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Article ; Online: Sulforhodamine B and exogenous surfactant effects on alveolar surface tension under acute respiratory distress syndrome conditions.

Nguyen, Tam L / Perlman, Carrie E

Journal of applied physiology (Bethesda, Md. : 1985)

2020 Volume 129, Issue 6, Page(s) 1505–1513

Abstract: In the acute respiratory distress syndrome (ARDS), alveolar surface tension, ...

Abstract	In the acute respiratory distress syndrome (ARDS), alveolar surface tension,
MeSH term(s)	Animals ; Pulmonary Surfactants ; Rats ; Respiratory Distress Syndrome/chemically induced ; Respiratory Distress Syndrome/drug therapy ; Rhodamines ; Surface Tension ; Surface-Active Agents
Chemical Substances	Pulmonary Surfactants ; Rhodamines ; Surface-Active Agents ; lissamine rhodamine B (2609-88-3)
Language	English
Publishing date	2020-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00422.2020
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Article ; Online: Sulforhodamine B and exogenous surfactant effects on alveolar surface tension in acute respiratory distress syndrome models

Nguyen, Tam L. / Perlman, Carrie E.

bioRxiv

Abstract: BACKGROUND In the acute respiratory distress syndrome (ARDS), elevated alveolar surface tension, T, may increase ventilation-induced lung injury. Exogenous surfactant therapy has not reduced ARDS mortality. Sulforhodamine B (SRB), which acts with albumin ...

Abstract	BACKGROUND In the acute respiratory distress syndrome (ARDS), elevated alveolar surface tension, T, may increase ventilation-induced lung injury. Exogenous surfactant therapy has not reduced ARDS mortality. Sulforhodamine B (SRB), which acts with albumin to improve native lung surfactant efficacy, could be an alternative T-lowering therapeutic. We test whether substances suspected of elevating T in ARDS raise T in the lungs – where, unlike in most in vitro tests, the surfactant monolayer is intact – and test the abilities of exogenous surfactant and SRB to reduce T. METHODS In isolated rat lungs, we micropuncture a surface alveolus and instill a solution containing a substance purported to raise T in ARDS: control saline, cell debris, secretory phospholipase A2 (sPLA2), acid or mucins. We test each substance alone; with albumin, to model proteinaceous edema liquid; with albumin and subsequent exogenous surfactant; or with albumin and SRB. We determine T by combining servo-nulling pressure measurement with confocal microscopy, and applying the Laplace relation. RESULTS In the control group, saline, albumin and Infasurf do not alter T; SRB reduces T below normal. With albumin, the experimental substances raise T. With cell debris, surfactant does not alter T; SRB normalizes T. With sPLA2, surfactant normalizes T; SRB reduces T. With acid or mucins, neither surfactant nor SRB alters T. CONCLUSIONS The inability of surfactant to counter cell debris may contribute to the failure of surfactant therapy for ARDS. For non-aspiration ARDS, SRB, which can be delivered intravascularly to target injured lung regions, holds promise as a treatment. Summary In the acute respiratory distress syndrome (ARDS), surface tension, T, is believed to be elevated and surfactant therapy has failed to reduce mortality. Here, we test whether various substances suggested to contribute to elevated T in ARDS in fact raise T in the lungs. And we test the ability of exogenous surfactant and of a potential alternative therapeutic, sulforhodamine B (SRB), to reduce T. We find exogenous surfactant unable to lower T in the presence of cell debris but SRB, which can be administered intravascularly, a candidate for lowering T in non-aspiration ARDS.
Keywords	covid19
Publisher	BioRxiv
Document type	Article ; Online
DOI	10.1101/2020.04.08.031526
Database	COVID19

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Article ; Online: Sulforhodamine B and exogenous surfactant effects on alveolar surface tension under acute respiratory distress syndrome conditions

Nguyen, Tam L. / Perlman, Carrie E.

bioRxiv

Abstract: In the acute respiratory distress syndrome (ARDS), alveolar surface tension, T, may be elevated. Elevated T should increase ventilation-induced lung injury. Exogenous surfactant therapy, intended to lower T, has not reduced mortality. Sulforhodamine B ( ... ...

