• Note that the relationship is quadratic, and that airways can stiffen by as much as 50% without an alteration in the ability to bronchodilate. Further airway stiffening causes a dramatically reduced ability to bronchodilate. This suggests that at low levels of constriction stiffening of the wall due to ASM stimulation will not inhibit bronchodilation, but at severe levels of constriction the ASM is capable of severely stiffening the airway wall, and hence inhibiting bronchodilation.

• Do asthmatics live on the edge of this relationship?

• Asthmatics have a reduced ability to dilate airways with a Deep Inspiration (DI).

• Studies on isolated Airway Smooth Muscle (ASM) suggest that conditions that promote reduced length oscillations during breathing and sighs can serve to remodel the ASM, causing it to become more contractile. Which can lead to airway hyperreactivity (AHR).

• AHR in Asthmatics has been attributed to several causes: 1) ASM is remodeled Stronger & Stiffer? Reduced airway dilation due to airway wall stiffening? 2) More ASM Stronger & Stiffer? Reduced airway dilation due to airway wall stiffening? 3) Inflammation Reduced Load to ASM? Reduced airway dilation due to less tethering ? 4) Wall Remodeling Wall Stiffening? Altered coupling between wall and parenchyma

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POST-CHALLENGE

PRE-CHALLENGE

Parenchymal Tethering vs. Airway Wall Stiffness on In Vivo Airway Dilation During a Deep InspirationM.S. Hamilton, D.A. Affonce, and K.R. Lutchen

Biomedical Engineering Department, Boston University

Background

GoalTo evaluate whether ASM stimulation promotes either enhanced airway wall stiffness or reduced parenchymal tethering as a mechanisms that reduce airway dilation ability in vivo.

APPROACH:1) Build a system that allows airways to be expanded in a controlled setting while tracking airway resistance (Raw) as a surrogate of airway diameter2) Apply the system to excised lungs to distinguish whether alterations in tethering forces or wall stiffening are responsible for enhanced airway reactivity. Tethering: Diameter expansion versus volume expansion Wall Stiffening: Changes in pressure-area (P-A) relationshipMethods• Studies were performed on 9 excised bovine lung

• Tracheas were to a hollow tube that passed through the top of a sealed box

• A vacuum source was used to vary the pressure inside the box

• Airway opening and box pressure were recorded using two 50 cm H2O differential pressure transducers

• Airway opening flow was recorded using a Pneumotach connected to a 2 cm H 2O differential pressure transducer

• Lungs started out collapsed and then were subjected to the protocol shown in the flow diagram below

Lung Collapsed

0 cmH2O

Deep

Inspiration

Typical FRC

5 cmH2O

Deep

Inspiration

• 8 Hz pressure oscillation were superimposed over the above pressure maneuvers to allow tracking of R aw. Raw is used as a surrogate of airway diameter.

Data Analysis

• Pressure and flow signals were high and low pass filtered (HPF and LPF respectively)

• The low pass filtered data was used to create pressure and volume vs. time signals

• The high pass filtered data was run through a recursive least squared (RLS) algorithm to obtain Raw. Based on the methods of Jensen, et. al., JAP (91), 2001.

Time (s)0 250

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Results

• As transpulmonary pressure increased from 0 cm H2O to 30 cm H2O, airway resistance dropped from 18 cm H20/L/s to 1.5 cm H20/L/s. As the pressure was then reduced back to 5 cm H2O, the resistance increased to 4 cm H20/L/s. During the next deep inspiration the resistance dropped to 1 cm H20/L/s

• At low levels of baseline airway constriction (RPre-DI<10 cm H2O/L/s) Rmin appears linearly correlated with baseline constriction. However, when including conditions with severe baseline constriction, the relationship is more quadratic.

• Thus, in vivo ASM can be provoked to levels that severely inhibit the lungs capacity to dilate the airway tree with a DI maneuver. Is this due to ASM impact on wall stiffness or on reduced parenchymal tethering?

%Total DI Volume

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PRE-CHALLENGE

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0 cmH2O 5 cmH2O

• The trajectories were identical pre and post challenge suggesting that the coupling between volume expansion and diameter is not altered by ASM stimulation. Which would indicate that the degree of tethering was not altered by MCh. Therefore the question is does ASM provocation lead to alterations in the airway wall stiffness that causes a decreased ability of a DI to dilate the airways.

CPOST / CPRE

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STIFF WALLS FLOPPY WALLS

Figure 6: Impact of Wall Stiffening on Dilation Ability. Over all airways we have plotted the ratio of R min post-MCh relative to Rmin pre MCh as a function of the change in airway stiffness measured from lung compliance.

Conclusions

RPRE-DI (cmH2O/l/s)

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2O/l/

s)

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25 PRE CHALLENGEPOST CHALLENGE

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5

R2 = 0.8458

R2 = 0.8401

ReducedReducedDilationDilationAbilityAbility

• Sufficiently high ASM provocation can result in severely reduced ability to dilate airways (elevated R min)• Reduced dilation capacity is likely not due to a reduction in tethering forces (i.e. diameter versus volume

expansion is unchanged after ASM stimulation)• Reduced dilation capacity is correlated with indices of increased wall stiffening• Reduced bronchodilation following ASM stimulation is likely due to the impact of ASM contraction on

airway wall stiffening.• In Asthma, is the ASM already pre-conditioned to amplify this effect?

FIGURE 3: Relationship of Maximum Dilation Ability (Rmin) to baseline airway constriction represented by airway resistance prior to a DI (RPRE DI). Solid dots are pre-methacholine challenge, open symbols are post challenge.

Figure 2: Transpulmonary pressure and Raw vs. time for an example lung

Figure 1: Data Processing Schematic

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RLS Algorithm

HPF

LPF Pressure vs. TimeVolume vs. Time

Figure 4: Assessment of Tethering: Percent Diameter change as a function of percent volume change during a DI. For a fully collapsed on the left, and a lung maintained at FRC (5 cm H 2O) on the right. Shown in blue is pre-challenge, and in red is post-challenge.

Figure 5: Impact of MCh on effective lung airway pressure-area (P-A) curves. In blue is pre-challenge data and in red post-challenge data.

• Effective area was calculated from Raw, assuming that Raw is proportional to 1/d4. Note at any pressure area drops after MCh, and that the slope of the line is decreased after challenge indicating the airways are stiffer.

Asthma?