Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2014

Open Access 01-12-2014 | Research

Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma

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

Published in: Respiratory Research | Issue 1/2014

Login to get access

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.
In additional naïve sheep, a segmental bronchus was pre-contracted with methacholine (MCh) and treated with nebulized S-1226 administered via a bronchoscope catheter. Subsequent bronchodilatation was monitored by real time digital video recording.

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.
Appendix
Available only for authorised users
Literature
1.
2.
Sugita M, Kuribayashi K, Nakagomi T, Miyata S, Matsuyama T, Kitada O: Allergic bronchial asthma: airway inflammation and hyperresponsiveness. Intern Med. 2003, 42: 636-643. 10.2169/internalmedicine.42.636.PubMedCrossRef
3.
Kelly MM, O’Connor TM, Leigh R, Otis J, Gwozd C, Gauvreau GM, Gauldie J, O’Byrne PM: Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma. J Allergy Clin Immunol. 2010, 125: 349-356. 10.1016/j.jaci.2009.09.011.PubMedCrossRef
4.
Boser SR, Park H, Perry SF, Menache MG, Green FH: Fractal geometry of airway remodeling in human asthma. Am J Respir Crit Care Med. 2005, 172: 817-823. 10.1164/rccm.200411-1463OC.PubMedCrossRef
5.
Gotshall RW: Exercise-induced bronchoconstriction. Drugs. 2002, 62: 1725-1739. 10.2165/00003495-200262120-00003.PubMedCrossRef
6.
Tacon CE, Wiehler S, Holden NS, Newton R, Proud D, Leigh R: Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-{kappa}B. Am J Respir Cell Mol Biol. 2010, 43: 201-209. 10.1165/rcmb.2009-0216OC.PubMedCrossRef
7.
Masoli M, Fabian D, Holt S, Beasley R: The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004, 59: 469-478. 10.1111/j.1398-9995.2004.00526.x.PubMedCrossRef
8.
Bahadori K, Doyle-Waters MM, Marra C, Lynd L, Alasaly K, Swiston J, FitzGerald JM: Economic burden of asthma: a systematic review. BMC Pulm Med. 2009, 9: 24-10.1186/1471-2466-9-24.PubMedPubMedCentralCrossRef
9.
Ivanova JI, Bergman R, Birnbaum HG, Colice GL, Silverman RA, 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: 1229-1235. 10.1016/j.jaci.2012.01.039.PubMedCrossRef
10.
Chapman KR, Boulet LP, Rea RM, Franssen E: Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J. 2008, 31: 320-325. 10.1183/09031936.00039707.PubMedCrossRef
11.
Boulet LP, Becker A, Berube D, Beveridge R, Ernst P: Canadian Asthma Consensus Report, 1999. Canadian Asthma Consensus Group. CMAJ. 1999, 161: S1-S61.PubMed
12.
Lougheed MD, Lemiere C, Dell SD, Ducharme FM, Fitzgerald JM, Leigh R, Licskai C, Rowe BH, Bowie D, Becker A, Boulet LP: Canadian Thoracic Society Asthma Management Continuum-2010 Consensus Summary for children six years of age and over, and adults. Can Respir J. 2010, 17: 15-24.PubMedPubMedCentral
13.
Rowe BH, Sevcik W, Villa-Roel C: Management of severe acute asthma in the emergency department. Curr Opin Crit Care. 2011, 17: 335-341. 10.1097/MCC.0b013e328348bf09.PubMedCrossRef
14.
Chowdhury BA, Dal PG: The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med. 2010, 362: 1169-1171. 10.1056/NEJMp1002074.PubMedCrossRef
15.
McFadden ER: Acute severe asthma. Am J Respir Crit Care Med. 2003, 168: 740-759. 10.1164/rccm.200208-902SO.PubMedCrossRef
16.
Wener RR, Bel EH: Severe refractory asthma: an update. Eur Respir Rev. 2013, 22: 227-235. 10.1183/09059180.00001913.PubMedCrossRef
17.
