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  1. Article ; Online: Hepcidin Removal during Continuous Renal Replacement Therapy.

    Colbert, James F / Griffin, Benjamin R / Rolloff, Kristy / Erzen, Christopher L / Haeger, Sarah M / Altmann, Chris / Okamura, Kayo / Campbell, Ruth / Teitelbaum, Isaac / Faubel, Sarah

    Blood purification

    2023  Volume 53, Issue 1, Page(s) 23–29

    Abstract: ... at the time of enrollment, and then plasma and effluent were collected at 10:00 a.m. on the following 3 days ...

    Abstract Introduction: Patients with acute kidney injury (AKI) or end stage kidney disease (ESKD) may require continuous renal replacement therapy (CRRT) as a supportive intervention. While CRRT is effective at achieving solute control and fluid balance, the indiscriminate nature of this procedure raises the possibility that beneficial substances may similarly be removed. Hepcidin, an antimicrobial peptide with pivotal roles in iron homeostasis and pathogen clearance, has biochemical properties amenable to direct removal via CRRT. We hypothesized that serum hepcidin levels would significantly decrease after initiation of CRRT.
    Methods: In this prospective, observational trial, we enrolled 13 patients who required CRRT: 11 due to stage 3 AKI, and 2 due to critical illness in the setting of ESKD. Plasma was collected at the time of enrollment, and then plasma and effluent were collected at 10:00 a.m. on the following 3 days. Plasma samples were also collected from healthy controls, and we compared hepcidin concentrations in those with renal disease compared to normal controls, evaluated trends in hepcidin levels over time, and calculated the hepcidin sieving coefficient.
    Results: Plasma hepcidin levels were significantly higher in patients initiating CRRT than in normal controls (158 ± 60 vs. 17 ± 3 ng/mL respectively, p < 0.001). Hepcidin levels were highest prior to CRRT initiation (158 ± 60 ng/mL), and were significantly lower on day 1 (102 ± 24 ng/mL, p < 0.001) and day 2 (56 ± 14 ng/mL, p < 0.001) before leveling out on day 3 (51 ± 11 ng/mL). The median sieving coefficient was consistent at 0.82-0.83 for each of 3 days.
    Conclusions: CRRT initiation is associated with significant decreases in plasma hepcidin levels over the first 2 days of treatment regardless of indication for CRRT, or presence of underlying ESKD. Since reduced hepcidin levels are associated with increased mortality and our data implicate CRRT in hepcidin removal, larger clinical studies evaluating relevant clinical outcomes based on hepcidin trends in this population should be pursued.
    MeSH term(s) Humans ; Continuous Renal Replacement Therapy ; Renal Replacement Therapy/methods ; Prospective Studies ; Hepcidins ; Acute Kidney Injury ; Retrospective Studies ; Critical Illness/therapy
    Chemical Substances Hepcidins
    Language English
    Publishing date 2023-11-03
    Publishing country Switzerland
    Document type Observational Study ; Journal Article
    ZDB-ID 605548-5
    ISSN 1421-9735 ; 0253-5068
    ISSN (online) 1421-9735
    ISSN 0253-5068
    DOI 10.1159/000534297
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Heparan Sulfate in the Developing, Healthy, and Injured Lung.

    Haeger, Sarah M / Yang, Yimu / Schmidt, Eric P

    American journal of respiratory cell and molecular biology

    2016  Volume 55, Issue 1, Page(s) 5–11

    Abstract: Remarkable progress has been achieved in understanding the regulation of gene expression and protein translation, and how aberrancies in these template-driven processes contribute to disease pathogenesis. However, much of cellular physiology is ... ...

