Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury

Abstract Background Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke‐induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single‐chain urokinase plasminogen act...

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Main Authors: Marla R. Wolfson, Perenlei Enkhbaatar, Satoshi Fukuda, Christina L. Nelson, Robert O. Williams III, Soraya Hengsawas Surasarang, Sawittree Sahakijpijarn, Gennaro Calendo, Andrey A. Komissarov, Galina Florova, Krishna Sarva, Steven I. Idell, Thomas H. Shaffer
Format: Article
Language:English
Published: Wiley 2020-03-01
Series:Clinical and Translational Medicine
Subjects:
Online Access:https://doi.org/10.1002/ctm2.26
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spelling doaj-bad4ee72bd4245768ebac4aaa4449de02020-11-25T02:58:23ZengWileyClinical and Translational Medicine2001-13262020-03-0110125827410.1002/ctm2.26Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injuryMarla R. Wolfson0Perenlei Enkhbaatar1Satoshi Fukuda2Christina L. Nelson3Robert O. Williams III4Soraya Hengsawas Surasarang5Sawittree Sahakijpijarn6Gennaro Calendo7Andrey A. Komissarov8Galina Florova9Krishna Sarva10Steven I. Idell11Thomas H. Shaffer12Department of Thoracic Medicine & Surgery, Physiology & Pediatrics, and Temple Lung Center Lewis Katz School of Medicine at Temple University Philadelphia Pennsylvania USADepartment of Anesthesiology The University of Texas Medical Branch Galveston Texas USADepartment of Anesthesiology The University of Texas Medical Branch Galveston Texas USADepartment of Anesthesiology The University of Texas Medical Branch Galveston Texas USACollege of Pharmacy The University of Texas at Austin Austin Texas USACollege of Pharmacy The University of Texas at Austin Austin Texas USACollege of Pharmacy The University of Texas at Austin Austin Texas USADepartment of Thoracic Medicine & Surgery, Physiology & Pediatrics, and Temple Lung Center Lewis Katz School of Medicine at Temple University Philadelphia Pennsylvania USACellular and Molecular Biology and the Texas Lung Institute The University of Texas Health Science Center at Tyler Tyler Texas USACellular and Molecular Biology and the Texas Lung Institute The University of Texas Health Science Center at Tyler Tyler Texas USACellular and Molecular Biology and the Texas Lung Institute The University of Texas Health Science Center at Tyler Tyler Texas USACellular and Molecular Biology and the Texas Lung Institute The University of Texas Health Science Center at Tyler Tyler Texas USADepartment of Thoracic Medicine & Surgery, Physiology & Pediatrics, and Temple Lung Center Lewis Katz School of Medicine at Temple University Philadelphia Pennsylvania USAAbstract Background Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke‐induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single‐chain urokinase plasminogen activator (scuPA) moderated this adverse effect and supported transient improvement in gas exchange and lung mechanics. However, neither aerosolized plasminogen activator (PA) yielded durable improvements in physiologic responses or reduction in cast burden. Here, we hypothesized that perfluorochemical (PFC) liquids would facilitate PA distribution and sustain improvements in physiologic outcomes in ISALI. Methods Spontaneously breathing adult sheep (n = 36) received anesthesia and analgesia and were instrumented, exposed to cotton smoke inhalation, and supported by mechanical ventilation for 48 h. Groups (n = 6/group) were studied without supplemental treatment, or, starting 4 h post injury, they received intratracheal low volume (8 mL) PFC liquid alone or a dose range of tPA/PFC or scuPA/PFC suspensions (4 or 8 mg in 8 mL PFC) every 8 h. Outcomes were evaluated by sequential measurements of cardiopulmonary parameters, lung histomorphology, and biochemical analyses of bronchoalveolar lavage fluid. Results Dose‐response and PA‐type comparisons of outcomes demonstrated sustained superiority with low‐volume PFC suspensions of scuPA over tPA or PFC alone, favoring the highest dose of scuPA/PFC suspension over lower doses, without airway bleeding. Conclusions We propose that this improved profile over previously reported aerosolized delivery is likely related to improved dose distribution. Sustained salutary responses to scuPA/PFC suspension delivery in this translational model are encouraging and support the possibility that the observed outcomes could be of clinical importance.https://doi.org/10.1002/ctm2.26airway castsinhalational acute lung injuryperfluorochemicalsplasminogen activators
