LPS exposure failed to avert LPS-induced EBIS defects allowing us to suggest that activation of Tlr4-MyD88 dependent inflammatory pathway is involved in LPS-induced defects at EBISs. Thus, blocking the activation of the Tlr4-MyD88 signaling pathway may be an interesting approach to prevent infection-induced pathology at EBISs.
- Published
- 2021
- Full Text
- View/download PDF
4. Neonatal Leukocyte Physiology and Disorders
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JOHN T. BENJAMIN, BENJAMIN A. TORRES, and AKHIL MAHESHWARI
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- 2024
5. Contributors
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Steven H. Abman, Noorjahan Ali, Karel Allegaert, Jamie E. Anderson, Deidra A. Ansah, Bhawna Arya, David Askenazi, Susan W. Aucott, Stephen A. Back, Gerri R. Baer, H. Scott Baldwin, Jerasimos Ballas, Maneesh Batra, Cheryl Bayart, Gary A. Bellus, John T. Benjamin, Gerard T. Berry, Zeenia C. Billimoria, Gil Binenbaum, Matthew S. Blessing, Markus D. Boos, Brad Bosse, Maryse L. Bouchard, Heather A. Brandling-Bennett, Colleen Brown, Erin G. Brown, Katherine H. Campbell, Katie Carlberg, Brian S. Carter, Shilpi Chabra, Irene J. Chang, Edith Y. Cheng, Kai-wen Chiang, Robert D. Christensen, Terrence Chun, Ronald I. Clyman, Donna, Maria E. Cortezzo, C.M. Cotten, Sherry E. Courtney, Jonathan M. Davis, Alejandra G. de Alba Campomanes, Benjamin Dean, Ellen Dees, Sara B. De, Mauro, Scott C. Denne, Emöke Deschmann, Carolina Cecilia Di Blasi, Sara A. Di, Vall, Dan Doherty, David J. Durand, Nicolle Fernández Dyess, Eric C. Eichenwald, Kelsey B. Eitel, Rachel M. Engen, Kelly N. Evans, Diana L. Farmer, Emily Fay, Patricia Y. Fechner, Rachel Fleishman, Bobbi Fleiss, Joseph Flynn, Katherine T. Flynn-O’Brien, G. Kyle Fulton, Renata C. Gallagher, Estelle B. Gauda, W. Christopher Golden, Michelle M. Gontasz, Natasha González Estévez, Sidney M. Gospe, Pierre Gressens, Deepti Gupta, Sangeeta Hingorani, Ashley P. Hinson, Susan R. Hintz, W. Alan Hodson, Kara K. Hoppe, Alyssa Huang, Benjamin Huang, Kathy Huen, Katie A. Huff, Cristian Ionita, J. Craig Jackson, Jordan E. Jackson, Tom Jaksic, Patrick J. Javid, Julia Johnson, Cassandra D. Josephson, Emily S. Jungheim, Sandra E. Juul, Mohammad Nasser Kabbany, Heidi Karpen, Gregory Keefe, Jennifer C. Keene, Amaris M. Keiser, Roberta L. Keller, Thomas F. Kelly, Kate Khorsand, Grace Kim, John P. Kinsella, Allison S. Komorowski, Ildiko H. Koves, Joanne M. Lagatta, Satyan Lakshminrusimha, Christina Lam, John D. Lantos, Janessa B. Law, Su Yeon Lee, Ofer Levy, David B. Lewis, Philana Ling Lin, Scott A. Lorch, Tiffany L. Lucas, Akhil Maheshwari, Emin Maltepe, Erica Mandell, Winston M. Manimtim, Richard J. Martin, Dennis E. Mayock, Irene Mc, Aleer, Patrick McQuillen, Ann J. Melvin, Paul A. Merguerian, Lina Merjaneh, J. Lawrence Merritt, Valerie Mezger, Marian G. Michaels, Ulrike Mietzsch, Steven P. Miller, Thomas R. Moore, Karen F. Murray, Debika Nandi-Munshi, Niranjana Natarajan, Kathryn D. Ness, Josef Neu, Shahab Noori, Thomas Michael O’Shea, Julius T. Oatts, Nigel Paneth, Thomas A. Parker, Ravi Mangal Patel, Simran Patel, Anna A. Penn, Christian M. Pettker, Shabnam Peyvandi, Catherine Pihoker, Erin Plosa, Brenda Poindexter, Michael A. Posencheg, Mihai Puia-Dumitrescu, Vilmaris Quiñones Cardona, Samuel E. Rice-Townsend, Art Riddle, Elizabeth Robbins, Mark D. Rollins, Mark A. Rosen, Courtney K. Rowe, Inderneel Sahai, Sulagna C. Saitta, Parisa Salehi, Pablo J. Sanchez, Taylor Sawyer, Matthew A. Saxonhouse, Katherine M. Schroeder, David T. Selewski, T. Niroshi Senaratne, Istvan Seri, Emily E. Sharpe, Sarah E. Sheppard, Margarett Shnorhavorian, Robert Sidbury, La, Vone Simmons, Rebecca A. Simmons, Rachana Singh, Martha C. Sola-Visner, Lakshmi Srinivasan, Heidi J. Steflik, Robin H. Steinhorn, Caleb Stokes, Helen Stolp, Jennifer Sucre, Angela Sun, Dalal K. Taha, Jessica Tenney, Janet A. Thomas, George E. Tiller, Benjamin A. Torres, William E. Truog, Kirtikumar Upadhyay, Gregory C. Valentine, John N. van den Anker, Betty Vohr, Linda D. Wallen, Peter (Zhan Tao) Wang, Bradley A. Warady, Robert M. Ward, Jon F. Watchko, Elias Wehbi, Joern-Hendrik Weitkamp, David Werny, Klane K. White, K. Taylor Wild, Susan Wiley, Laurel Willig, George A. Woodward, Clyde J. Wright, Karyn Yonekawa, Elizabeth Yu, and Elaine H. Zackai
- Published
- 2024
6. Epithelial Outgrowth Through Mesenchymal Rings Drives Alveologenesis
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Nicholas M. Negretti, Yeongseo Son, Philip Crooke, Erin J. Plosa, John T. Benjamin, Christopher S. Jetter, Claire Bunn, Nicholas Mignemi, John Marini, Alice N. Hackett, Meaghan Ransom, David Nichols, Susan H. Guttentag, Heather H. Pua, Timothy S. Blackwell, William Zacharias, David B. Frank, John A. Kozub, Anita Mahadevan-Jansen, Jonathan A. Kropski, Christopher V.E. Wright, Bryan Millis, and Jennifer M. S. Sucre
- Abstract
Determining how alveoli are formed and maintained is critical to understanding lung organogenesis and regeneration after injury. While technological barriers have heretofore limited real-time observation of alveologenesis, we have now used scanned oblique plane illumination microscopy of living lung slices to observe specific cellular behaviors at high resolution over several days. Contrary to the prevailing paradigm that alveoli form by airspace subdivision via ingrowing septa, we find that alveoli form by ballooning epithelial outgrowth supported by stable mesenchymal ring structures. Our systematic analysis allowed creation of a computational model of finely-timed cellular structural changes that drive alveologenesis under normal conditions or with perturbed intercellular Wnt signaling. This new paradigm and platform can be leveraged for mechanistic studies and screening for therapies to promote lung regeneration.One-Sentence SummaryLong-term live analysis of neonatal lungs supports a dynamic epithelial outgrowth model for alveologenesis.
