Nebulized Perflubron and Carbon Dioxide Rapidly Dilate Constricted Airways in an Ovine Model of Allergic Asthma

Overview

Journal Respir Res

Specialty Pulmonary Medicine

Date 2014 Oct 31

PMID 25355286

Citations 6

Authors

Tamer Y El Mays

Parichita Choudhury

Richard Leigh

Emmanuel Koumoundouros

Joanne Van Der Velden

Grishma Shrestha

Cora A Pieron

John H Dennis

Francis Hy Green

Ken J Snibson

Affiliations

Soon will be listed here.

Abstract

Background: The low toxicity of perfluorocarbons (PFCs), their high affinity for respiratory gases and their compatibility with lung surfactant have made them useful candidates for treating respiratory diseases such as adult respiratory distress syndrome. We report results for treating acute allergic and non-allergic bronchoconstriction in sheep using S-1226 (a gas mixture containing carbon dioxide and small volumes of nebulized perflubron). The carbon dioxide, which is highly soluble in perflubron, was used to relax airway smooth muscle.

Methods: Sheep previously sensitized to house dust mite (HDM) were challenged with HDM aerosols to induce early asthmatic responses. At the maximal responses (characterised by an increase in lung resistance), the sheep were either not treated or treated with one of the following; nebulized S-1226 (perflubron + 12% CO2), nebulized perflubron + medical air, 12% CO2, salbutamol or medical air. Lung resistance was monitored for up to 20 minutes after cessation of treatment.

Results: Treatment with S-1226 for 2 minutes following HDM challenge resulted in a more rapid, more profound and more prolonged decline in lung resistance compared with the other treatment interventions. Video bronchoscopy showed an immediate and complete (within 5 seconds) re-opening of MCh-constricted airways following treatment with S-1226.

Conclusions: S-1226 is a potent and rapid formulation for re-opening constricted airways. Its mechanism(s) of action are unknown. The formulation has potential as a rescue treatment for acute severe asthma.

Citing Articles

Carbon dioxide and MAPK signalling: towards therapy for inflammation.

Galganska H, Jarmuszkiewicz W, Galganski L Cell Commun Signal. 2023; 21(1):280.

PMID: 37817178 PMC: 10566067. DOI: 10.1186/s12964-023-01306-x.

Asthmatic allergen inhalation sensitises carotid bodies to lysophosphatidic acid.

Jendzjowsky N, Roy A, Wilson R J Neuroinflammation. 2021; 18(1):191.

PMID: 34465362 PMC: 8408927. DOI: 10.1186/s12974-021-02241-9.

Humidified Warmed CO Treatment Therapy Strategies Can Save Lives With Mitigation and Suppression of SARS-CoV-2 Infection: An Evidence Review.

El-Betany A, Behiry E, Gumbleton M, Harding K Front Med (Lausanne). 2021; 7:594295.

PMID: 33425942 PMC: 7793941. DOI: 10.3389/fmed.2020.594295.

A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma.

Swystun V, Green F, Dennis J, Rampakakis E, Lalli G, Fadayomi M Trials. 2018; 19(1):321.

PMID: 29914544 PMC: 6006836. DOI: 10.1186/s13063-018-2720-6.

A phase I, placebo-controlled, randomized, double-blind, single ascending dose-ranging study to evaluate the safety and tolerability of a novel biophysical bronchodilator (S-1226) administered by nebulization in healthy volunteers.

Green F, Leigh R, Fadayomi M, Lalli G, Chiu A, Shrestha G Trials. 2016; 17:361.

PMID: 27464582 PMC: 4964056. DOI: 10.1186/s13063-016-1489-8.

References

Abraham W, Delehunt J, Yerger L, Marchette B . Characterization of a late phase pulmonary response after antigen challenge in allergic sheep. Am Rev Respir Dis. 1983; 128(5):839-44. DOI: 10.1164/arrd.1983.128.5.839. View

Fisher H, Hansen T . Site of action of inhaled 6 per cent carbon dioxide in the lungs of asthmatic subjects before and after exercise. Am Rev Respir Dis. 1976; 114(5):861-70. DOI: 10.1164/arrd.1976.114.5.861. View

