Skip to main content
Top
Published in: Lung 3/2017

01-06-2017 | Acute Lung Injury

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

Authors: Mir M. K. Abbas, B. Patel, Q. Chen, W. Jiang, B. Moorthy, R. Barrios, J. B. Puschett

Published in: Lung | Issue 3/2017

Login to get access

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.
Footnotes
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.
 
Literature
7.
go back to reference Heffner JE, Zamora CA (1990) Clinical predictors of prolonged translaryngeal intubation in patients with the adult respiratory distress syndrome. Chest 97(2):447–452CrossRefPubMed Heffner JE, Zamora CA (1990) Clinical predictors of prolonged translaryngeal intubation in patients with the adult respiratory distress syndrome. Chest 97(2):447–452CrossRefPubMed
8.
go back to reference Fowler AA, Hamman RF, Good JT et al (1983) Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 98(5 Pt 1):593–597CrossRefPubMed Fowler AA, Hamman RF, Good JT et al (1983) Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 98(5 Pt 1):593–597CrossRefPubMed
10.
go back to reference Pepe PE, Potkin RT, Reus DH et al (1982) Clinical predictors of the adult respiratory distress syndrome. Am J Surg 144(1):124–130CrossRefPubMed Pepe PE, Potkin RT, Reus DH et al (1982) Clinical predictors of the adult respiratory distress syndrome. Am J Surg 144(1):124–130CrossRefPubMed
11.
go back to reference Calfee CS, Eisner MD, Ware LB et al (2007) Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders. Crit Care Med 35(10):2243–2250CrossRefPubMedPubMedCentral Calfee CS, Eisner MD, Ware LB et al (2007) Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders. Crit Care Med 35(10):2243–2250CrossRefPubMedPubMedCentral
12.
go back to reference Pelosi P, Brazzi L, Gattinoni L (2002) Prone position in acute respiratory distress syndrome. Eur Respir J 20(4):1017–1028CrossRefPubMed Pelosi P, Brazzi L, Gattinoni L (2002) Prone position in acute respiratory distress syndrome. Eur Respir J 20(4):1017–1028CrossRefPubMed
13.
go back to reference Meade MO, Cook DJ, Guyatt GH et al (2008) Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299(6):637–645. doi:10.1001/jama.299.6.637 CrossRefPubMed Meade MO, Cook DJ, Guyatt GH et al (2008) Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299(6):637–645. doi:10.​1001/​jama.​299.​6.​637 CrossRefPubMed
15.
go back to reference Bagrov AY, Fedorova OV (1998) Effects of two putative endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na+, K+-pump in human mesenteric arteries. J Hypertens 16(12 Pt 2):1953–1958CrossRefPubMed Bagrov AY, Fedorova OV (1998) Effects of two putative endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na+, K+-pump in human mesenteric arteries. J Hypertens 16(12 Pt 2):1953–1958CrossRefPubMed
16.
go back to reference Fedorova OV, Kolodkin NI, Agalakova NI et al (2001) Marinobufagenin, an endogenous alpha-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats. Hypertension 37(2 Pt 2):462–466CrossRefPubMed Fedorova OV, Kolodkin NI, Agalakova NI et al (2001) Marinobufagenin, an endogenous alpha-1 sodium pump ligand, in hypertensive Dahl salt-sensitive rats. Hypertension 37(2 Pt 2):462–466CrossRefPubMed
17.
go back to reference Pamnani MB, Chen S, Yuan CM et al. (1994) Chronic blood pressure effects of bufalin, a sodium-potassium ATPase inhibitor, in rats. Hypertension 23 (1 Suppl):I106–109**CrossRefPubMed Pamnani MB, Chen S, Yuan CM et al. (1994) Chronic blood pressure effects of bufalin, a sodium-potassium ATPase inhibitor, in rats. Hypertension 23 (1 Suppl):I106–109**CrossRefPubMed
18.
go back to reference Schoner W (2002) Endogenous cardiac glycosides, a new class of steroid hormones. Eur J Biochem 269(10):2440–2448CrossRefPubMed Schoner W (2002) Endogenous cardiac glycosides, a new class of steroid hormones. Eur J Biochem 269(10):2440–2448CrossRefPubMed
22.
go back to reference Pugin J, Verghese G, Widmer MC et al (1999) The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med 27(2):304–312CrossRefPubMed Pugin J, Verghese G, Widmer MC et al (1999) The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med 27(2):304–312CrossRefPubMed
24.
go back to reference Matthay MA, Zimmerman GA, Esmon C et al (2003) Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group. Am J Respir Crit Care Med 167(7):1027–1035. doi:10.1164/rccm.200208-966WS CrossRefPubMed Matthay MA, Zimmerman GA, Esmon C et al (2003) Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group. Am J Respir Crit Care Med 167(7):1027–1035. doi:10.​1164/​rccm.​200208-966WS CrossRefPubMed
29.
32.