- Published
- 2022
7. Alveolar Repair Following Lipopolysaccharide-induced Injury Requires Cell-Extracellular Matrix Interactions
- Author
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Jennifer M.S. Sucre, Fabian Bock, Nicholas M. Negretti, John T. Benjamin, Peter M. Gulleman, Xinyu Dong, Kimberly T. Ferguson, Christopher S. Jetter, Wei Han, Yang Liu, Seunghyi Kook, Jason J. Gokey, Susan H. Guttentag, Jonathan A. Kropski, Timothy S. Blackwell, Roy Zent, and Erin J. Plosa
- Abstract
During alveolar repair, alveolar type 2 (AT2) epithelial cell progenitors rapidly proliferate and differentiate into flat type 1 alveolar epithelial cells. Failure of normal alveolar repair mechanisms can lead to loss of alveolar structure (emphysema) or development of fibrosis, depending on the type and severity of injury. To test if β1-containing integrins are required during repair following acute injury, we administeredE. colilipopolysaccharide (LPS) by intratracheal injection to mice with a post-developmental deletion of β1 integrin in AT2 cells. While control mice recovered from LPS injury without structural abnormalities, β1-deficient mice had more severe inflammation and developed emphysema. In addition, recovering alveoli were repopulated with an abundance of rounded epithelial cells co-expressing type 2, type 1, and mixed intermediate cell state markers, with few mature type 1 cells. β1-deficient AT2 cells showed persistently increased proliferation after injury, which was blocked by inhibiting NF-κB activation in these cells. Lineage tracing experiments revealed that β1-deficient AT2 cells failed to differentiate into mature type 1 alveolar epithelial cells. Together, these findings demonstrate that functional alveolar repair after injury with terminal alveolar epithelial differentiation requires β1-containing integrins.
- Published
- 2022
8. Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A
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John T. Benjamin, Alissa Cutrone, Meaghan Ransom, Jennifer M.S. Sucre, Erin J. Plosa, Zachary Anderson, Namasivayam Ambalavanan, Christopher S. Jetter, Timothy S. Blackwell, Kasey C. Vickers, Ethan Lee, Susan H. Guttentag, Andries Zijlstra, Melanie Königshoff, Bryan A. Millis, Quanhu Sheng, and Benjamin A. Fensterheim
- Subjects
Pulmonary and Respiratory Medicine ,In situ hybridization ,Hyperoxia ,Lung injury ,Critical Care and Intensive Care Medicine ,Wnt-5a Protein ,Andrology ,In vivo ,Humans ,Medicine ,Lung ,Wnt Signaling Pathway ,Bronchopulmonary Dysplasia ,business.industry ,Mesenchymal stem cell ,Infant, Newborn ,Wnt signaling pathway ,Original Articles ,respiratory system ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Bronchopulmonary dysplasia ,cardiovascular system ,medicine.symptom ,business - Abstract
Rationale: Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth that affects infants born in the saccular stage of lung development at
- Published
- 2020
9. A single-cell atlas of mouse lung development
- Author
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Nicholas M. Negretti, Erin J. Plosa, John T. Benjamin, Bryce A. Schuler, A. Christian Habermann, Christopher S. Jetter, Peter Gulleman, Claire Bunn, Alice N. Hackett, Meaghan Ransom, Chase J. Taylor, David Nichols, Brittany K. Matlock, Susan H. Guttentag, Timothy S. Blackwell, Nicholas E. Banovich, Jonathan A. Kropski, and Jennifer M. S. Sucre
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Organogenesis ,Embryonic Development ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Epithelial Cells ,Mesenchymal Stem Cells ,Embryo, Mammalian ,Mice ,Techniques and Resources ,Animals ,Cell Lineage ,RNA-Seq ,Single-Cell Analysis ,Transcriptome ,Molecular Biology ,Lung ,Developmental Biology - Abstract
Lung organogenesis requires precise timing and coordination to effect spatial organization and function of the parenchymal cells. To provide a systematic broad-based view of the mechanisms governing the dynamic alterations in parenchymal cells over crucial periods of development, we performed a single-cell RNA-sequencing time-series yielding 102,571 epithelial, endothelial and mesenchymal cells across nine time points from embryonic day 12 to postnatal day 14 in mice. Combining computational fate-likelihood prediction with RNA in situ hybridization and immunofluorescence, we explore lineage relationships during the saccular to alveolar stage transition. The utility of this publicly searchable atlas resource (www.sucrelab.org/lungcells) is exemplified by discoveries of the complexity of type 1 pneumocyte function and characterization of mesenchymal Wnt expression patterns during the saccular and alveolar stages – wherein major expansion of the gas-exchange surface occurs. We provide an integrated view of cellular dynamics in epithelial, endothelial and mesenchymal cell populations during lung organogenesis.
