Brian C. Harvey

Can tidal breathing with deep inspirations of intact airways create sustained bronchoprotection or bronchodilation

Fluctuating forces imposed on the airway smooth muscle due to breathing are believed to regulate hyperresponsiveness in vivo. However, recent animal and human isolated airway studies have shown that typical breathing-sized transmural pressure (Ptm) oscillations around a fixed mean are ineffective at mitigating airway constriction. To help understand this discrepancy, we hypothesized that Ptm oscillations capable of producing the same degree of bronchodilation as observed in airway smooth muscle strip studies requires imposition of strains larger than those expected to occur in vivo. First, we applied increasingly larger amplitude Ptm oscillations to a statically constricted airway from a Ptm simulating normal functional residual capacity of 5 cmH2O. Tidal-like oscillations (5-10 cmH2O) imposed 4.9 ± 2.0% strain and resulted in 11.6 ± 4.8% recovery, while Ptm oscillations simulating a deep inspiration at every breath (5-30 cmH2O) achieved 62.9 ± 12.1% recovery. These same Ptm oscillations were then applied starting from a Ptm = 1 cmH2O, resulting in approximately double the strain for each oscillation amplitude. When extreme strains were imposed, we observed full recovery. On combining the two data sets, we found a linear relationship between strain and resultant recovery. Finally, we compared the impact of Ptm oscillations before and after constriction to Ptm oscillations applied only after constriction and found that both loading conditions had a similar effect on narrowing. We conclude that, while sufficiently large strains applied to the airway wall are capable of producing substantial bronchodilation, the Ptm oscillations necessary to achieve those strains are not expected to occur in vivo.

Can breathing-like pressure oscillations reverse or prevent narrowing of small intact airways?

Periodic length fluctuations of airway smooth muscle during breathing are thought to modulate airway responsiveness in vivo. Recent animal and human intact airway studies have shown that pressure fluctuations simulating breathing can only marginally reverse airway narrowing and are ineffective at protecting against future narrowing. However, these previous studies were performed on relatively large (>5 mm diameter) airways, which are inherently stiffer than smaller airways for which a preponderance of airway constriction in asthma likely occurs. The goal of this study was to determine the effectiveness of breathing-like transmural pressure oscillations to reverse induced narrowing and/or protect against future narrowing of smaller, more compliant intact airways. We constricted smaller (luminal diameter = 2.92 ± 0.29 mm) intact airway segments twice with ACh (10(-6) M), once while applying tidal-like pressure oscillations (5-15 cmH2O) before, during, and after inducing constriction (Pre + Post) and again while only imposing the tidal-like pressure oscillation after induced constriction (Post Only). Smaller airways were 128% more compliant than previously studied larger airways. This increased compliance translated into 196% more strain and 76% greater recovery (41 vs. 23%) because of tidal-like pressure oscillations. Larger pressure oscillations (5-25 cmH2O) caused more recovery (77.5 ± 16.5%). However, pressure oscillations applied before and during constriction resulted in the same steady-state diameter as when pressure oscillations were only applied after constriction. These data show that reduced straining of the airways before a challenge likely does not contribute to the emergence of airway hyperreactivity observed in asthma but may serve to sustain a given level of constriction.

Modeling variability in air pollution-related health damages from individual airport emissions

ABSTRACT In this study, we modeled concentrations of fine particulate matter (PM2.5) and ozone (O3) attributable to precursor emissions from individual airports in the United States, developing airport‐specific health damage functions (deaths per 1000 t of precursor emissions) and physically‐interpretable regression models to explain variability in these functions. We applied the Community Multiscale Air Quality model using the Decoupled Direct Method to isolate PM2.5‐ or O3‐related contributions from precursor pollutants emitted by 66 individual airports. We linked airport‐ and pollutant‐specific concentrations with population data and literature‐based concentration‐response functions to create health damage functions. Deaths per 1000 t of primary PM2.5 emissions ranged from 3 to 160 across airports, with variability explained by population patterns within 500 km of the airport. Deaths per 1000 t of precursors for secondary PM2.5 varied across airports from 0.1 to 2.7 for NOx, 0.06 to 2.9 for SO2, and 0.06 to 11 for VOCs, with variability explained by population patterns and ambient concentrations influencing particle formation. Deaths per 1000 t of O3 precursors ranged from −0.004 to 1.0 for NOx and 0.03 to 1.5 for VOCs, with strong seasonality and influence of ambient concentrations. Our findings reinforce the importance of location‐ and source‐specific health damage functions in design of health‐maximizing emissions control policies. Graphical abstract Figure. No Caption available. HighlightsWe modeled aviation emissions of fine particulate matter and ozone precursors.We developed airport‐specific health damage functions (deaths per ton emissions).We developed regression models to explain variability in health damage functions.Highest contributing airports to health impacts are located near dense urban areas.

Tidal stretches differently regulate the contractile and cytoskeletal elements in intact airways.