Tough SC, Green FH, Paul JE, Wigle DT, Butt JC: Sudden death from asthma in 108 children and young adults. J Asthma. 1996, 33: 179-188. 10.3109/02770909609054550.PubMedCrossRef
18.
Oddo M, Feihl F, Schaller MD, Perret C: Management of mechanical ventilation in acute severe asthma: practical aspects. Intensive Care Med. 2006, 32: 501-510. 10.1007/s00134-005-0045-x.PubMedCrossRef
19.
20.
Duane SF, Weir EK, Stewart RM, Niewoehner DE: Distal airway responses to changes in oxygen and carbon dioxide tensions. Respir Physiol. 1979, 38: 303-311. 10.1016/0034-5687(79)90056-2.PubMedCrossRef
21.
Twort CH, Cameron IR: Effects of PCO2, pH and extracellular calcium on contraction of airway smooth muscle from rats. Respir Physiol. 1986, 66: 259-267. 10.1016/0034-5687(86)90078-2.PubMedCrossRef
22.
El Mays TY, Saifeddine M, Choudhury P, Hollenberg MD, Green FH: Carbon dioxide enhances substance P-induced epithelium-dependent bronchial smooth muscle relaxation in Sprague-Dawley rats. Can J Physiol Pharmacol. 2011, 89: 513-520. 10.1139/y11-052.PubMedCrossRef
23.
Thomas M, McKinley RK, Freeman E, Foy C: Prevalence of dysfunctional breathing in patients treated for asthma in primary care: cross sectional survey. BMJ. 2001, 322: 1098-1100. 10.1136/bmj.322.7294.1098.PubMedPubMedCentralCrossRef
24.
Fisher HK, Holton P, Buxton RS, Nadel JA: Resistance to breathing during exercise-induced asthma attacks. Am Rev Respir Dis. 1970, 101: 885-896.PubMed
25.
McFadden ER, Stearns DR, Ingram RH, Leith DE: Relative contributions of hypocarbia and hyperpnea as mechanisms in postexercise asthma. J Appl Physiol. 1977, 42: 22-27.PubMed
26.
van den Elshout FJ, van Herwaarden CL, Folgering HT: Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects. Thorax. 1991, 46: 28-32. 10.1136/thx.46.1.28.PubMedPubMedCentralCrossRef
27.
Fisher HK, Hansen TA: 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: 861-870.PubMed
28.
Wolfson MR, Shaffer TH: Pulmonary applications of perfluorochemical liquids: ventilation and beyond. Paediatr Respir Rev. 2005, 6: 117-127. 10.1016/j.prrv.2005.03.010.PubMedCrossRef
29.
Lehmler HJ, Bummer PM, Jay M: Liquid ventilation - a new way to deliver drugs to diseased lungs?. Chemtech. 1999, 29: 7-12.
30.
Schürch S: Perfluorocarbon-surfactant interactions: biophysical aspects. Am Soc Artif Intern Organs. 2006, 52: 487-10.1097/00002480-200607000-00026.CrossRef
31.
Rotta AT, Gunnarsson B, Fuhrman BP, Wiryawan B, Hernan LJ, Steinhorn DM: Perfluorooctyl bromide (perflubron) attenuates oxidative injury to biological and nonbiological systems. Pediatr Crit Care Med. 2003, 4: 233-238. 10.1097/01.PCC.0000059729.21375.D0.PubMedCrossRef
32.
Smith TM, Steinhorn DM, Thusu K, Fuhrman BP, Dandona P: A liquid perfluorochemical decreases the in vitro production of reactive oxygen species by alveolar macrophages. Crit Care Med. 1995, 23: 1533-1539. 10.1097/00003246-199509000-00014.PubMedCrossRef
33.
Varani J, Hirschl RB, Dame M, Johnson K: Perfluorocarbon protects lung epithelial cells from neutrophil-mediated injury in an in vitro model of liquid ventilation therapy. Shock. 1996, 6: 339-344. 10.1097/00024382-199611000-00007.PubMedCrossRef
34.
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: 1658-1666. 10.1378/chest.113.6.1658.PubMedCrossRef
35.
Shashikant BN, Miller TL, Jeng MJ, Davis J, Shaffer TH, Wolfson MR: Differential impact of perfluorochemical physical properties on the physiologic, histologic, and inflammatory profile in acute lung injury. Crit Care Med. 2005, 33: 1096-1103. 10.1097/01.CCM.0000163218.79770.29.PubMedCrossRef