- Published
- 2021
10. Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice
- Author
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John T. Benjamin, Bibhash C. Paria, and Sourav Panja
- Subjects
0301 basic medicine ,Lipopolysaccharides ,Chemokine ,Lipopolysaccharide ,Neutrophils ,chemokines ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Pregnancy ,implantation ,Biology (General) ,Pregnancy Complications, Infectious ,Spectroscopy ,early pregnancy ,biology ,lipopolysaccharide ,non-decidual stromal zone ,General Medicine ,Computer Science Applications ,Chemistry ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Signal Transduction ,Stromal cell ,decidual stromal zone ,QH301-705.5 ,leukocytes ,Catalysis ,Article ,Inorganic Chemistry ,Andrology ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Blastocyst ,Embryo Implantation ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Inflammation ,uterus ,business.industry ,Monocyte ,Macrophages ,Organic Chemistry ,medicine.disease ,cytokines ,Toll-Like Receptor 4 ,Disease Models, Animal ,030104 developmental biology ,chemistry ,TRIF ,Myeloid Differentiation Factor 88 ,biology.protein ,business - Abstract
Maternal infection-induced early pregnancy complications arise from perturbation of the immune environment at the uterine early blastocyst implantation site (EBIS), yet the underlying mechanisms remain unclear. Here, we demonstrated in a mouse model that the progression of normal pregnancy from days 4 to 6 induced steady migration of leukocytes away from the uterine decidual stromal zone (DSZ) that surrounds the implanted blastocyst. Uterine macrophages were found to be CD206+ M2-polarized. While monocytes were nearly absent in the DSZ, DSZ cells were found to express monocyte marker protein Ly6C. Systemic endotoxic lipopolysaccharide (LPS) exposure on day 5 of pregnancy led to: (1) rapid (at 2 h) induction of neutrophil chemoattractants that promoted huge neutrophil infiltrations at the EBISs by 24 h, (2) rapid (at 2 h) elevation of mRNA levels of MyD88, but not Trif, modulated cytokines at the EBISs, and (3) dose-dependent EBIS defects by day 7 of pregnancy. Yet, elimination of maternal neutrophils using anti-Ly6G antibody prior to LPS exposure failed to avert LPS-induced EBIS defects allowing us to suggest that activation of Tlr4-MyD88 dependent inflammatory pathway is involved in LPS-induced defects at EBISs. Thus, blocking the activation of the Tlr4-MyD88 signaling pathway may be an interesting approach to prevent infection-induced pathology at EBISs.
- Published
- 2021
11. AP-3-dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells
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Shufang Meng, Alexa Jaume, Christopher S. Jetter, Ping Wang, Jason J. Gokey, John T. Benjamin, Jennifer M.S. Sucre, Hayley A. Hanby, Michael S. Marks, Seunghyi Kook, Susan H. Guttentag, and Laura Goetzl
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Male ,Endosome ,Adaptor Protein Complex 3 ,Pulmonary Fibrosis ,Cell ,Primary Cell Culture ,Endosomes ,Phosphatidylserines ,Lamellar granule ,Cell Line ,Mice ,Cell Movement ,Lysosome ,Pulmonary fibrosis ,Organelle ,medicine ,Animals ,Humans ,Phospholipid Transfer Proteins ,Lung ,Adaptor Proteins, Signal Transducing ,Adenosine Triphosphatases ,Multidisciplinary ,Chemistry ,Cell migration ,Biological Transport ,YAP-Signaling Proteins ,Flippase ,respiratory system ,Biological Sciences ,medicine.disease ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Gene Expression Regulation ,Hermanski-Pudlak Syndrome ,rab GTP-Binding Proteins ,Alveolar Epithelial Cells ,Female ,Lysosomes ,Peroxiredoxin VI ,Signal Transduction ,Transcription Factors - Abstract
Lamellar bodies (LBs) are lysosome-related organelles (LROs) of surfactant-producing alveolar type 2 (AT2) cells of the distal lung epithelium. Trafficking pathways to LBs have been understudied but are likely critical to AT2 cell homeostasis given associations between genetic defects of endosome to LRO trafficking and pulmonary fibrosis in Hermansky Pudlak syndrome (HPS). Our prior studies uncovered a role for AP-3, defective in HPS type 2, in trafficking Peroxiredoxin-6 to LBs. We now show that the P4-type ATPase ATP8A1 is sorted by AP-3 from early endosomes to LBs through recognition of a C-terminal dileucine-based signal. Disruption of the AP-3/ATP8A1 interaction causes ATP8A1 accumulation in early sorting and/or recycling endosomes, enhancing phosphatidylserine exposure on the cytosolic leaflet. This in turn promotes activation of Yes-activating protein, a transcriptional coactivator, augmenting cell migration and AT2 cell numbers. Together, these studies illuminate a mechanism whereby loss of AP-3-mediated trafficking contributes to a toxic gain-of-function that results in enhanced and sustained activation of a repair pathway associated with pulmonary fibrosis.
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- 2021
12. A Single Cell Atlas of Lung Development
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John T. Benjamin, Nicholas E. Banovich, A. Christian Habermann, Peter Gulleman, Jonathan A. Kropski, Chase J. Taylor, Brittany K. Matlock, David E. Nichols, Bryce A. Schuler, Jennifer M.S. Sucre, Christopher S. Jetter, Timothy S. Blackwell, Nicholas M. Negretti, Erin J. Plosa, and Susan H. Guttentag
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Lung ,medicine.anatomical_structure ,Parenchyma ,Cell ,Mesenchymal stem cell ,medicine ,RNA ,Organogenesis ,In situ hybridization ,respiratory system ,Biology ,Embryonic stem cell ,Cell biology - Abstract
SummaryLung organogenesis requires precisely timed shifts in the spatial organization and function of parenchymal cells, especially during the later stages of lung development. To investigate the mechanisms governing lung parenchymal dynamics during development, we performed a single cell RNA sequencing (scRNA-seq) time-series yielding 92,238 epithelial, endothelial, and mesenchymal cells across 8 time points from embryonic day 12 (E12) to postnatal day 14 (P14) in mice. We combined new computational analyses with RNAin situhybridization to explore transcriptional velocity, fate likelihood prediction, and spatiotemporal localization of cell populations during the transition between the saccular and alveolar stages. We interrogated this atlas to illustrate the complexity of type 1 pneumocyte function during the saccular and alveolar stages, and we demonstrate an integrated view of the cellular dynamics during lung development.
- Published
- 2021
13. Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD
- Author
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Kalsang Dolma, Riet van der Meer, Matthew Xin, J. Edwin Blalock, Seunghyi Kook, Wei Han, Shivangi Dave, John T. Benjamin, Jonathan A. Kropski, David S. Nichols, Peter C. Dinella, Susan H. Guttentag, Erin J. Plosa, Christopher S. Jetter, Timothy S. Blackwell, Jennifer M.S. Sucre, Amit Gaggar, Lisa R. Young, Charitharth Vivek Lal, Ashley Catanzarite, Sergey Gutor, Peter Gulleman, Dawn C. Newcomb, and Bradley W. Richmond
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0301 basic medicine ,Genetically modified mouse ,Pathology ,medicine.medical_specialty ,Neutrophils ,Mice, Transgenic ,Inflammation ,Elastic fiber assembly ,Mice ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Medicine ,COPD ,Lung ,biology ,business.industry ,General Medicine ,respiratory system ,medicine.disease ,Elastin ,respiratory tract diseases ,Pulmonary Alveoli ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Neutrophil elastase ,biology.protein ,Respiratory epithelium ,medicine.symptom ,Leukocyte Elastase ,business ,Research Article - Abstract
Emerging evidence indicates that early life events can increase the risk for developing chronic obstructive pulmonary disease (COPD). Using an inducible transgenic mouse model for NF-κB activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage (P3–P5) but not alveolar stage (P10–P12) of lung development disrupted elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progressed through 24 months of age. Neutrophil depletion prevented disruption of elastic fiber assembly and restored normal lung development. Mechanistic studies uncovered a role for neutrophil elastase (NE) in downregulating expression of critical elastic fiber assembly components, particularly fibulin-5 and elastin. Further, purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation downregulated elastin and fibulin-5 expression by saccular-stage mouse lung fibroblasts. Together, our studies define a critical developmental window for assembling the elastin scaffold in the distal lung, which is required to support lung structure and function throughout the lifespan. Although neutrophils play a well-recognized role in COPD development in adults, neutrophilic inflammation may also contribute to early-life predisposition to COPD.