collection DOAJ
language English
format Article
sources DOAJ
author Marla R. Wolfson
Perenlei Enkhbaatar
Satoshi Fukuda
Christina L. Nelson
Robert O. Williams III
Soraya Hengsawas Surasarang
Sawittree Sahakijpijarn
Gennaro Calendo
Andrey A. Komissarov
Galina Florova
Krishna Sarva
Steven I. Idell
Thomas H. Shaffer
spellingShingle Marla R. Wolfson
Perenlei Enkhbaatar
Satoshi Fukuda
Christina L. Nelson
Robert O. Williams III
Soraya Hengsawas Surasarang
Sawittree Sahakijpijarn
Gennaro Calendo
Andrey A. Komissarov
Galina Florova
Krishna Sarva
Steven I. Idell
Thomas H. Shaffer
Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury
Clinical and Translational Medicine
airway casts
inhalational acute lung injury
perfluorochemicals
plasminogen activators
author_facet Marla R. Wolfson
Perenlei Enkhbaatar
Satoshi Fukuda
Christina L. Nelson
Robert O. Williams III
Soraya Hengsawas Surasarang
Sawittree Sahakijpijarn
Gennaro Calendo
Andrey A. Komissarov
Galina Florova
Krishna Sarva
Steven I. Idell
Thomas H. Shaffer
author_sort Marla R. Wolfson
title Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury
title_short Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury
title_full Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury
title_fullStr Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury
title_full_unstemmed Perfluorochemical‐facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke‐induced acute lung injury
title_sort perfluorochemical‐facilitated plasminogen activator delivery to the airways: a novel treatment for inhalational smoke‐induced acute lung injury
publisher Wiley
series Clinical and Translational Medicine
issn 2001-1326
publishDate 2020-03-01
description Abstract Background Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke‐induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single‐chain urokinase plasminogen activator (scuPA) moderated this adverse effect and supported transient improvement in gas exchange and lung mechanics. However, neither aerosolized plasminogen activator (PA) yielded durable improvements in physiologic responses or reduction in cast burden. Here, we hypothesized that perfluorochemical (PFC) liquids would facilitate PA distribution and sustain improvements in physiologic outcomes in ISALI. Methods Spontaneously breathing adult sheep (n = 36) received anesthesia and analgesia and were instrumented, exposed to cotton smoke inhalation, and supported by mechanical ventilation for 48 h. Groups (n = 6/group) were studied without supplemental treatment, or, starting 4 h post injury, they received intratracheal low volume (8 mL) PFC liquid alone or a dose range of tPA/PFC or scuPA/PFC suspensions (4 or 8 mg in 8 mL PFC) every 8 h. Outcomes were evaluated by sequential measurements of cardiopulmonary parameters, lung histomorphology, and biochemical analyses of bronchoalveolar lavage fluid. Results Dose‐response and PA‐type comparisons of outcomes demonstrated sustained superiority with low‐volume PFC suspensions of scuPA over tPA or PFC alone, favoring the highest dose of scuPA/PFC suspension over lower doses, without airway bleeding. Conclusions We propose that this improved profile over previously reported aerosolized delivery is likely related to improved dose distribution. Sustained salutary responses to scuPA/PFC suspension delivery in this translational model are encouraging and support the possibility that the observed outcomes could be of clinical importance.
topic airway casts
inhalational acute lung injury
perfluorochemicals
plasminogen activators
url https://doi.org/10.1002/ctm2.26
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