    Abstract Remarkable progress has been achieved in understanding the regulation of gene expression and protein translation, and how aberrancies in these template-driven processes contribute to disease pathogenesis. However, much of cellular physiology is controlled by non-DNA, nonprotein mediators, such as glycans. The focus of this Translational Review is to highlight the importance of a specific glycan polymer-the glycosaminoglycan heparan sulfate (HS)-on lung health and disease. We demonstrate how HS contributes to lung physiology and pathophysiology via its actions as both a structural constituent of the lung parenchyma as well as a regulator of cellular signaling. By highlighting current uncertainties in HS biology, we identify opportunities for future high-impact pulmonary and critical care translational investigations.
    MeSH term(s) Acute Disease ; Animals ; Chronic Disease ; Heparitin Sulfate/metabolism ; Humans ; Lung/embryology ; Lung/metabolism ; Lung/physiopathology ; Lung Injury/metabolism ; Lung Injury/physiopathology ; Signal Transduction
    Chemical Substances Heparitin Sulfate (9050-30-0)
    Language English
    Publishing date 2016
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2016-0043TR
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: More than a biomarker: the systemic consequences of heparan sulfate fragments released during endothelial surface layer degradation (2017 Grover Conference Series).

    Oshima, Kaori / Haeger, Sarah M / Hippensteel, Joseph A / Herson, Paco S / Schmidt, Eric P

    Pulmonary circulation

    2017  Volume 8, Issue 1, Page(s) 2045893217745786

    Abstract: Advances in tissue fixation and imaging techniques have yielded increasing appreciation for the glycosaminoglycan-rich endothelial glycocalyx and its in vivo manifestation, the endothelial surface layer (ESL). Pathological loss of the ESL during critical ...

    Abstract Advances in tissue fixation and imaging techniques have yielded increasing appreciation for the glycosaminoglycan-rich endothelial glycocalyx and its in vivo manifestation, the endothelial surface layer (ESL). Pathological loss of the ESL during critical illness promotes local endothelial dysfunction and, consequently, organ injury. Glycosaminoglycan fragments, such as heparan sulfate, are released into the plasma of animals and humans after ESL degradation and have thus served as a biomarker of endothelial injury. The development of state-of-the-art glycomic techniques, however, has revealed that these circulating heparan sulfate fragments are capable of influencing growth factor and other signaling pathways distant to the site of ESL injury. This review summarizes the current state of knowledge concerning the local (i.e. endothelial injury) and systemic (i.e. para- or endocrine) consequences of ESL degradation and identifies opportunities for future, novel investigations.
    Language English
    Publishing date 2017-06-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2638089-4
    ISSN 2045-8940 ; 2045-8932
    ISSN (online) 2045-8940
    ISSN 2045-8932
    DOI 10.1177/2045893217745786
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Circulating Heparan Sulfate Fragments Attenuate Histone-Induced Lung Injury Independently of Histone Binding.

    Zhang, Yanlin / Haeger, Sarah M / Yang, Yimu / Dailey, Kyrie L / Ford, Joshay A / Schmidt, Eric P

    Shock (Augusta, Ga.)

    2017  Volume 48, Issue 6, Page(s) 666–673

    Abstract: Extracellular histones are cationic damage-associated molecular pattern molecules capable of directly inducing cellular injury via charge-mediated interactions with plasma membranes. Accordingly, histones released into the plasma during critical illness ... ...