Recent reports suggest that tidal stretches do not cause significant and sustainable dilation of constricted intact airways ex vivo. To better understand the underlying mechanisms, we aimed to map the physiological stretch-induced molecular changes related to cytoskeletal (CSK) structure and contractile force generation through integrin receptors. Using ultrasound, we measured airway constriction in isolated intact airways during 90 minutes of static transmural pressure (Ptm) of 7.5 cmH2O or dynamic variations between Ptm of 5 and 10 cmH20 mimicking breathing. Integrin and focal adhesion kinase activity increased during Ptm oscillations which was further amplified during constriction. While Ptm oscillations reduced β-actin and F-actin formation implying lower CSK stiffness, it did not affect tubulin. However, constriction was amplified when the microtubule structure was disassembled. Without constriction, α-smooth muscle actin (ASMA) level was higher and smooth muscle myosin heavy chain 2 was lower during Ptm oscillations. Alternatively, during constriction, overall molecular motor activity was enhanced by Ptm oscillations, but ASMA level became lower. Thus, ASMA and motor protein levels change in opposite directions due to stretch and contraction maintaining similar airway constriction levels during static and dynamic Ptm. We conclude that physiological Ptm variations affect cellular processes in intact airways with constriction determined by the balance among contractile and CSK molecules and structure.

A hybrid method for restoring the fidelity of ultrasound images of vessels

Distortions in ultrasound images of vessels can be significant even though these effects are negligible at larger scale imaging. System and propagation effects operate on a scale comparable to the dimensions of thin walls and features in longitudinal views. As a result , diagnostic inferences based on observed geometric features in the image such as lumen diameter and wall thickness may be in error. Also, these distortions can vary from imaging system to system as well as the settings and spatial locations within the same system. A hybrid approach combines measurements with wave models to reduce system and propagation effects on the image. First, a simulation model was developed that included reflections, reverberations , absorption and causal phase velocity dispersion as well as system transmit characteristics. Second, a sequence of measurement and modeling steps was used to extract data and incorporate it into correction and inverse filtering. The methodology was tested on a disk-shaped tissue mimicking phantom material and verified by independent physical measurements. Raw rf beamformed data was captured from a Terason 3000 ultrasound imaging system connected to a 5-12 MHz linear array. A tissue mimicking phantom in the shape of a disk was characterized by independent physical measurements. The thickness obtained from outer surface to outer surface (as is usually done in edge detection algorithms for vessel walls) from rf data gave a value of 1.00 cm or 5 % error compared to the corrected result of 0.987 cm, an error of 0.7%. Pulses from the top and bottom surfaces, originally .505 and .711 mm, were reduced by 83 % to 0.087 and .119 mm, respectively, after correction. Data from a more relevant thin walled tube of inner diameter 0.5mm provided an uncorrected value of 0.37 mm 26 %error and a corrected value of 0.493 mm (1.6 % error).A bovine bronchial airway, mounted in a tank filled with Krebs solution and subjected to doses of acetylcholine to simulate asthma like reactions, was observed to close down at higher doses. Early results showed that corrected images indicate the inner diameter was still open. A combination of correcting for propagation effects and inverse filtering has resulted in higher resolution images that are significantly more accurate representations of vessels and has provided ultrasound measured tissue parameters of absorption and sound speed for the vessel walls.

Spatial distribution of airway wall displacements during breathing and bronchoconstriction measured by ultrasound elastography using finite element image registration

HighlightsDisplacement distribution within airway wall estimated using image registration.Deformation of airway wall during pressure changes of breathing is heterogeneous.Medial layer of airway wall experiences highest strains during breathing.Airway narrows and stiffens heterogeneously in response to an agonist. ABSTRACT With every breath, the airways within the lungs are strained. This periodic stretching is thought to play an important role in determining airway caliber in health and disease. Particularly, deep breaths can mitigate excessive airway narrowing in healthy subjects, but this beneficial effect is absent in asthmatics, perhaps due to an inability to stretch the airway smooth muscle (ASM) embedded within an airway wall. The heterogeneous composition throughout an airway wall likely modulates the strain felt by the ASM but the magnitude of ASM strain is difficult to measure directly. In this study, we optimized a finite element image registration method to measure the spatial distribution of displacements and strains throughout an airway wall during pressure inflation within the physiological breathing range before and after induced narrowing with acetylcholine (ACh). The method was shown to be repeatable, and displacements estimated from different image sequences of the same deformation agreed to within 5.3 &mgr;m (0.77%). We found the magnitude and spatial distribution of displacements were radially and longitudinally heterogeneous. The region in the middle layer of the airway experienced the largest radial strain due to a transmural pressure (Ptm) increase simulating tidal breathing and a deep inspiration (DI), while the region containing the ASM (i.e., closest to the lumen) strained least. During induced narrowing with ACh, we observed temporal longitudinal heterogeneity of the airway wall. After constriction, the displacements and strain are much smaller than the relaxed airway and the pattern of strains changed, suggesting the airway stiffened heterogeneously.

High resolution elastography for determining local airway wall deformation during bronchoconstriction

Excessive shortening of airway smooth muscle (ASM) is responsible for airway hyperresponsiveness (AHR) in asthma but its cause is poorly understood. The forces of breathing have been implicated as preventing AHR in vivo by straining the ASM. However, it is unclear the extent of ASM strain within the airway wall and recent evidence from intact airway studies suggest tidal breathing does not modulate AHR. The ASM is embedded inside the airway wall with heterogeneous mechanical properties which affect the strain felt by the ASM as well as the mechanical load opposing ASM shortening. We captured two ultrasound images of a cross section of an intact airway and applied an image registration technique to calculate the displacement field resulting from a small deformation. The displacement field was then used as an input to solve an inverse problem to estimate the shear modulus distribution. The estimates were compared to the strain of the airway wall and Youngs modulus calculated using a thin-walled cylinder approximation.