- Published
- 2021
14. Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 infection in the lung epithelium
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Meghan E. Kapp, Steven A. Webber, Chase J. Taylor, John T. Benjamin, Jonathan A. Kropski, Erin J. Plosa, Nicholas E. Banovich, Bryce A. Schuler, Lior Z. Braunstein, Susan H. Guttentag, Michael Koval, David S. Nichols, A. Christian Habermann, Christopher S. Jetter, Timothy S. Blackwell, Peter Gulleman, Alice Hackett, and Jennifer M.S. Sucre
- Subjects
Lung ,Protease ,medicine.medical_treatment ,RNA ,Priming (immunology) ,Autopsy ,respiratory system ,Biology ,medicine.disease_cause ,TMPRSS2 ,respiratory tract diseases ,medicine.anatomical_structure ,Immunology ,medicine ,Respiratory epithelium ,Coronavirus - Abstract
The SARS-CoV-2 novel coronavirus global pandemic (COVID-19) has led to millions of cases and hundreds of thousands of deaths around the globe. While the elderly appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of the developing mouse lung with temporally-resolved RNA-in-situ hybridization (ISH) in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primerTMPRSS2was highest in ciliated cells and type I alveolar epithelial cells (AT1), andTMPRSS2expression was increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases revealed SARS-CoV-2 RNA was detected most frequently in ciliated and secretory cells in the airway epithelium and AT1 cells in the peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressingTMPRSS2.Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in the lung epithelium, and suggest that developmental regulation ofTMPRSS2may underlie the relative protection of infants and children from severe respiratory illness.
- Published
- 2020
15. Dysregulated Mesenchymal Wnt Signaling After Saccular Stage Hyperoxia Injury Is Driven by NF-kb
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Jennifer M.S. Sucre, Ethan Lee, Kasey C. Vickers, Erin J. Plosa, S.H. Guttentag, M. Koenigshoff, Christopher S. Jetter, Timothy S. Blackwell, and John T. Benjamin
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Hyperoxia ,Mesenchymal stem cell ,medicine ,Wnt signaling pathway ,Stage (cooking) ,medicine.symptom ,Biology ,Cell biology - Published
- 2020
16. β1 Integrin regulates adult lung alveolar epithelial cell inflammation
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Roy Zent, John T. Benjamin, Susan H. Guttentag, Erin J. Plosa, Ambra Pozzi, Linda A. Gleaves, Scott M. Haake, Seunghyi Kook, Wei Han, Timothy S. Blackwell, Lisa R. Young, Jennifer M.S. Sucre, Vasiliy V. Polosukhin, and Peter M. Gulleman
- Subjects
0301 basic medicine ,Aging ,Pathology ,medicine.medical_specialty ,Chemokine ,Receptors, CCR2 ,Integrin ,Inflammation ,Lung injury ,Epithelium ,Mice ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Cell Adhesion ,medicine ,Animals ,Efferocytosis ,Cell adhesion ,Lung ,Chemokine CCL2 ,Tissue homeostasis ,Mice, Knockout ,biology ,business.industry ,Integrin beta1 ,Macrophages ,Pneumonia ,General Medicine ,respiratory system ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Alveolar Epithelial Cells ,030220 oncology & carcinogenesis ,biology.protein ,Chemokines ,medicine.symptom ,business ,Research Article - Abstract
Integrins, the extracellular matrix receptors that facilitate cell adhesion and migration, are necessary for organ morphogenesis; however, their role in maintaining adult tissue homeostasis is poorly understood. To define the functional importance of β(1) integrin in adult mouse lung, we deleted it after completion of development in type 2 alveolar epithelial cells (AECs). Aged β(1) integrin–deficient mice exhibited chronic obstructive pulmonary disease–like (COPD-like) pathology characterized by emphysema, lymphoid aggregates, and increased macrophage infiltration. These histopathological abnormalities were preceded by β(1) integrin–deficient AEC dysfunction such as excessive ROS production and upregulation of NF-κB–dependent chemokines, including CCL2. Genetic deletion of the CCL2 receptor, Ccr2, in mice with β(1) integrin–deficient type 2 AECs impaired recruitment of monocyte-derived macrophages and resulted in accelerated inflammation and severe premature emphysematous destruction. The lungs exhibited reduced AEC efferocytosis and excessive numbers of inflamed type 2 AECs, demonstrating the requirement for recruited monocytes/macrophages in limiting lung injury and remodeling in the setting of a chronically inflamed epithelium. These studies support a critical role for β(1) integrin in alveolar homeostasis in the adult lung.