    Abstract Extracellular histones are cationic damage-associated molecular pattern molecules capable of directly inducing cellular injury via charge-mediated interactions with plasma membranes. Accordingly, histones released into the plasma during critical illness are known to contribute to the onset and propagation of lung injury. Vascular injury (with consequent degradation of the endothelial glycocalyx) simultaneously releases anionic heparan sulfate fragments (hexa- to octasaccharides in size) into the plasma. It is unknown whether this endogenous release of heparan sulfate fragments modulates charge-dependent histone cytotoxicity, or if exogenous heparan sulfate fragments could therapeutically attenuate histone-induced lung injury. Using isothermic calorimetry, we found that extracellular histones only bind to heparan sulfate fragments ≥ 10 saccharides in size, suggesting that glycocalyx-derived heparan sulfate hexa/octasaccharides are incapable of intercepting/neutralizing circulating histones. However, we found that even heparan sulfate fragments incapable of histone binding (e.g., tetrasaccharides) attenuated histone-induced lung injury in vivo, suggesting a direct, size-independent protective effect of heparan sulfate. We found that histones had no effect on human neutrophils ex vivo but exerted toll-like receptor-independent cytotoxicity on human pulmonary microvascular endothelial cells in vitro. This cytotoxicity could be prevented by either the addition of negatively charged (i.e., highly sulfated) heparan sulfate tetrasaccharides (incapable of binding histones) or decasaccharides (capable of binding histones). Taken together, our findings suggest that heparan sulfate oligosaccharides may directly exert pulmonary endothelial-protective effects that attenuate histone-mediated lung injury.
    MeSH term(s) Animals ; Heparitin Sulfate/chemistry ; Heparitin Sulfate/pharmacology ; Histones/toxicity ; Lung Injury/chemically induced ; Lung Injury/drug therapy ; Lung Injury/metabolism ; Lung Injury/pathology ; Male ; Mice ; Oligosaccharides/chemistry ; Oligosaccharides/pharmacology
    Chemical Substances Histones ; Oligosaccharides ; Heparitin Sulfate (9050-30-0)
    Language English
    Publishing date 2017-05-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1185432-7
    ISSN 1540-0514 ; 1073-2322
    ISSN (online) 1540-0514
    ISSN 1073-2322
    DOI 10.1097/SHK.0000000000000907
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome.

    Rizzo, Alicia N / Haeger, Sarah M / Oshima, Kaori / Yang, Yimu / Wallbank, Alison M / Jin, Ying / Lettau, Marie / McCaig, Lynda A / Wickersham, Nancy E / McNeil, J Brennan / Zakharevich, Igor / McMurtry, Sarah A / Langouët-Astrié, Christophe J / Kopf, Katrina W / Voelker, Dennis R / Hansen, Kirk C / Shaver, Ciara M / Kerchberger, V Eric / Peterson, Ryan A /
    Kuebler, Wolfgang M / Ochs, Matthias / Veldhuizen, Ruud Aw / Smith, Bradford J / Ware, Lorraine B / Bastarache, Julie A / Schmidt, Eric P

    JCI insight

    2022  Volume 7, Issue 2

    Abstract: Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer ... ...

    Abstract Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in patients with ARDS. Using mass spectrometry of airspace fluid noninvasively collected from mechanically ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation. Male patients had increased shedding, which correlated with airspace concentrations of matrix metalloproteinases. Selective epithelial glycocalyx degradation in mice was sufficient to induce surfactant dysfunction, a key characteristic of ARDS, leading to microatelectasis and decreased lung compliance. Rapid colorimetric quantification of airspace glycosaminoglycans was feasible and could provide point-of-care prognostic information to clinicians and/or be used for predictive enrichment in clinical trials.
    MeSH term(s) Alveolar Epithelial Cells/metabolism ; Alveolar Epithelial Cells/pathology ; Animals ; Duration of Therapy ; Female ; Glycocalyx/metabolism ; Glycosaminoglycans/analysis ; Glycosaminoglycans/metabolism ; Humans ; Lung Diseases, Interstitial/etiology ; Lung Diseases, Interstitial/metabolism ; Male ; Mice ; Predictive Value of Tests ; Prognosis ; Pulmonary Atelectasis/diagnosis ; Pulmonary Atelectasis/etiology ; Pulmonary Atelectasis/prevention & control ; Reproducibility of Results ; Respiration, Artificial/adverse effects ; Respiration, Artificial/methods ; Respiratory Distress Syndrome/diagnosis ; Respiratory Distress Syndrome/etiology ; Respiratory Distress Syndrome/metabolism ; Sex Factors
    Chemical Substances Glycosaminoglycans
    Language English
    Publishing date 2022-01-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.154573
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Circulating heparin oligosaccharides rapidly target the hippocampus in sepsis, potentially impacting cognitive functions.

