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Involvement of the Bufadienolides in the Detection and Therapy of the Acute Respiratory Distress Syndrome

  • Acute Lung Injury
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Abstract

Purpose

The acute respiratory distress syndrome (ARDS) represents a major challenge for clinicians as well as basic scientists. The mortality rate for ARDS has been maintained within the range of 40–52%. The authors have examined the involvement of the “cardiotonic steroids” in the pathogenesis and therapy of ARDS. We have studied the possible role of the bufadienolide, marinobufagenin (MBG), in the pathogenesis of ARDS in both a rat model of ARDS and in patients afflicted with that disorder. In addition, the potential therapeutic benefit of an antagonist of MBG, resibufogenin (RBG), in an animal model has been evaluated.

Method

A syndrome resembling human ARDS was produced in the rat by exposing the animals to 100% oxygen for 48 h. In other animals, RBG was administered to these “hyperoxic” rats, and the serum MBG was measured. In human ICU patients, urinary samples were examined for levels of MBG, and the values were compared to those obtained from other ICU patients admitted with diagnoses other than ARDS.

Results

(1) Exposure of rats to hyperoxia produced a histologic picture which resembled that of human ARDS. (2) Serum levels of MBG in the “hyperoxic” rats substantially exceeded those obtained in animals exposed to ambient oxygen levels and were reduced to normal by RBG. (3) In ARDS patients, substantial elevations in urinary MBG were obtained compared to those in non-ARDS ICU patients.

Conclusions

MBG may serve as an important biomarker for the development of ARDS, and RBG may represent a preventative/therapy in this disorder.

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Notes

  1. A life threatening disorder characterized by severe hypoxemia, dyspnea, and bilateral pulmonary opacities in radiographic and computed tomographic (CT) scans.

  2. An endogenous bufadienolide that regulates the ubiquitous Na+/K+ ATPase enzyme and is implicated in states characterized by volume expansion and increased vascular permeability.

  3. A pregnancy-specific disorder characterized by high blood pressure and proteinuria.

  4. A bufadienolide that is an antagonist of MBG and it is shown to prevent all of the manifestations of preeclampsia in a rat model.

Abbreviations

ARDS:

Acute Respiratory Distress Syndrome

MBG:

Marinobufagenin

RBG:

Resibufogenin

PE:

Preeclampsia

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Acknowledgements

These studies were supported by the Texas A&M University College of Veterinary Medicine and Biosciences, College Station, Texas and the Jules B. Puschett Research Endowment Fund, Houston, Texas. All the authors take responsibility for the accuracy of the data presented in this manuscript: All of them have read the manuscript prior to submission for publication. Mr. Abbas and Dr. Puschett wrote the majority of the paper which was approved by the other co-authors.

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Authors and Affiliations

  1. Department of Veterinary Pathobiology, School of Veterinary Medicine and Biosciences, Texas A&M University, VMS Room 216, 4467 TAMU, College Station, TX, 77843-4467, USA

    Mir M. K. Abbas, Q. Chen & J. B. Puschett

  2. Pulmonary Disease Critical Care, Memorial Hermann Hospital, Houston, TX, USA

    B. Patel

  3. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, 1102 Bates Ave. Suite C.530.04, Houston, TX, 77030, USA

    W. Jiang & B. Moorthy

  4. Department of Pathology, Houston Methodist Research Institute, Houston, TX, USA

    R. Barrios

  5. Department of Medicine, School of Medicine, Texas A&M University, College Station, TX, USA

    J. B. Puschett

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  1. Mir M. K. Abbas
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  2. B. Patel
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  3. Q. Chen
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  4. W. Jiang
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  5. B. Moorthy
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  6. R. Barrios
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  7. J. B. Puschett
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Corresponding authors

Correspondence to B. Moorthy or J. B. Puschett.

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Conflict of interest

Dr. Puschett has an equity interest in Bufogen, LLC and no other conflicts of interest. We did get permission from the Texas A&M Animal Use committee, the Baylor IRB as well as the Human Use Committee at the Baylor College of Medicine, the Texas Children’s Hospital, Houston, TX and the University of Texas-Houston/ Memorial Hermann Hospital-Human Use Committee.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed written consent was obtained from all patients involved in this study.

Additional information

Notation of prior abstract presentation: The observations in this manuscript have been presented in abstract form at a conference, Experimental Biology 2016 held in San Diego on the 4th of April, 2016.

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Abbas, M.M.K., Patel, B., Chen, Q. et al. Involvement of the Bufadienolides in the Detection and Therapy of the Acute Respiratory Distress Syndrome. Lung 195, 323–332 (2017). https://doi.org/10.1007/s00408-017-9989-1

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