- Published
- 2020
17. Successful Establishment of Primary Type II Alveolar Epithelium with 3D Organotypic Coculture
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John T. Benjamin, Seunghyi Kook, Linda A. Gleaves, Adel Eskaros, Janice A. Williams, Laura Goetzl, Jonathan A. Kropski, Susan H. Guttentag, Christopher S. Jetter, Timothy S. Blackwell, Holli A. Loomans, Lisa R. Young, Andries Zijlstra, Erin J. Plosa, Carla L. Calvi, Jennifer M.S. Sucre, and Ping Wang
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,endocrine system ,Alveolar Epithelium ,Clinical Biochemistry ,Cell Communication ,Lamellar granule ,Biology ,Lung injury ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,Pulmonary surfactant ,medicine ,Humans ,Proliferation Marker ,Progenitor cell ,Lung ,Molecular Biology ,Cells, Cultured ,Epithelial Cells ,Lung Injury ,Cell Biology ,Fibroblasts ,respiratory system ,medicine.disease ,Coculture Techniques ,Cell biology ,Major Technical Advances ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,cardiovascular system ,hormones, hormone substitutes, and hormone antagonists ,circulatory and respiratory physiology - Abstract
Alveolar type II (AT2) epithelial cells are uniquely specialized to produce surfactant in the lung and act as progenitor cells in the process of repair after lung injury. AT2 cell injury has been implicated in several lung diseases, including idiopathic pulmonary fibrosis and bronchopulmonary dysplasia. The inability to maintain primary AT2 cells in culture has been a significant barrier in the investigation of pulmonary biology. We have addressed this knowledge gap by developing a three-dimensional (3D) organotypic coculture using primary human fetal AT2 cells and pulmonary fibroblasts. Grown on top of matrix-embedded fibroblasts, the primary human AT2 cells establish a monolayer and have direct contact with the underlying pulmonary fibroblasts. Unlike conventional two-dimensional (2D) culture, the structural and functional phenotype of the AT2 cells in our 3D organotypic culture was preserved over 7 days of culture, as evidenced by the presence of lamellar bodies and by production of surfactant proteins B and C. Importantly, the AT2 cells in 3D cocultures maintained the ability to replicate, with approximately 60% of AT2 cells staining positive for the proliferation marker Ki67, whereas no such proliferation is evident in 2D cultures of the same primary AT2 cells. This organotypic culture system enables interrogation of AT2 epithelial biology by providing a reductionist in vitro model in which to investigate the response of AT2 epithelial cells and AT2 cell–fibroblast interactions during lung injury and repair.
- Published
- 2018
18. Bacterial-derived Neutrophilic Inflammation Drives Lung Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease
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Bradley W. Richmond, Marshall Guo, John T. Benjamin, Rui-Hong Du, Linda A. Gleaves, Timothy S. Blackwell, Riet van der Meer, Vasiliy V. Polosukhin, Austin McKissack, Dong-Sheng Cheng, Wei Han, and Yongqin Zhang
- Subjects
Cyclopropanes ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Neutrophils ,Clinical Biochemistry ,Aminopyridines ,Bacillus ,Receptors, Cell Surface ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Parenchyma ,Pneumonia, Bacterial ,medicine ,Animals ,Receptor ,Molecular Biology ,Small Airway Remodeling ,Roflumilast ,Lung ,business.industry ,Cell Biology ,respiratory system ,medicine.disease ,Mice, Mutant Strains ,respiratory tract diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Pulmonary Emphysema ,030228 respiratory system ,Benzamides ,Immunology ,Airway Remodeling ,Airway ,business ,Polymeric immunoglobulin receptor ,medicine.drug - Abstract
Loss of secretory IgA is common in the small airways of patients with chronic obstructive pulmonary disease and may contribute to disease pathogenesis. Using mice that lack secretory IgA in the airways due to genetic deficiency of polymeric Ig receptor (pIgR-/- mice), we investigated the role of neutrophils in driving the fibrotic small airway wall remodeling and emphysema that develops spontaneously in these mice. By flow cytometry, we found an increase in the percentage of neutrophils among CD45+ cells in the lungs, as well as an increase in total neutrophils, in pIgR-/- mice compared with wild-type controls. This increase in neutrophils in pIgR-/- mice was associated with elastin degradation in the alveolar compartment and around small airways, along with increased collagen deposition in small airway walls. Neutrophil depletion using anti-Ly6G antibodies or treatment with broad-spectrum antibiotics inhibited development of both emphysema and small airway remodeling, suggesting that airway bacteria provide the stimulus for deleterious neutrophilic inflammation in this model. Exogenous bacterial challenge using lysates prepared from pathogenic and nonpathogenic bacteria worsened neutrophilic inflammation and lung remodeling in pIgR-/- mice. This phenotype was abrogated by antiinflammatory therapy with roflumilast. Together, these studies support the concept that disruption of the mucosal immune barrier in small airways contributes to chronic obstructive pulmonary disease progression by allowing bacteria to stimulate chronic neutrophilic inflammation, which, in turn, drives progressive airway wall fibrosis and emphysematous changes in the lung parenchyma.
- Published
- 2018
19. Inverse Relationship between Soluble RAGE and Risk for Bronchopulmonary Dysplasia
- Author
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Judy L. Aschner, James C. Slaughter, Lisa R. Young, John T. Benjamin, Steven Steele, Paul E. Moore, Erin J. Plosa, Timothy S. Blackwell, Jennifer M.S. Sucre, and Riet van der Meer
- Subjects
Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Receptor for Advanced Glycation End Products ,Gestational Age ,Critical Care and Intensive Care Medicine ,Gastroenterology ,Rage (emotion) ,California ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Correspondence ,medicine ,Humans ,030212 general & internal medicine ,Bronchopulmonary Dysplasia ,Extramural ,business.industry ,Infant, Newborn ,Gestational age ,Infant, Low Birth Weight ,medicine.disease ,Low birth weight ,030228 respiratory system ,Bronchopulmonary dysplasia ,Female ,medicine.symptom ,business ,Biomarkers ,Infant, Premature - Published
- 2018
20. rhIGF-1 Therapy: A Silver Bullet for Bronchopulmonary Dysplasia Prevention?
- Author
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John T. Benjamin and Erin J. Plosa
- Subjects
Pulmonary and Respiratory Medicine ,Male ,Postnatal Care ,medicine.medical_specialty ,Hypertension, Pulmonary ,Critical Care and Intensive Care Medicine ,Rats, Sprague-Dawley ,angiogenesis ,Pregnancy ,pulmonary hypertension ,medicine ,Animals ,Humans ,Insulin-Like Growth Factor I ,Lung ,lung development ,Bronchopulmonary Dysplasia ,business.industry ,prematurity ,Editorials ,Infant, Newborn ,Infant ,Original Articles ,Pediatrics and Lung Development/Pulmonary Vascular Disease ,medicine.disease ,Surgery ,Rats ,insulin-like growth factor-1 ,Bronchopulmonary dysplasia ,Silver bullet ,Animals, Newborn ,Models, Animal ,Female ,business ,Infant, Premature - Abstract
Rationale: Antenatal factors, such as chorioamnionitis, preeclampsia, and postnatal injury, are associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. IGF-1 (insulin-like growth factor-1) is markedly decreased in normal preterm infants, but whether IGF-1 treatment can prevent BPD or PH is unknown. Objectives: To evaluate whether postnatal treatment with rhIGF-1 (recombinant human IGF-1)/BP3 (binding peptide 3) improves lung growth and prevents PH in two antenatal models of BPD induced by intraamniotic exposure to endotoxin (ETX) or sFlt-1 (soluble fms-like tyrosine kinase 1), and in a postnatal model due to prolonged hyperoxia. Methods: ETX or sFlt-1 were administered into the amniotic sac of pregnant rats at Embryonic Day 20 to simulate antenatal models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by cesarean section at Embryonic Day 22 and treated with rhIGF-1/BP3 (0.02–20 mg/kg/d intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RACs), vessel density, and right ventricular hypertrophy (RVH). Direct effects of rhIGF-1/BP3 (250 ng/ml) on fetal lung endothelial cell proliferation and tube formation and alveolar type 2 cell proliferation were studied by standard methods in vitro. Measurements and Main Results: Antenatal ETX and antenatal sFlt-1 reduced RAC and decreased RVH in infant rats. In both models, postnatal rhIGF-1/BP3 treatment restored RAC and RVH to normal values when compared with placebo injections. rhIGF-1/BP3 treatment also preserved lung structure and prevented RVH after postnatal hyperoxia. In vitro studies showed that rhIGF-1/BP3 treatment increased lung endothelial cell and alveolar type 2 cell proliferation. Conclusions: Postnatal rhIGF-1/BP3 treatment preserved lung structure and prevented RVH in antenatal and postnatal BPD models. rhIGF-1/BP3 treatment may provide a novel strategy for the prevention of BPD in preterm infants.