    Zhang, Xing / Han, Xiaorui / Xia, Ke / Xu, Yongmei / Yang, Yimu / Oshima, Kaori / Haeger, Sarah M / Perez, Mario J / McMurtry, Sarah A / Hippensteel, Joseph A / Ford, Joshay A / Herson, Paco S / Liu, Jian / Schmidt, Eric P / Linhardt, Robert J

    Proceedings of the National Academy of Sciences of the United States of America

    2019  Volume 116, Issue 19, Page(s) 9208–9213

    Abstract: Sepsis induces heparanase-mediated degradation of the endothelial glycocalyx, a heparan sulfate-enriched endovascular layer critical to vascular homeostasis, releasing highly sulfated domains of heparan sulfate into the circulation. These domains are ... ...

    Abstract Sepsis induces heparanase-mediated degradation of the endothelial glycocalyx, a heparan sulfate-enriched endovascular layer critical to vascular homeostasis, releasing highly sulfated domains of heparan sulfate into the circulation. These domains are oligosaccharides rich in heparin-like trisulfated disaccharide repeating units. Using a chemoenzymatic approach, an undecasaccharide containing a uniformly
    MeSH term(s) Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Cognition ; Heparin/blood ; Heparitin Sulfate/metabolism ; Hippocampus/physiology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Oligosaccharides/blood ; Sepsis/blood ; Sepsis/metabolism ; Sepsis/psychology
    Chemical Substances Brain-Derived Neurotrophic Factor ; Oligosaccharides ; Heparin (9005-49-6) ; Heparitin Sulfate (9050-30-0)
    Language English
    Publishing date 2019-04-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1902227116
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  7. Article ; Online: Loss of endothelial sulfatase-1 after experimental sepsis attenuates subsequent pulmonary inflammatory responses.

    Oshima, Kaori / Han, Xiaorui / Ouyang, Yilan / El Masri, Rana / Yang, Yimu / Haeger, Sarah M / McMurtry, Sarah A / Lane, Trevor C / Davizon-Castillo, Pavel / Zhang, Fuming / Yue, Xinping / Vivès, Romain R / Linhardt, Robert J / Schmidt, Eric P

    American journal of physiology. Lung cellular and molecular physiology

    2019  Volume 317, Issue 5, Page(s) L667–L677

    Abstract: Sepsis patients are at increased risk for hospital-acquired pulmonary infections, potentially due to postseptic immunosuppression known as the compensatory anti-inflammatory response syndrome (CARS). CARS has been attributed to leukocyte dysfunction, ... ...

    Abstract Sepsis patients are at increased risk for hospital-acquired pulmonary infections, potentially due to postseptic immunosuppression known as the compensatory anti-inflammatory response syndrome (CARS). CARS has been attributed to leukocyte dysfunction, with an unclear role for endothelial cells. The pulmonary circulation is lined by an endothelial glycocalyx, a heparan sulfate-rich layer essential to pulmonary homeostasis. Heparan sulfate degradation occurs early in sepsis, leading to lung injury. Endothelial synthesis of new heparan sulfates subsequently allows for glycocalyx reconstitution and endothelial recovery. We hypothesized that remodeling of the reconstituted endothelial glycocalyx, mediated by alterations in the endothelial machinery responsible for heparan sulfate synthesis, contributes to CARS. Seventy-two hours after experimental sepsis, coincident with glycocalyx reconstitution, mice demonstrated impaired neutrophil and protein influx in response to intratracheal lipopolysaccharide (LPS). The postseptic reconstituted glycocalyx was structurally remodeled, with enrichment of heparan sulfate disaccharides sulfated at the 6-
    MeSH term(s) Animals ; Endothelial Cells/enzymology ; Female ; Glycocalyx/metabolism ; Lipopolysaccharides/pharmacology ; Lung/drug effects ; Lung/immunology ; Lung/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Pneumonia/etiology ; Pneumonia/metabolism ; Pneumonia/prevention & control ; Sepsis/chemically induced ; Sepsis/complications ; Sepsis/pathology ; Sulfotransferases/deficiency
    Chemical Substances Lipopolysaccharides ; Sulf1 protein, mouse (EC 2.8.2.-) ; Sulfotransferases (EC 2.8.2.-)
    Language English
    Publishing date 2019-08-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00175.2019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors.