Abstract	In the acute respiratory distress syndrome (ARDS), alveolar surface tension, T, may be elevated. Elevated T should increase ventilation-induced lung injury. Exogenous surfactant therapy, intended to lower T, has not reduced mortality. Sulforhodamine B (SRB) might, alternatively, be employed to lower T. We test whether substances suspected of elevating T in ARDS raise T in the lungs and test the abilities of exogenous surfactant and SRB to reduce T. In isolated rat lungs, we micropuncture a surface alveolus and instill a solution of a purported T-raising substance: control saline, cell debris, secretory phospholipase A2 (sPLA2), acid or mucins. We test each substance alone; with albumin, to model proteinaceous edema liquid; with albumin and exogenous surfactant; or with albumin and SRB. We determine T in situ in the lungs by combining servo-nulling pressure measurement with confocal microscopy, and applying the Laplace relation. With control saline, albumin does not alter T, additional surfactant raises T and additional SRB lowers T. The experimental substances, without or with albumin, raise T. Excepting under aspiration conditions, addition of surfactant or SRB lowers T. Exogenous surfactant activity is concentration and ventilation dependent. Sulforhodamine B, which could be delivered intravascularly, holds promise as an alternative therapeutic. New and Noteworthy In the acute respiratory distress syndrome (ARDS), lowering surface tension, T, should reduce ventilation injury yet exogenous surfactant has not reduced mortality. We show with direct T-determination in isolated lungs that substances suggested to elevate T in ARDS indeed raise T, and exogenous surfactant reduces T. Further, we extend our previous finding that sulforhodamine B (SRB) reduces T below normal in healthy lungs and show that SRB, too, reduces T under ARDS conditions.
Keywords	covid19
Publisher	BioRxiv
Document type	Article ; Online
DOI	10.1101/2020.04.08.031526
Database	COVID19

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Article ; Online: Tracheal acid or surfactant instillation raises alveolar surface tension.

Nguyen, Tam L / Perlman, Carrie E

Journal of applied physiology (Bethesda, Md. : 1985)

2018 Volume 125, Issue 5, Page(s) 1357–1367

Abstract: Whether alveolar liquid surface tension, T, is elevated in the acute respiratory distress syndrome (ARDS) has not been demonstrated in situ in the lungs. Neither is it known how exogenous surfactant, which has failed to treat ARDS, affects in situ T. We ... ...

Abstract	Whether alveolar liquid surface tension, T, is elevated in the acute respiratory distress syndrome (ARDS) has not been demonstrated in situ in the lungs. Neither is it known how exogenous surfactant, which has failed to treat ARDS, affects in situ T. We aim to determine T in an acid-aspiration ARDS model before and after exogenous surfactant administration. In isolated rat lungs, we combine servo-nulling pressure measurement and confocal microscopy to determine alveolar liquid T according to the Laplace relation. Administering 0.01 N (pH 1.9) HCl solution by alveolar injection or tracheal instillation, to model gastric liquid aspiration, raises T. Subsequent surfactant administration fails to normalize T. Furthermore, in normal lungs, tracheal instillation of control saline or exogenous surfactant raises T. Lavaging the trachea with saline and injecting the lavage solution into the alveolus raises T, suggesting that tracheal instillation may wash T-raising airway contents to the alveolus. Adding 0.01 N HCl or 5 mM CaCl
MeSH term(s)	Animals ; Hydrochloric Acid ; In Vitro Techniques ; Instillation, Drug ; Male ; Pulmonary Alveoli/drug effects ; Pulmonary Surfactants/pharmacology ; Pulmonary Surfactants/therapeutic use ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome, Adult/chemically induced ; Respiratory Distress Syndrome, Adult/drug therapy ; Surface Tension/drug effects
Chemical Substances	Pulmonary Surfactants ; Hydrochloric Acid (QTT17582CB)
Language	English
Publishing date	2018-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00397.2017
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Article ; Online: Intravenous sulforhodamine B reduces alveolar surface tension, improves oxygenation, and reduces ventilation injury in a respiratory distress model.

Wu, You / Nguyen, Tam L / Perlman, Carrie E

Journal of applied physiology (Bethesda, Md. : 1985)

2020 Volume 130, Issue 5, Page(s) 1305–1316

Abstract: In the neonatal respiratory distress syndrome (NRDS) and acute respiratory distress syndrome (ARDS), mechanical ventilation supports gas exchange but can cause ventilation-induced lung injury (VILI) that contributes to high mortality. Further, surface ... ...