go back to reference Moorthy B, Parker KM, Smith CV et al (2000) Potentiation of oxygen-induced lung injury in rats by the mechanism-based cytochrome P-450 inhibitor, 1-aminobenzotriazole. J Pharmacol Exp Ther 292(2):553–560PubMed Moorthy B, Parker KM, Smith CV et al (2000) Potentiation of oxygen-induced lung injury in rats by the mechanism-based cytochrome P-450 inhibitor, 1-aminobenzotriazole. J Pharmacol Exp Ther 292(2):553–560PubMed
33.
go back to reference The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342(18):1301–1308. doi:10.1056/NEJM200005043421801 CrossRef The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342(18):1301–1308. doi:10.​1056/​NEJM200005043421​801 CrossRef
35.
go back to reference Mure M, Martling CR, Lindahl SG (1997) Dramatic effect on oxygenation in patients with severe acute lung insufficiency treated in the prone position. Crit Care Med 25(9):1539–1544CrossRefPubMed Mure M, Martling CR, Lindahl SG (1997) Dramatic effect on oxygenation in patients with severe acute lung insufficiency treated in the prone position. Crit Care Med 25(9):1539–1544CrossRefPubMed
36.
go back to reference Blanch L, Mancebo J, Perez M et al (1997) Short-term effects of prone position in critically ill patients with acute respiratory distress syndrome. Intensive Care Med 23(10):1033–1039CrossRefPubMed Blanch L, Mancebo J, Perez M et al (1997) Short-term effects of prone position in critically ill patients with acute respiratory distress syndrome. Intensive Care Med 23(10):1033–1039CrossRefPubMed
37.
go back to reference Mercat A, Richard JC, Vielle B et al (2008) Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299(6):646–655. doi:10.1001/jama.299.6.646 CrossRefPubMed Mercat A, Richard JC, Vielle B et al (2008) Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299(6):646–655. doi:10.​1001/​jama.​299.​6.​646 CrossRefPubMed
38.
go back to reference Briel M, Meade M, Mercat A et al (2010) Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 303(9):865–873. doi:10.1001/jama.2010.218 CrossRefPubMed Briel M, Meade M, Mercat A et al (2010) Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 303(9):865–873. doi:10.​1001/​jama.​2010.​218 CrossRefPubMed
41.
go back to reference Zapol WM, Snider MT, Hill JD et al (1979) Extracorporeal membrane oxygenation in severe acute respiratory failure: a randomized prospective study. JAMA 242(20):2193–2196CrossRefPubMed Zapol WM, Snider MT, Hill JD et al (1979) Extracorporeal membrane oxygenation in severe acute respiratory failure: a randomized prospective study. JAMA 242(20):2193–2196CrossRefPubMed
42.
go back to reference Manktelow C, Bigatello LM, Hess D et al (1997) Physiologic determinants of the response to inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology 87(2):297–307CrossRefPubMed Manktelow C, Bigatello LM, Hess D et al (1997) Physiologic determinants of the response to inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology 87(2):297–307CrossRefPubMed
43.
go back to reference Meade MO, Cook DJ, Griffith LE et al (2008) A study of the physiologic responses to a lung recruitment maneuver in acute lung injury and acute respiratory distress syndrome. Respir Care 53(11):1441–1449PubMed Meade MO, Cook DJ, Griffith LE et al (2008) A study of the physiologic responses to a lung recruitment maneuver in acute lung injury and acute respiratory distress syndrome. Respir Care 53(11):1441–1449PubMed
45.
go back to reference Goodman BE, Fleischer RS, Crandall ED (1983) Evidence for active Na+ transport by cultured monolayers of pulmonary alveolar epithelial cells. Am J Physiol 245(1):C78–C83PubMed Goodman BE, Fleischer RS, Crandall ED (1983) Evidence for active Na+ transport by cultured monolayers of pulmonary alveolar epithelial cells. Am J Physiol 245(1):C78–C83PubMed
46.
go back to reference Mason RJ, Williams MC, Widdicombe JH et al (1982) Transepithelial transport by pulmonary alveolar type II cells in primary culture. Proc Natl Acad Sci U S A 79(19):6033–6037CrossRefPubMedPubMedCentral Mason RJ, Williams MC, Widdicombe JH et al (1982) Transepithelial transport by pulmonary alveolar type II cells in primary culture. Proc Natl Acad Sci U S A 79(19):6033–6037CrossRefPubMedPubMedCentral
47.
go back to reference Matalon S, Benos DJ, Jackson RM (1996) Biophysical and molecular properties of amiloride-inhibitable Na+ channels in alveolar epithelial cells. Am J Physiol 271(1 Pt 1):L1–L22PubMed Matalon S, Benos DJ, Jackson RM (1996) Biophysical and molecular properties of amiloride-inhibitable Na+ channels in alveolar epithelial cells. Am J Physiol 271(1 Pt 1):L1–L22PubMed
48.
go back to reference Matthay MA, Folkesson HG, Verkman AS (1996) Salt and water transport across alveolar and distal airway epithelia in the adult lung. Am J Physiol 270(4 Pt 1):L487–L503PubMed Matthay MA, Folkesson HG, Verkman AS (1996) Salt and water transport across alveolar and distal airway epithelia in the adult lung. Am J Physiol 270(4 Pt 1):L487–L503PubMed