Rotta A, Steinhorn D . Partial liquid ventilation reduces pulmonary neutrophil accumulation in an experimental model of systemic endotoxemia and acute lung injury. Crit Care Med. 1998; 26(10):1707-15. DOI: 10.1097/00003246-199810000-00026. View

Duane S, Weir E, Stewart R, Niewoehner D . Distal airway responses to changes in oxygen and carbon dioxide tensions. Respir Physiol. 1979; 38(3):303-11. DOI: 10.1016/0034-5687(79)90056-2. View

Boser S, Park H, Perry S, Menache M, Green F . Fractal geometry of airway remodeling in human asthma. Am J Respir Crit Care Med. 2005; 172(7):817-23. DOI: 10.1164/rccm.200411-1463OC. View

van den Elshout F, van Herwaarden C, Folgering H . Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects. Thorax. 1991; 46(1):28-32. PMC: 1020910. DOI: 10.1136/thx.46.1.28. View

Kasperska-Zajac A, Brzoza Z, Rogala B . Platelet-activating factor (PAF): a review of its role in asthma and clinical efficacy of PAF antagonists in the disease therapy. Recent Pat Inflamm Allergy Drug Discov. 2008; 2(1):72-6. DOI: 10.2174/187221308783399306. View

Mariassy A, St George J, Nishio S, Plopper C . Tracheobronchial epithelium of the sheep: III. Carbohydrate histochemical and cytochemical characterization of secretory epithelial cells. Anat Rec. 1988; 221(1):540-9. DOI: 10.1002/ar.1092210110. View

Kirschvink N, Reinhold P . Use of alternative animals as asthma models. Curr Drug Targets. 2008; 9(6):470-84. DOI: 10.2174/138945008784533525. View

10.

Oddo M, Feihl F, Schaller M, Perret C . Management of mechanical ventilation in acute severe asthma: practical aspects. Intensive Care Med. 2006; 32(4):501-10. DOI: 10.1007/s00134-005-0045-x. View

11.

Ivanova J, Bergman R, Birnbaum H, Colice G, Silverman R, McLaurin K . Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma. J Allergy Clin Immunol. 2012; 129(5):1229-35. DOI: 10.1016/j.jaci.2012.01.039. View

12.

Lougheed M, Lemiere C, Dell S, Ducharme F, FitzGerald J, Leigh R . Canadian Thoracic Society Asthma Management Continuum--2010 Consensus Summary for children six years of age and over, and adults. Can Respir J. 2010; 17(1):15-24. PMC: 2866209. DOI: 10.1155/2010/827281. View

13.

Astin T, Barer G, Shaw J, Warren P . The action of carbon dioxide on constricted airways. J Physiol. 1973; 235(3):607-23. PMC: 1350783. DOI: 10.1113/jphysiol.1973.sp010407. View

14.

Uchida T, Nakazawa K, Yokoyama K, Makita K, Amaha K . The combination of partial liquid ventilation and inhaled nitric oxide in the severe oleic acid lung injury model. Chest. 1998; 113(6):1658-66. DOI: 10.1378/chest.113.6.1658. View

15.

Masoli M, Fabian D, Holt S, Beasley R . The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004; 59(5):469-78. DOI: 10.1111/j.1398-9995.2004.00526.x. View

16.

Bijaoui E, Tuck S, Remmers J, Bates J . Estimating respiratory mechanics in the presence of flow limitation. J Appl Physiol (1985). 1999; 86(1):418-26. DOI: 10.1152/jappl.1999.86.1.418. View

17.

INGRAM Jr R . Effects of airway versus arterial CO2 changes on lung mechanics in dogs. J Appl Physiol. 1975; 38(4):603-7. DOI: 10.1152/jappl.1975.38.4.603. View

18.

Smith T, Steinhorn D, Thusu K, Fuhrman B, Dandona P . A liquid perfluorochemical decreases the in vitro production of reactive oxygen species by alveolar macrophages. Crit Care Med. 1995; 23(9):1533-9. DOI: 10.1097/00003246-199509000-00014. View

19.

Abraham W . Modeling of asthma, COPD and cystic fibrosis in sheep. Pulm Pharmacol Ther. 2008; 21(5):743-54. DOI: 10.1016/j.pupt.2008.01.010. View

20.

McFadden Jr E . Acute severe asthma. Am J Respir Crit Care Med. 2003; 168(7):740-59. DOI: 10.1164/rccm.200208-902SO. View