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Lung Mechanics: Theory and Practice IV Measuring Lung Mechanics in Mice

Lung Mechanics: Theory and Practice IV Measuring Lung Mechanics in Mice. Jason H.T. Bates, PhD, DSc Research Professor of Medicine Vermont Lung Center University of Vermont College of Medicine. Measuring lung volume by plethysmography. Lundblad et al. Ann Biomed Eng 32: 1420-1427, 2004.

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Lung Mechanics: Theory and Practice IV Measuring Lung Mechanics in Mice

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  1. Lung Mechanics: Theory and Practice IVMeasuring Lung Mechanics in Mice Jason H.T. Bates, PhD, DSc Research Professor of Medicine Vermont Lung Center University of Vermont College of Medicine

  2. Measuring lung volume by plethysmography

  3. Lundblad et al. Ann Biomed Eng 32: 1420-1427, 2004.

  4. Lung mechanics (R and E) depend on… • frequency • flow • tidal volume • mean lung volume • volume history • etc.

  5. Under what conditions should we assess respiratory mechanics? These factors are all likely to change during an intervention, so…

  6. At One Extreme: Controlling Everything • anesthetized and paralyzed (eliminates spontaneous effort) • tracheostomized (eliminates upper airways) • mechanically ventilated (controls frequency, tidal volume, volume history) • PEEP (controls mean lung volume)

  7. P cyl piston to animal V cyl Challenging aerosols Forced oscillation technique in mice The flexiVentTM

  8. The flexiVent…

  9. apply sinewave oscillations • in flow to the lungs to • determine R and E • apply broad-band oscillations • in flow to the lungs to • determine impedance • apply step changes in volume to • the lungs to determine the • pressure-volume curve The flexiVent can…

  10. Lots of drugs • Lots of stress The forced oscillation technique in anesthetized, tracheostomized, paralyzed animals gives great data, but... What physiological effects do these unnatural conditions have?

  11. No stress • No drugs At The Other Extreme:Controlling Nothing • Conscious unrestrained animal free to move about inside a closed chamber

  12. Unfortunately… There is currently no completely noninvasive way to assess lung mechanical function in mice (PenH notwithstanding). The use and misuse of Penh in animal models of lung disease. J.H.T. Bates and 21 co-authors. Am J Respir Cell Mol Biol 31: 373-374, 2004.

  13. PenH = (T1/T2) x (P1/P2)

  14. There are two reasons why chamber pressure varies as a mouse breathes?

  15. Reason No. 1… • As air is inspired into the lungs it becomes heated and humidified to BTPS conditions, and so it expands. The amount of expansion is proportional to the volume inspired.

  16. Reason No. 2… • Inspiration requires a negative alveolar pressure. This requires expansion of alveolar gas by an amount proportional to flow.

  17. Only reason no. 2 pertains to lung mechanics. Reason no. 1 reflects the pattern of breathing. We can eliminate reason no. 2 by conditioning the gas in the plethysmograph chamber before it is inspired by the animal. (Lundblad et al. J Appl Physiol 93: 1198-1207, 2002)

  18. breathing ambient air breathing heated, humidified air

  19. When the box gas is conditioned to BTPS: Pb(t) Time

  20. If accurately tracking changes in mean lung volume is a problem:

  21. Chamber pressure Time Thoracic volume Time UnrestrainedVideoAssistedPlethysmography

  22. Back-lighting panel Latex glove finger (in place of mouse) Double walls for circulating water Stopcock to tracheal cannula

  23. Vertical view Tracking changes in lung volume Horizontal view Equivalent cuboidal mouse

  24. A B C D Latex mouse

  25. A B Real dead mouse

  26. live mouse

  27. The first measurements of Raw in a conscious, unrestrained mouse

  28. UVAP is a work in progress. We hope UVAP will eventually become a user-friendly tool allowing researchers to assess lung function in mice noninvasively. In the meantime…

  29. With unrestrained plethysmography, the subject is happy, but... …breathing pattern, lung volume, etc. may change with intervention, making it impossible to detect changes in lung mechanics separately from effects due to changes in the breathing pattern.

  30. You can’t have it both ways (unfortunately)! (J.H.T. Bates and C.G. Irvin. J Appl Physiol 94: 1297-1306, 2003) The Phenotyping Uncertainty Principle… Most precise (forced oscillation technique) Least invasive (unrestrained plethysmography)

  31. Summary • The forced oscillation technique (e.g. flexiVent) gives very precise assessment of lung mechanics in mice, but at the expense of highly unnatural measurement conditions. • Unrestrained plethysmography allows for natural and convenient measurement conditions, but at the almost complete expense of precision and specificity.

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