Abstract	In the neonatal respiratory distress syndrome (NRDS) and acute respiratory distress syndrome (ARDS), mechanical ventilation supports gas exchange but can cause ventilation-induced lung injury (VILI) that contributes to high mortality. Further, surface tension,
MeSH term(s)	Animals ; COVID-19 ; Humans ; Lung ; Male ; Rats ; Respiration, Artificial ; Respiratory Distress Syndrome ; Rhodamines ; SARS-CoV-2 ; Surface Tension
Chemical Substances	Rhodamines ; lissamine rhodamine B (2609-88-3)
Language	English
Publishing date	2020-11-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00421.2020
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Article: Strategies to Overcome Biological Barriers Associated with Pulmonary Drug Delivery.

Plaunt, Adam J / Nguyen, Tam L / Corboz, Michel R / Malinin, Vladimir S / Cipolla, David C

Pharmaceutics

2022 Volume 14, Issue 2

Abstract: While the inhalation route has been used for millennia for pharmacologic effect, the biological barriers to treating lung disease created real challenges for the pharmaceutical industry until sophisticated device and formulation technologies emerged over ...

Abstract	While the inhalation route has been used for millennia for pharmacologic effect, the biological barriers to treating lung disease created real challenges for the pharmaceutical industry until sophisticated device and formulation technologies emerged over the past fifty years. There are now several inhaled device technologies that enable delivery of therapeutics at high efficiency to the lung and avoid excessive deposition in the oropharyngeal region. Chemistry and formulation technologies have also emerged to prolong retention of drug at the active site by overcoming degradation and clearance mechanisms, or by reducing the rate of systemic absorption. These technologies have also been utilized to improve tolerability or to facilitate uptake within cells when there are intracellular targets. This paper describes the biological barriers and provides recent examples utilizing formulation technologies or drug chemistry modifications to overcome those barriers.
Language	English
Publishing date	2022-01-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14020302
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Article ; Online: Accelerated deflation promotes homogeneous airspace liquid distribution in the edematous lung.

Wu, You / Nguyen, Tam L / Perlman, Carrie E

Journal of applied physiology (Bethesda, Md. : 1985)

2017 Volume 122, Issue 4, Page(s) 739–751

Abstract: Edematous lungs contain regions with heterogeneous alveolar flooding. Liquid is trapped in flooded alveoli by a pressure barrier-higher liquid pressure at the border than in the center of flooded alveoli-that is proportional to surface tension, ...

Abstract	Edematous lungs contain regions with heterogeneous alveolar flooding. Liquid is trapped in flooded alveoli by a pressure barrier-higher liquid pressure at the border than in the center of flooded alveoli-that is proportional to surface tension,
MeSH term(s)	Animals ; Disease Models, Animal ; Male ; Pressure ; Pulmonary Alveoli/injuries ; Pulmonary Alveoli/physiopathology ; Pulmonary Edema/physiopathology ; Pulmonary Ventilation/physiology ; Rats ; Rats, Sprague-Dawley ; Respiration ; Respiratory Mechanics/physiology ; Surface Tension
Language	English
Publishing date	2017-04-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00526.2016
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Article ; Online: Therapeutics for filovirus infection: traditional approaches and progress towards in silico drug design.

Shurtleff, Amy C / Nguyen, Tam L / Kingery, David A / Bavari, Sina

Expert opinion on drug discovery

2012 Volume 7, Issue 10, Page(s) 935–954

Abstract: Introduction: Ebolaviruses and marburgviruses cause severe and often lethal human hemorrhagic fevers. As no FDA-approved therapeutics are available for these infections, efforts to discover new therapeutics are important, especially because these ... ...