- Published
- 2020
21. Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data
- Author
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Elaine L. Shelton, John T. Benjamin, Naoko Brown, Nahid Waleh, Christopher W. Hooper, Donald C. McCurnin, Stanley D. Poole, Jeff Reese, Erin J. Plosa, Steven R. Seidner, Ginger L. Milne, Ronald I. Clyman, and Noah J. Ehinger
- Subjects
Vasodilation ,Betamethasone ,Polymerase Chain Reaction ,Pediatrics ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Ductus arteriosus ,Ductus Arteriosus, Patent ,030219 obstetrics & reproductive medicine ,biology ,medicine.anatomical_structure ,Echocardiography ,Maternal Exposure ,cardiovascular system ,Public Health and Health Services ,Gestation ,Patent ,Female ,Infant, Premature ,medicine.drug ,medicine.medical_specialty ,Prostaglandin ,Article ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,In vivo ,030225 pediatrics ,biology.animal ,Internal medicine ,medicine ,Animals ,Humans ,Premature ,business.industry ,Gene Expression Profiling ,Infant ,Ductus Arteriosus ,Oxygen ,Endocrinology ,chemistry ,Gene Expression Regulation ,Pediatrics, Perinatology and Child Health ,Prostaglandin inhibitor ,Prostaglandins ,business ,Baboon ,Papio - Abstract
Background Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results. Methods We used preterm baboons, mice and humans (≤276/7 weeks gestation) to examine betamethasone’s effects on ductus gene expression and constriction both in vitro and in vivo. Results In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone’s effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally-regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone’s contractile effects were only apparent when prostaglandin signaling was inhibited, whereas, at 26-27 weeks gestation betamethasone’s contractile effects were apparent even in the absence of prostaglandin inhibitors. Conclusions We speculate that betamethasone’s contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone’s effects vary according to the infant’s developmental age at birth.
- Published
- 2018
22. Cutting Edge: IL-1α and Not IL-1β Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality
- Author
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Clayton Bennett, Daniel J. Moore, Ryan Loveland, Riet van der Meer, James L. Wynn, John T. Benjamin, and Ashley Royce
- Subjects
0301 basic medicine ,Male ,Sepsis mortality ,Inflammatory response ,Immunology ,Interleukin-1beta ,Inflammation ,Article ,Sepsis ,03 medical and health sciences ,Paracrine signalling ,Mice ,0302 clinical medicine ,Mediator ,Interleukin-1alpha ,medicine ,Immunology and Allergy ,Animals ,Humans ,Receptor ,Receptors, Interleukin-1 Type I ,business.industry ,Infant, Newborn ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Animals, Newborn ,Lethality ,Female ,medicine.symptom ,business ,030215 immunology ,Signal Transduction - Abstract
Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1α and IL-1β, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1α or IL-1β in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1α and IL-1β, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1α and not IL-1β is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates.
- Published
- 2018
23. Neonatal Leukocyte Physiology and Disorders
- Author
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John T. Benjamin, Benjamin A. Torres, and Akhil Maheshwari
- Subjects
Fetus ,Immune system ,Antigen ,Immunology ,medicine ,Biology ,medicine.disease ,Immunodeficiency - Abstract
The developing neonate is exposed to a plethora of antigens and must evolve innate and adaptive immune responses to combat pathogenic microorganisms and at the same time, develop tolerance to self-antigens and commensal microbes. While some components of the immune system are functionally at par with adults, immaturity in others may result in a state of immunodeficiency in the neonate. This chapter highlights the qualitative and quantitative differences in distribution and function of leukocyte populations that together shape the immune responses in the fetus, neonate and the adult. Knowledge of these differences may enable a better understanding of the inherent susceptibility of the neonate to various infections.