36.
Kandler MA, von der Hardt K, Gericke N, Chada M, Dotsch J, Rascher W: Dose response to aerosolized perflubron in a neonatal swine model of lung injury. Pediatr Res. 2004, 56: 191-197. 10.1203/01.PDR.0000132667.47744.F4.PubMedCrossRef
37.
von der Hardt K, Kandler MA, Brenn G, Scheuerer K, Schoof E, Dotsch J, Rascher W: Comparison of aerosol therapy with different perfluorocarbons in surfactant-depleted animals. Crit Care Med. 2004, 32: 1200-1206. 10.1097/01.CCM.0000124876.31138.F6.PubMedCrossRef
38.
Bischof RJ, Snibson K, Shaw R, Meeusen EN: Induction of allergic inflammation in the lungs of sensitized sheep after local challenge with house dust mite. Clin Exp Allergy. 2003, 33: 367-375. 10.1046/j.1365-2222.2003.01534.x.PubMedCrossRef
39.
Snibson KJ, Bischof RJ, Slocombe RF, Meeusen EN: Airway remodelling and inflammation in sheep lungs after chronic airway challenge with house dust mite. Clin Exp Allergy. 2005, 35: 146-152. 10.1111/j.1365-2222.2005.02137.x.PubMedCrossRef
40.
Respiratory therapy equipment: Part 1-Nebulizing systems and their components. European Nebulizer Standard: EN 13544-1:2007+A1:2009. 2009, 1-43.
41.
Shaw RJ, McNeill MM, Gatehouse TK, Douch PG: Quantification of total sheep IgE concentration using anti-ovine IgE monoclonal antibodies in an enzyme immunoassay. Vet Immunol Immunopathol. 1997, 57: 253-265. 10.1016/S0165-2427(97)00010-X.PubMedCrossRef
42.
Koumoundouros E, Snibson K, Mareels IY: Oesophageal techniques for deriving the lung dynamics of quietly breathing sheep. Conf Proc IEEE Eng Med Biol Soc. 2008, 2008: 2435-2438.PubMed
43.
Abraham WM, Delehunt JC, Yerger L, Marchette B: Characterization of a late phase pulmonary response after antigen challenge in allergic sheep. Am Rev Respir Dis. 1983, 128: 839-844.PubMed
44.
Rice AJ, Reynolds PN, Reynolds AM, Holmes MD, Scicchitano R: Tachykinin-induced bronchoconstriction in sheep is NK-1 receptor mediated and exhibits tachyphylaxis. Respirology. 2001, 6: 113-123. 10.1046/j.1440-1843.2001.00315.x.PubMedCrossRef
45.
Bijaoui E, Tuck SA, Remmers JE, Bates JH: Estimating respiratory mechanics in the presence of flow limitation. J Appl Physiol. 1999, 86: 418-426. 10.1063/1.370746.PubMedCrossRef
46.
Choudhury P, El Mays T, Snibson K, Wilson R, Leigh R, Dennis J, Nelson DE, Green FHY: Investigations of mechanisms of carbon dioxide-induced bronchial smooth muscle relaxation. Am J Respir Crit Care Med. 2012, 185: A2848-
47.
Ingram RH: Effects of airway versus arterial CO2 changes on lung mechanics in dogs. J Appl Physiol. 1975, 38: 603-607.PubMed
48.
Ten Berge RE, Weening EC, Roffel AF, Zaagsma J: Beta 2- but not beta 3-adrenoceptors mediate prejunctional inhibition of non-adrenergic non-cholinergic contraction of guinea pig main bronchi. Eur J Pharmacol. 1995, 275: 199-206. 10.1016/0014-2999(94)00771-X.PubMedCrossRef
49.
Al-Saiedy M, Nelson E, El Mays T, Amrein M, Green F: Perflubron enhances mucin plug clearance in vitro in the presence of natural surfactant. Eur Respir J. 2013, 42 (Suppl. 57): 124s-ERS International Congress, Barcelona, Spain. Ref Type: Abstract
50.
Bachofen H, Schurch S: Alveolar surface forces and lung architecture. Comp Biochem Physiol A Mol Integr Physiol. 2001, 129: 183-193. 10.1016/S1095-6433(01)00315-4.PubMedCrossRef
51.
Schurch S, Bachofen H, Possmayer F: Surface activity in situ, in vivo, and in the captive bubble surfactometer. Comp Biochem Physiol A Mol Integr Physiol. 2001, 129: 195-207. 10.1016/S1095-6433(01)00316-6.PubMedCrossRef