50.
go back to reference Johnson MD, Widdicombe JH, Allen L et al (2002) Alveolar epithelial type I cells contain transport proteins and transport sodium, supporting an active role for type I cells in regulation of lung liquid homeostasis. Proc Natl Acad Sci U S A 99(4):1966–1971. doi:10.1073/pnas.042689399 CrossRefPubMedPubMedCentral Johnson MD, Widdicombe JH, Allen L et al (2002) Alveolar epithelial type I cells contain transport proteins and transport sodium, supporting an active role for type I cells in regulation of lung liquid homeostasis. Proc Natl Acad Sci U S A 99(4):1966–1971. doi:10.​1073/​pnas.​042689399 CrossRefPubMedPubMedCentral
51.
go back to reference Ridge KM, Rutschman DH, Factor P et al (1997) Differential expression of Na-K-ATPase isoforms in rat alveolar epithelial cells. Am J Physiol 273(1 Pt 1):L246–L255PubMed Ridge KM, Rutschman DH, Factor P et al (1997) Differential expression of Na-K-ATPase isoforms in rat alveolar epithelial cells. Am J Physiol 273(1 Pt 1):L246–L255PubMed
54.
go back to reference Fridman AI, Matveev SA, Agalakova NI et al (2002) Marinobufagenin, an endogenous ligand of alpha-1 sodium pump, is a marker of congestive heart failure severity. J Hypertens 20(6):1189–1194CrossRefPubMed Fridman AI, Matveev SA, Agalakova NI et al (2002) Marinobufagenin, an endogenous ligand of alpha-1 sodium pump, is a marker of congestive heart failure severity. J Hypertens 20(6):1189–1194CrossRefPubMed
55.
go back to reference Bagrov AY, Fedorova OV, Dmitrieva RI et al (1998) Characterization of a urinary bufodienolide Na+, K+-ATPase inhibitor in patients after acute myocardial infarction. Hypertension 31(5):1097–1103CrossRefPubMed Bagrov AY, Fedorova OV, Dmitrieva RI et al (1998) Characterization of a urinary bufodienolide Na+, K+-ATPase inhibitor in patients after acute myocardial infarction. Hypertension 31(5):1097–1103CrossRefPubMed
56.
59.
go back to reference Brown MA, Zammit VC, Lowe SA (1989) Capillary permeability and extracellular fluid volumes in pregnancy-induced hypertension. Clin Sci 77(6):599–604CrossRefPubMed Brown MA, Zammit VC, Lowe SA (1989) Capillary permeability and extracellular fluid volumes in pregnancy-induced hypertension. Clin Sci 77(6):599–604CrossRefPubMed
61.
go back to reference Bagrov AY, Fedorova OV, Austin-Lane JL et al (1995) Endogenous marinobufagenin-like immunoreactive factor and Na+, K + ATPase inhibition during voluntary hypoventilation. Hypertension 26(5):781–788CrossRefPubMed Bagrov AY, Fedorova OV, Austin-Lane JL et al (1995) Endogenous marinobufagenin-like immunoreactive factor and Na+, K + ATPase inhibition during voluntary hypoventilation. Hypertension 26(5):781–788CrossRefPubMed
66.
go back to reference Bachofen M, Weibel ER (1982) Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med 3(1):35–56PubMed Bachofen M, Weibel ER (1982) Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med 3(1):35–56PubMed
68.
go back to reference Donnelly SC, Haslett C, Reid PT et al (1997) Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat Med 3(3):320–323CrossRefPubMed Donnelly SC, Haslett C, Reid PT et al (1997) Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat Med 3(3):320–323CrossRefPubMed
70.
go back to reference Nakos G, Kitsiouli EI, Tsangaris I et al (1998) Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS. Alterations in leukocytes, proteins, PAF and surfactant components. Intensive Care Med 24(4):296–303CrossRefPubMed Nakos G, Kitsiouli EI, Tsangaris I et al (1998) Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS. Alterations in leukocytes, proteins, PAF and surfactant components. Intensive Care Med 24(4):296–303CrossRefPubMed
71.
go back to reference Uddin MN, Horvat D, Glaser SS, Mitchell BM, Puschett JB (2008) Examination of the cellular mechanisms by which marinobufagenin inhibits cytotrophoblasts function. J Biol Chem 283:17946–17953CrossRefPubMed Uddin MN, Horvat D, Glaser SS, Mitchell BM, Puschett JB (2008) Examination of the cellular mechanisms by which marinobufagenin inhibits cytotrophoblasts function. J Biol Chem 283:17946–17953CrossRefPubMed
Metadata
Title
Involvement of the Bufadienolides in the Detection and Therapy of the Acute Respiratory Distress Syndrome
Authors
Mir M. K. Abbas
B. Patel
Q. Chen
W. Jiang
B. Moorthy
R. Barrios
J. B. Puschett
Publication date
01-06-2017
Publisher
Springer US
Published in
Lung / Issue 3/2017
Print ISSN: 0341-2040
Electronic ISSN: 1432-1750
DOI
https://doi.org/10.1007/s00408-017-9989-1

Other articles of this Issue 3/2017

Lung 3/2017 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.