- Published
- 2018
24. Contributors
- Author
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Steven H. Abman, Karel Allegaert, Bhawna Arya, David Askenazi, Timur Azhibekov, Stephen A. Back, H. Scott Baldwin, Roberta A. Ballard, Eduardo Bancalari, Carlton M. Bates, Maneesh Batra, Cheryl B. Bayart, Gary A. Bellus, Thomas J. Benedetti, John T. Benjamin, James T. Bennett, Gerard T. Berry, Gil Binenbaum, Markus D. Boos, Maryse Bouchard, Heather A. Brandling-Bennett, Darcy E. Broughton, Zane Brown, Katherine H. Campbell, Suzan L. Carmichael, Brian S. Carter, Stephen Cederbaum, Shilpi Chabra, Justine Chang, Edith Y. Cheng, Karen M. Chisholm, Robert D. Christensen, Terrence Chun, Nelson Claure, Ronald I. Clyman, Tarah T. Colaizy, DonnaMaria E. Cortezzo, C. Michael Cotten, Michael L. Cunningham, Alejandra G. de Alba Campomanes, Ellen Dees, Sara B. DeMauro, Scott C. Denne, Emöke Deschmann, Carolina Cecilia, Robert M. DiBlasi, Reed A. Dimmitt, Sara A. DiVall, Orchid Djahangirian, Dan Doherty, Eric C. Eichenwald, Rachel Engen, Cyril Engmann, Jacquelyn R. Evans, Kelly N. Evans, Diana L. Farmer, Patricia Y. Fechner, Patricia Ferrieri, Neil N. Finer, Rachel A. Fleishman, Bobbi Fleiss, Joseph T. Flynn, Katherine T. Flynn-O'Brien, Mark R. Frey, Lydia Furman, Renata C. Gallagher, Estelle B. Gauda, Christine A. Gleason, Michael J. Goldberg, Adam B. Goldin, Sidney M. Gospe, Pierre Gressens, Deepti Gupta, Susan H. Guttentag, Chad R. Haldeman-Englert, Thomas N. Hansen, Anne V. Hing, Sangeeta Hingorani, Susan R. Hintz, Shinjiro Hirose, W. Alan Hodson, Kara K. Hoppe, Margaret K. Hostetter, Benjamin Huang, Sarah Bauer Huang, Terrie E. Inder, Cristian Inoita, J. Craig Jackson, Deepak Jain, Lucky Jain, Patrick J. Javid, Cassandra D. Josephson, Emily S. Jungheim, Sandra E. Juul, Anup Katheria, Benjamin A. Keller, Roberta L. Keller, Thomas F. Kelly, Kate Khorsand, Grace Kim, John P. Kinsella, Ildiko H. Koves, Christina Lam, Erin R. Lane, John D. Lantos, Daniel J. Ledbetter, Ben Lee, Harvey L. Levy, Ofer Levy, Mark B. Lewin, David B. Lewis, P. Ling Lin, Tiffany Fangtse Lin, Scott A. Lorch, Akhil Maheshwari, Emin Maltepe, Ketzela J. Marsh, Richard J. Martin, Dennis E. Mayock, Ryan Michael McAdams, Irene McAleer, Steven J. McElroy, Kera M. McNelis, Patrick McQuillen, William L. Meadow, Paul A. Merguerian, Lina Merjaneh, J. Lawrence Merritt, Valerie Mezger, Marian G. Michaels, Steven P. Miller, Sowmya S. Mohan, Thomas J. Mollen, Thomas R. Moore, Jeffrey C. Murray, Karen F. Murray, Debika Nandi-Munshi, Niranjana Natarajan, Jeffrey J. Neil, Kathryn D. Ness, Josef Neu, Angel Siu-Ying, Shahab Noori, Lila O'Mahony, Jonathan P. Palma, Nigel Paneth, Thomas A. Parker, Ravi Mangal Patel, Anna A. Penn, Christian M. Pettker, Shabnam Peyvandi, Cate Pihoker, Erin Plosa, Brenda B. Poindexter, Michael A. Posencheg, Benjamin E. Reinking, Samuel Rice-Townsend, Morgan K. Richards, C. Peter Richardson, Kelsey Richardson, Kevin M. Riggle, Elizabeth Robbins, Mark D. Rollins, Mark A. Rosen, Courtney K. Rowe, Inderneel Sahai, Sulagna C. Saitta, Parisa Salehi, Pablo Sanchez, Matthew A. Saxonhouse, Richard J. Schanler, Mark R. Schleiss, Thomas Scholz, Andrew L. Schwaderer, David Selewski, Zachary M. Sellers, Istvan Seri, Margarett Shnorhavorian, Eric Sibley, Robert Sidbury, Rebecca Simmons, Caitlin Smith, Martha C. Sola-Visner, Lakshmi Srinivasan, Robin H. Steinhorn, David K. Stevenson, Helen Stolp, Craig Taplin, Peter Tarczy-Hornoch, James A. Taylor, Janet A. Thomas, Tracy Thompson, George E. Tiller, Benjamin A. Torres, Christopher Michael Traudt, John N. van den Anker, Margaret M. Vernon, Betty Vohr, Valencia P. Walker, Linda D. Wallen, Matthew B. Wallenstein, Peter (Zhan Tao) Wang, Bradley A. Warady, Robert M. Ward, Jon F. Watchko, Elias Wehbi, Joern-Hendrik Weitkamp, David Werny, Klane K. White, Laurel Willig, David Woodrum, George A. Woodward, Clyde J. Wright, Jeffrey A. Wright, Karyn Yonekawa, and Elaine H. Zackai
- Published
- 2018
25. A Shared Pattern of β-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis
- Author
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Linda A. Gleaves, Bryan A. Millis, Christopher S. Jetter, Susan H. Guttentag, Timothy S. Blackwell, Jonathan A. Kropski, Lisa R. Young, Namasivayam Ambalavanan, Jennifer M.S. Sucre, John T. Benjamin, and Gail H. Deutsch
- Subjects
0301 basic medicine ,Adult ,Mesenchyme ,Lung injury ,Article ,Pathology and Forensic Medicine ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,Fetus ,Axin Protein ,Pregnancy ,AXIN2 ,Medicine ,Animals ,Humans ,Phosphorylation ,Lung ,beta Catenin ,Bronchopulmonary Dysplasia ,Cell Nucleus ,business.industry ,Wnt signaling pathway ,Epithelial Cells ,respiratory system ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,respiratory tract diseases ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Bronchopulmonary dysplasia ,Animals, Newborn ,A549 Cells ,Catenin ,Pregnancy Trimester, Second ,Cancer research ,Tyrosine ,Female ,business ,Protein Processing, Post-Translational ,Signal Transduction - Abstract
Wnt/β-catenin signaling is necessary for normal lung development, and abnormal Wnt signaling contributes to the pathogenesis of both bronchopulmonary dysplasia (BPD) and idiopathic pulmonary fibrosis (IPF), fibrotic lung diseases that occur during infancy and aging, respectively. Using a library of human normal and diseased human lung samples, we identified a distinct signature of nuclear accumulation of β-catenin phosphorylated at tyrosine 489 and epithelial cell cytosolic localization of β-catenin phosphorylated at tyrosine 654 in early normal lung development and fibrotic lung diseases BPD and IPF. Furthermore, this signature was recapitulated in murine models of BPD and IPF. Image analysis of immunofluorescence colocalization demonstrated a consistent pattern of elevated nuclear phosphorylated β-catenin in the lung epithelium and surrounding mesenchyme in BPD and IPF, closely resembling the pattern observed in 18-week fetal lung. Nuclear β-catenin phosphorylated at tyrosine 489 associated with an increased expression of Wnt target gene AXIN2, suggesting that the observed β-catenin signature is of functional significance during normal development and injury repair. The association of specific modifications of β-catenin during normal lung development and again in response to lung injury supports the widely held concept that repair of lung injury involves the recapitulation of developmental programs. Furthermore, these observations suggest that β-catenin phosphorylation has potential as a therapeutic target for the treatment and prevention of both BPD and IPF.
