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

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, 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

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.

Figures

Figure 1
Figure 1
Sidestream nebulizer aerosol size distribution. Aerosol size is on the X-axis is plotted against the normative and cumulative underside aerosol distributions. The blue boxes profile the normative size distribution of nebulized perflubron, the near symmetry suggests a log-normal distribution of aerosol particles. The red squares plot the same data but as a cumulative size distribution of particle size against cumulative undersize %. The cumulative size distribution is used to interpolate the MMAD as the particle size at 50% of the cumulative mass – in this case the MMAD is 1.1 um. The Geometric Standard Deviation (GSD) of the MMAD is calculated using the intercepts at 15.8% and 84.1% (approximated by grey lines in Figure) using the formula GSD = sq rt (size 84.1um / size 15.8 um).
Figure 2
Figure 2
Effect of S-1226 on lung resistance in the sheep model of asthma. Changes in lung resistance following treatment with S-1226 in 9 different sheep. The treatment was delivered for 2 minutes and lung resistance was measured immediately, and at 1–10 minutes and 10–20 minutes after treatment cessation. All nine sheep showed an immediate and sustained decline in lung resistance following S-1226 treatment given at the peak of the early phase response to inhaled allergen (HDM).
Figure 3
Figure 3
Comparison between S-1226 and other bronchodilators in the sheep model of asthma. This figure shows the % decline in lung resistance following treatment with S-1226, 12% CO2, perflubron, salbutamol, medical air or no treatment in HDM challenged sheep. Measurements were taken immediately, 1–10 minutes and 10–20 minutes after treatment. Treatment with S-1226 showed significant and sustained declines in lung resistance compared to medical air or no treatment. In addition S-1226 showed a significantly greater decline in lung resistance compared to salbutamol. P-values show significant difference from S-1226; *p <0.05, # p ≤ 0.01.
Figure 4
Figure 4
Video bronchoscopy of the effect of S-1226. Bronchoscopic still images of sheep airways pre and post MCh and seconds after initiating treatment with nebulized S-1226 (arrow heads indicate tissue dye). The video presentation is available online under Additional file 1.

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