1. 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 POST-CHALLENGE PRE-CHALLENGE Parenchymal Tethering vs. Airway Wall Stiffness on In Vivo Airway Dilation During a Deep Inspiration M.S. Hamilton, D.A. Affonce, and K.R. Lutchen Biomedical Engineering Department, Boston University Background Goal To 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 (R aw ) as a surrogate of airway diameter 2) 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) relationship Methods 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 H 2 O differential pressure transducers Airway opening flow was recorded using a Pneumotach connected to a 2 cm H 2 O differential pressure transducer Lungs started out collapsed and then were subjected to the protocol shown in the flow diagram below Lung Collapsed 0 cmH 2 O Deep Inspiration Typical FRC 5 cmH 2 O Deep Inspiration 8 Hz pressure oscillation were superimposed over the above pressure maneuvers to allow tracking of R aw. R aw 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 R aw. Based on the methods of Jensen, et. al., JAP (91), 2001. Results As transpulmonary pressure increased from 0 cm H 2 O to 30 cm H 2 O, airway resistance dropped from 18 cm H 2 0/L/s to 1.5 cm H 2 0/L/s. As the pressure was then reduced back to 5 cm H 2 O, the resistance increased to 4 cm H 2 0/L/s. During the next deep inspiration the resistance dropped to 1 cm H 2 0/L/s At low levels of baseline airway constriction (R Pre-DI <10 cm H 2 O/L/s) R min 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? PRE-CHALLENGE POST-CHALLENGE 0 cmH 2 O 5 cmH 2 O 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. STIFF WALLSFLOPPY 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 R min pre MCh as a function of the change in airway stiffness measured from lung compliance. Conclusions ReducedDilationAbility 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 (R min ) to baseline airway constriction represented by airway resistance prior to a DI (R PRE DI ). Solid dots are pre-methacholine challenge, open symbols are post challenge. Figure 2: Transpulmonary pressure and R aw vs. time for an example lung Figure 1: Data Processing Schematic 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 2 O) 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 R aw, assuming that R aw is proportional to 1/d 4. 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?