- Published
- 2017
26. Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome
- Author
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John T. Benjamin, Taylor P. Sherrill, William Lawson, Harikrishna Tanjore, Rinat Zaynagetdinov, Aidong Qi, Lisa R. Young, Peter M. Gulleman, Sergey V. Novitskiy, Timothy S. Blackwell, Chelsi W Short, and Andrew P McBride
- Subjects
0301 basic medicine ,Male ,CCR2 ,Receptors, CCR2 ,Pulmonary Fibrosis ,education ,Protein Serine-Threonine Kinases ,Bleomycin ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Fibrosis ,Transforming Growth Factor beta ,Pulmonary fibrosis ,medicine ,Animals ,Chemokine CCL2 ,Lung ,biology ,business.industry ,Macrophages ,Interstitial lung disease ,Receptor, Transforming Growth Factor-beta Type II ,Epithelial Cells ,General Medicine ,Transforming growth factor beta ,respiratory system ,medicine.disease ,Mice, Inbred C57BL ,Pulmonary Alveoli ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Hermanski-Pudlak Syndrome ,biology.protein ,Cancer research ,Female ,Disease Susceptibility ,business ,Receptors, Transforming Growth Factor beta ,Research Article - Abstract
Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic remodeling are incompletely understood. Since increased macrophage recruitment precedes pulmonary fibrosis in HPS, we investigated whether crosstalk between AECs and macrophages determines fibrotic susceptibility. We found that AECs from HPS mice produce excessive MCP-1, which was associated with increased macrophages in the lungs of unchallenged HPS mice. Blocking MCP-1/CCR2 signaling in HPS mice with genetic deficiency of CCR2 or targeted deletion of MCP-1 in AECs normalized macrophage recruitment, decreased AEC apoptosis, and reduced lung fibrosis in these mice following treatment with low-dose bleomycin. We observed increased TGF-β production by HPS macrophages, which was eliminated by CCR2 deletion. Selective deletion of TGF-β in myeloid cells or of TGF-β signaling in AECs through deletion of TGFBR2 protected HPS mice from AEC apoptosis and bleomycin-induced fibrosis. Together, these data reveal a feedback loop in which increased MCP-1 production by dysfunctional AECs results in recruitment and activation of lung macrophages that produce TGF-β, thus amplifying the fibrotic cascade through AEC apoptosis and stimulation of fibrotic remodeling.
- Published
- 2016
27. Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18
- Author
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Lyle L. Moldawer, Mansour Mohamadzadeh, Andrew F. Marshall, Henry V. Baker, Natacha Colliou, James L. Wynn, Jörn-Hendrik Weitkamp, Daniel J. Moore, Ricardo Ungaro, Patrick Lahni, Edward R. Sherwood, Hector R. Wong, Steven J. McElroy, Irina Zharkikh, M. Cecilia Lopez, John T. Benjamin, Christopher S Wilson, Jin-Hua Liu, Erin J. Plosa, Jacek Hawiger, and Philip O. Scumpia
- Subjects
0301 basic medicine ,Male ,Systemic inflammation ,Inbred C57BL ,sepsis ,Mice ,0302 clinical medicine ,Monoclonal ,2.1 Biological and endogenous factors ,Molecular Targeted Therapy ,Aetiology ,Pediatric ,Multidisciplinary ,Neonatal sepsis ,Effector ,pathogenesis ,Interleukin-17 ,Interleukin-18 ,Antibodies, Monoclonal ,Interleukin ,Hematology ,Acquired immune system ,Survival Rate ,IL-17 ,Treatment Outcome ,Infectious Diseases ,Interleukin 18 ,Female ,Interleukin 17 ,medicine.symptom ,Neonatal Sepsis ,Infection ,IL-18 ,Biology ,Antibodies ,Sepsis ,03 medical and health sciences ,Clinical Research ,medicine ,Animals ,Inflammatory and immune system ,medicine.disease ,Newborn ,Mice, Inbred C57BL ,030104 developmental biology ,Good Health and Well Being ,Animals, Newborn ,Immunology ,neonate ,030215 immunology - Abstract
Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18-null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G(+) myeloid cells, and blocking IL-17A reduced IL-18-potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18-mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis.
- Published
- 2016
28. Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization
- Author
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Erin J. Plosa, Lawrence S. Prince, Amanda M. Im, Peter M. Gulleman, Wei Han, Roy Zent, Vasiliy V. Polosukhin, Rinat Zaynagetdinov, Lisa R. Young, John T. Benjamin, Riet van der Meer, Timothy S. Blackwell, Nada Bulus, and Linda A. Gleaves
- Subjects
Cell type ,Mesenchyme ,Organogenesis ,Integrin ,Inflammation ,Enzyme-Linked Immunosorbent Assay ,Bronchoalveolar Lavage ,Thiobarbituric Acid Reactive Substances ,Extracellular matrix ,Mice ,Cell Movement ,medicine ,Cell Adhesion ,Animals ,Pulmonary surfactant-associated protein C ,Cell adhesion ,Molecular Biology ,Lung ,Research Articles ,Chemokine CCL2 ,Epithelial cell differentiation ,Microscopy, Confocal ,biology ,Integrases ,Integrin beta1 ,Epithelial Cells ,Cell Biology ,respiratory system ,Pulmonary Surfactant-Associated Protein C ,Epithelium ,Cell biology ,Extracellular Matrix ,Pulmonary Alveoli ,medicine.anatomical_structure ,Immunology ,biology.protein ,medicine.symptom ,Reactive Oxygen Species ,Developmental Biology - Abstract
Integrin-dependent interactions between cells and extracellular matrix regulate lung development; however, specific roles for β1-containing integrins in individual cell types, including epithelial cells, remain incompletely understood. In this study, the functional importance of β1 integrin in lung epithelium during mouse lung development was investigated by deleting the integrin from E10.5 onwards using surfactant protein C promoter-driven Cre. These mutant mice appeared normal at birth but failed to gain weight appropriately and died by 4 months of age with severe hypoxemia. Defects in airway branching morphogenesis in association with impaired epithelial cell adhesion and migration, as well as alveolarization defects and persistent macrophage-mediated inflammation were identified. Using an inducible system to delete β1 integrin after completion of airway branching, we showed that alveolarization defects, characterized by disrupted secondary septation, abnormal alveolar epithelial cell differentiation, excessive collagen I and elastin deposition, and hypercellularity of the mesenchyme occurred independently of airway branching defects. By depleting macrophages using liposomal clodronate, we found that alveolarization defects were secondary to persistent alveolar inflammation. β1 integrin-deficient alveolar epithelial cells produced excessive monocyte chemoattractant protein 1 and reactive oxygen species, suggesting a direct role for β1 integrin in regulating alveolar homeostasis. Taken together, these studies define distinct functions of epithelial β1 integrin during both early and late lung development that affect airway branching morphogenesis, epithelial cell differentiation, alveolar septation and regulation of alveolar homeostasis.
- Published
- 2014
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