    Haeger, Sarah M / Thompson, Joshua J / Kalra, Sean / Cleaver, Timothy G / Merrick, Daniel / Wang, Xiao-Jing / Malkoski, Stephen P

    Oncogene

    2016  Volume 35, Issue 5, Page(s) 577–586

    Abstract: Non-small-cell lung cancer (NSCLC) is a common malignancy with a poor prognosis. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor-suppressor loss. Smad4 is an established tumor suppressor in pancreatic and colon cancer; ...

    Abstract Non-small-cell lung cancer (NSCLC) is a common malignancy with a poor prognosis. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor-suppressor loss. Smad4 is an established tumor suppressor in pancreatic and colon cancer; however, the consequences of Smad4 loss in lung cancer are largely unknown. We evaluated Smad4 expression in human NSCLC samples and examined Smad4 alterations in large NSCLC data sets and found that reduced Smad4 expression is common in human NSCLC and occurs through a variety of mechanisms, including mutation, homozygous deletion and heterozygous loss. We modeled Smad4 loss in lung cancer by deleting Smad4 in airway epithelial cells and found that Smad4 deletion both initiates and promotes lung tumor development. Interestingly, both Smad4(-/-) mouse tumors and human NSCLC samples with reduced Smad4 expression demonstrated increased DNA damage, whereas Smad4 knockdown in lung cancer cells reduced DNA repair and increased apoptosis after DNA damage. In addition, Smad4-deficient NSCLC cells demonstrated increased sensitivity to both chemotherapeutics that inhibit DNA topoisomerase and drugs that block double-strand DNA break repair by non-homologous end joining. In sum, these studies establish Smad4 as a lung tumor suppressor and suggest that the defective DNA repair phenotype of Smad4-deficient tumors can be exploited by specific therapeutic strategies.
    MeSH term(s) Animals ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; DNA Repair ; Gene Knockdown Techniques ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Smad4 Protein/deficiency ; Smad4 Protein/genetics ; Smad4 Protein/metabolism ; Topoisomerase Inhibitors/pharmacology
    Chemical Substances SMAD4 protein, human ; Smad4 Protein ; Smad4 protein, mouse ; Topoisomerase Inhibitors
    Language English
    Publishing date 2016-02-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/onc.2015.112
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  9. Article ; Online: Epithelial Heparan Sulfate Contributes to Alveolar Barrier Function and Is Shed during Lung Injury.

    Haeger, Sarah M / Liu, Xinyue / Han, Xiaorui / McNeil, J Brennan / Oshima, Kaori / McMurtry, Sarah A / Yang, Yimu / Ouyang, Yilan / Zhang, Fuming / Nozik-Grayck, Eva / Zemans, Rachel L / Tuder, Rubin M / Bastarache, Julie A / Linhardt, Robert J / Schmidt, Eric P

    American journal of respiratory cell and molecular biology

    2018  Volume 59, Issue 3, Page(s) 363–374

    Abstract: The lung epithelial glycocalyx is a carbohydrate-enriched layer lining the pulmonary epithelial surface. Although epithelial glycocalyx visualization has been reported, its composition and function remain unknown. Using immunofluorescence and mass ... ...

