What role does the airway smooth muscle (ASM) play in producing the asthmatic phenotype of airway hyperresponsiveness (AHR)? A plethora of studies confirm that length oscillations of isolated ASM can modulate and mitigate its net response to an agonist. Two related hypotheses at the molecular level have emerged to explain isolated ASM findings, namely that the normal responses to stretch arise from perturbed equilibrium of actin-myosin crossbridges and/or cytoskeletal fluidization of the ASM cell. However, a gap exists in bridging molecular level hypotheses from isolated ASM studies to actual AHR for an intact airway as it constricts in three-dimensions. Many important interactions occur within an intact airway's extracellular matrix (ECM) that can impact ASM contractility and hence airway constriction in situ. We have developed a unique ultrasound imaging-based system to dynamically probe intact airways. Here, the ASM is in its natural geometric state embedded within the airway wall's ECM, and the airway is exposed to physiologically relevant transmural pressure (Ptm) fluctuations. This system allows for concurrent real-time measurements of luminal diameter and wall thickness over the full length of an intact airway during any physiological Ptm fluctuations and/or induced constriction. These measurements allow us to calculate an extensive set of macroscopic mechanical properties of the intact airway system. We can also apply biochemical and histological approaches to examine the microscopic properties of the ASM cells and ECM fibers. Jointly, these preliminary data suggest in intact airways, Ptm variations may invoke cellular mechanisms of crossbridge detachment and/or actin de-polymerization (perhaps associated with cytoskeletal fluidization) but without necessarily resulting in airway dilation. Based on this, we propose to test the following hypothesis: HYPOTHESIS: In the intact airway system, transmural pressure variations during physiological breathing are insufficient to attenuate responsiveness because the mechanical properties of the airway wall's ECM prevent the effective disruption of ASM crossbridge cycling and actin polymerization. Corollary: In vivo, AHR in asthma cannot be explained simply as the inability to properly strain the ASM.
Aim 1 : To determine the contribution of dynamic Ptm variations to the responsiveness of intact airways.
Aim 2 : To determine the intra- and extracellular consequences of dynamic Ptm variations on intact airways.
Aim 3 : To determine how airway wall structural constituents and ASM cellular processes impact the responsiveness of intact airways exposed to dynamic transmural pressure variations. This proposal will address the crucial questions of if and how mechanisms associated with ASM contraction in isolation are relevant in a dynamic and complex intact airway system and, hence, relevant in modulating airway responsiveness. Our proposal represents an essential step to understand mechanisms relevant to airway hyperresponsiveness.
Asthma treatments are designed to target the smooth muscle, or inflammation, or airway wall remodeling, or some combination thereof;what works """"""""best"""""""" for some subjects may be minimally effective in another. Our results will have a significant impact on interpreting previous and future studies based on isolated ASM strips and ASM cell cultures. Finally, we also expect that our results will eventually become useful in the treatment of asthmatic patients because we will provide a link between cellular processes and airway function, and hence symptoms.
|Harvey, Brian C; Lutchen, Kenneth R; Barbone, Paul E (2017) Spatial distribution of airway wall displacements during breathing and bronchoconstriction measured by ultrasound elastography using finite element image registration. Ultrasonics 75:174-184|
|Harvey, Brian C; Parameswaran, Harikrishnan; Lutchen, Kenneth R (2015) Can breathing-like pressure oscillations reverse or prevent narrowing of small intact airways? J Appl Physiol (1985) 119:47-54|
|Lui, Justin K; Parameswaran, Harikrishnan; Albert, Mitchell S et al. (2015) Linking Ventilation Heterogeneity Quantified via Hyperpolarized 3He MRI to Dynamic Lung Mechanics and Airway Hyperresponsiveness. PLoS One 10:e0142738|
|Bartolák-Suki, Erzsébet; LaPrad, Adam S; Harvey, Brian C et al. (2014) Tidal stretches differently regulate the contractile and cytoskeletal elements in intact airways. PLoS One 9:e94828|
|Parameswaran, Harikrishnan; Lutchen, Kenneth R; Suki, Béla (2014) A computational model of the response of adherent cells to stretch and changes in substrate stiffness. J Appl Physiol (1985) 116:825-34|
|Harvey, Brian C; Parameswaran, Harikrishnan; Lutchen, Kenneth R (2013) Can tidal breathing with deep inspirations of intact airways create sustained bronchoprotection or bronchodilation? J Appl Physiol (1985) 115:436-45|
|LaPrad, Adam S; Lutchen, Kenneth R; Suki, Béla (2013) A mechanical design principle for tissue structure and function in the airway tree. PLoS Comput Biol 9:e1003083|
|LaPrad, Adam S; Szabo, Thomas L; Suki, Béla et al. (2010) Tidal stretches do not modulate responsiveness of intact airways in vitro. J Appl Physiol (1985) 109:295-304|