52.
Cheng G, Ueda T, Sugiyama K, Toda M, Fukuda T: Compositional and functional changes of pulmonary surfactant in a guinea-pig model of chronic asthma. Respir Med. 2001, 95: 180-186. 10.1053/rmed.2000.1012.PubMedCrossRef
53.
Winkler C, Hohlfeld JM: Surfactant and allergic airway inflammation. Swiss Med Wkly. 2013, 143: w13818-PubMed
54.
Croce MA, Fabian TC, Patton JH, Melton SM, Moore M, Trenthem LL: Partial liquid ventilation decreases the inflammatory response in the alveolar environment of trauma patients. J Trauma. 1998, 45: 273-280. 10.1097/00005373-199808000-00012.PubMedCrossRef
55.
Rotta AT, Steinhorn DM: Partial liquid ventilation reduces pulmonary neutrophil accumulation in an experimental model of systemic endotoxemia and acute lung injury. Crit Care Med. 1998, 26: 1707-1715. 10.1097/00003246-199810000-00026.PubMedCrossRef
56.
Kirschvink N, Reinhold P: Use of alternative animals as asthma models. Curr Drug Targets. 2008, 9: 470-484. 10.2174/138945008784533525.PubMedCrossRef
57.
Van der Velden J, Snibson KJ: Airway disease: the use of large animal models for drug discovery. Pulm Pharmacol Ther. 2011, 24: 525-532. 10.1016/j.pupt.2011.02.001.PubMedCrossRef
58.
Zosky GR, Sly PD: Animal models of asthma. Clin Exp Allergy. 2007, 37: 973-988. 10.1111/j.1365-2222.2007.02740.x.PubMedCrossRef
59.
Abraham WM: Modeling of asthma, COPD and cystic fibrosis in sheep. Pulm Pharmacol Ther. 2008, 21: 743-754. 10.1016/j.pupt.2008.01.010.PubMedCrossRef
60.
Tomioka K, Garrido R, Ahmed A, Stevenson JS, Abraham WM: YM461, a PAF antagonist, blocks antigen-induced late airway responses and airway hyperresponsiveness in allergic sheep. Eur J Pharmacol. 1989, 170: 209-215. 10.1016/0014-2999(89)90541-4.PubMedCrossRef
61.
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: 72-76. 10.2174/187221308783399306.PubMedCrossRef
62.
Mariassy AT, St George JA, Nishio SJ, Plopper CG: Tracheobronchial epithelium of the sheep: III. Carbohydrate histochemical and cytochemical characterization of secretory epithelial cells. Anat Rec. 1988, 221: 540-549. 10.1002/ar.1092210110.PubMedCrossRef
63.
Koumoundouros E, Bischof RJ, Meeusen EN, Mareels IM, Snibson KJ: Chronic airway disease: deteriorating pulmonary function in sheep associated with repeated challenges of house dust mite. Exp Lung Res. 2006, 32: 321-330. 10.1080/01902140600916960.PubMedCrossRef
Metadata
Title
Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma
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
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2014
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-014-0098-x

Other articles of this Issue 1/2014

Respiratory Research 1/2014 Go to the issue

Research

Combined exposure to cigarette smoke and nontypeable Haemophilus influenzae drives development of a COPD phenotype in mice

Research

Atrial fibrosis in a chronic murine model of obstructive sleep apnea: mechanisms and prevention by mesenchymal stem cells

Research

Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials

Research

The role of bronchial epithelial cells in the pathogenesis of COPD in Z-alpha-1 antitrypsin deficiency

Research

Regenerative defect in vastus lateralis muscle of patients with chronic obstructive pulmonary disease

Research

Protective effects of intratracheally administered quercetin on lipopolysaccharide-induced acute lung injury
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

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
Image Credits