    Abstract The lung epithelial glycocalyx is a carbohydrate-enriched layer lining the pulmonary epithelial surface. Although epithelial glycocalyx visualization has been reported, its composition and function remain unknown. Using immunofluorescence and mass spectrometry, we identified heparan sulfate (HS) and chondroitin sulfate within the lung epithelial glycocalyx. In vivo selective enzymatic degradation of epithelial HS, but not chondroitin sulfate, increased lung permeability. Using mass spectrometry and gel electrophoresis approaches to determine the fate of epithelial HS during lung injury, we detected shedding of 20 saccharide-long or greater HS into BAL fluid in intratracheal LPS-treated mice. Furthermore, airspace HS in clinical samples from patients with acute respiratory distress syndrome correlated with indices of alveolar permeability, reflecting the clinical relevance of these findings. The length of HS shed during intratracheal LPS-induced injury (≥20 saccharides) suggests cleavage of the proteoglycan anchoring HS to the epithelial surface, rather than cleavage of HS itself. We used pharmacologic and transgenic animal approaches to determine that matrix metalloproteinases partially mediate HS shedding during intratracheal LPS-induced lung injury. Although there was a trend toward decreased alveolar permeability after treatment with the matrix metalloproteinase inhibitor, doxycycline, this did not reach statistical significance. These studies suggest that epithelial HS contributes to the lung epithelial barrier and its degradation is sufficient to increase lung permeability. The partial reduction of HS shedding achieved with doxycycline is not sufficient to rescue epithelial barrier function during intratracheal LPS-induced lung injury; however, whether complete attenuation of HS shedding is sufficient to rescue epithelial barrier function remains unknown.
    MeSH term(s) Animals ; Capillary Permeability/drug effects ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Glycocalyx/metabolism ; Heparitin Sulfate/metabolism ; Lipopolysaccharides/pharmacology ; Lung Injury/chemically induced ; Lung Injury/drug therapy ; Mice ; Respiratory Distress Syndrome/drug therapy ; Syndecans/metabolism
    Chemical Substances Lipopolysaccharides ; Syndecans ; lipopolysaccharide A ; Heparitin Sulfate (9050-30-0)
    Language English
    Publishing date 2018-03-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2017-0428OC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: A model-specific role of microRNA-223 as a mediator of kidney injury during experimental sepsis.

    Colbert, James F / Ford, Joshay A / Haeger, Sarah M / Yang, Yimu / Dailey, Kyrie L / Allison, Kristen C / Neudecker, Viola / Evans, Christopher M / Richardson, Vanessa L / Brodsky, Kelley S / Faubel, Sarah / Eltzschig, Holger K / Schmidt, Eric P / Ginde, Adit A

    American journal of physiology. Renal physiology

    2017  Volume 313, Issue 2, Page(s) F553–F559

    Abstract: Sepsis outcomes are heavily dependent on the development of septic organ injury, but no interventions exist to interrupt or reverse this process. microRNA-223 (miR-223) is known to be involved in both inflammatory gene regulation and host-pathogen ... ...

    Abstract Sepsis outcomes are heavily dependent on the development of septic organ injury, but no interventions exist to interrupt or reverse this process. microRNA-223 (miR-223) is known to be involved in both inflammatory gene regulation and host-pathogen interactions key to the pathogenesis of sepsis. The goal of this study was to determine the role of miR-223 as a mediator of septic kidney injury. Using miR-223 knockout mice and multiple models of experimental sepsis, we found that miR-223 differentially influences acute kidney injury (AKI) based on the model used. In the absence of miR-223, mice demonstrated exaggerated AKI in sterile models of sepsis (LPS injection) and attenuated AKI in a live-infection model of sepsis (cecal ligation and puncture). We demonstrated that miR-223 expression is induced in kidney homogenate after cecal ligation and puncture, but not after LPS or fecal slurry injection. We investigated additional potential mechanistic explanations including differences in peritoneal bacterial clearance and host stool virulence. Our findings highlight the complex role of miR-223 in the pathogenesis of septic kidney injury, as well as the importance of differences in experimental sepsis models and their consequent translational applicability.
    MeSH term(s) Acute Kidney Injury/etiology ; Acute Kidney Injury/metabolism ; Animals ; Disease Models, Animal ; Lipopolysaccharides ; Male ; Methicillin-Resistant Staphylococcus aureus ; Mice, Inbred C57BL ; Mice, Knockout ; MicroRNAs/metabolism ; Sepsis/complications ; Sepsis/metabolism
    Chemical Substances Lipopolysaccharides ; MIRN223 microRNA, mouse ; MicroRNAs
    Language English
    Publishing date 2017-05-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 603837-2
    ISSN 1522-1466 ; 0363-6127
    ISSN (online) 1522-1466
    ISSN 0363-6127
    DOI 10.1152/ajprenal.00493.2016
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