Abstract	Introduction: Ebolaviruses and marburgviruses cause severe and often lethal human hemorrhagic fevers. As no FDA-approved therapeutics are available for these infections, efforts to discover new therapeutics are important, especially because these pathogens are considered biothreats and emerging infectious diseases. All methods for discovering new therapeutics should be considered, including compound library screening in vitro against virus and in silico structure-based drug design, where possible, if sufficient biochemical and structural information is available. Areas covered: This review covers the structure and function of filovirus proteins, as they have been reported to date, as well as some of the current antiviral screening approaches. The authors discuss key studies mapping small-molecule modulators that were found through library and in silico screens to potential sites on viral proteins or host proteins involved in virus trafficking and pathogenesis. A description of ebolavirus and marburgvirus diseases and available animal models is also presented. Expert opinion: To discover novel therapeutics with potent efficacy using sophisticated computational methods, more high-resolution crystal structures of filovirus proteins and more details about the protein functions and host interaction will be required. Current compound screening efforts are finding active antiviral compounds, but an emphasis on discovery research to investigate protein structures and functions enabling in silico drug design would provide another avenue for finding antiviral molecules. Additionally, targeting of protein-protein interactions may be a future avenue for drug discovery since disrupting catalytic sites may not be possible for all proteins.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Computer Simulation ; Drug Design ; Filoviridae ; Filoviridae Infections/drug therapy ; Filoviridae Infections/physiopathology ; Humans ; Viral Proteins/chemistry ; Viral Proteins/physiology
Chemical Substances	Antiviral Agents ; Viral Proteins
Language	English
Publishing date	2012-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2259618-5
ISSN	1746-045X ; 1746-0441
ISSN (online)	1746-045X
ISSN	1746-0441
DOI	10.1517/17460441.2012.714364
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Article: NMR analysis of the monomeric form of a mutant unliganded bovine neurophysin: comparison with the crystal structure of a neurophysin dimer.

Nguyen, Tam L / Breslow, Esther

Biochemistry

2002 Volume 41, Issue 18, Page(s) 5920–5930

Abstract: Determination of the structure of the unliganded monomeric state of neurophysin is central to an understanding of the allosteric relationship between neurophysin peptide-binding and dimerization. We examined this state by NMR, using the weakly dimerizing ...

Abstract	Determination of the structure of the unliganded monomeric state of neurophysin is central to an understanding of the allosteric relationship between neurophysin peptide-binding and dimerization. We examined this state by NMR, using the weakly dimerizing H80E mutant of bovine neurophysin-I. The derived structure, to which more than one conformer appeared to contribute, was compared with the crystal structure of the unliganded des 1-6 bovine neurophysin-II dimer. Significant conformational differences between the two proteins were evident in the orientation of the 3,10 helix, in the 50-58 loop, in beta-turns, and in specific intrachain contacts between amino- and carboxyl domains. However, both had similar secondary structures, in independent confirmation of earlier circular dichroism studies. Previously suggested interactions between the amino terminus and the 50-58 loop in the monomer were also confirmed. Comparison of the observed differences between the two proteins with demonstrated effects of dimerization on the NMR spectrum of bovine neurophysin-I, and preliminary investigation of the effects of dimerization on H80E spectra, allowed tentative distinction between the contributions of sequence and self-association differences to the difference in conformation. Regions altered by dimerization encompass most binding site residues, providing a potential explanation of differences in binding affinity between the unliganded monomeric and dimeric states. Differences between monomer and dimer states in turns, interdomain contacts, and within the interdomain segment of the 50-58 loop suggest that the effects of dimerization on intrasubunit conformation reflect the need to adjust the relative positions of the interface segments of the two domains for optimal interaction with the adjacent subunit and/or reflect the dual role of some residues as participants both at the interface and in interdomain contacts.
MeSH term(s)	Allosteric Regulation ; Amino Acid Sequence ; Animals ; Binding Sites ; Cattle ; Crystallography, X-Ray ; Dimerization ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Neurophysins/chemistry ; Neurophysins/genetics ; Neurophysins/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation
Chemical Substances	Ligands ; Neurophysins
Language	English
Publishing date	2002-03-04
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi012067k
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Article: Enhancing molecular flux through nanopores by means of attractive interactions.

Kasianowicz, John J / Nguyen, Tam L / Stanford, Vincent M

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

2006 Volume 103, Issue 31, Page(s) 11431–11432

MeSH term(s)	Animals ; Binding Sites ; Ion Channels/chemistry ; Ion Channels/metabolism ; Models, Molecular ; Models, Theoretical ; Nanotechnology ; Protein Conformation ; Static Electricity ; Thermodynamics
Chemical Substances	Ion Channels
Language	English
Publishing date	2006-07-25
Publishing country	United States
Document type	Comment ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0603951103
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