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

Erzsébet Bartolák-Suki,Béla Suki,Adam S Laprad,Brian C Harvey,Kenneth R Lutchen

doi:10.1371/journal.pone.0094828

Abstract

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.

Highlights

A hallmark characteristic of asthma is airway hyperresponsiveness (AHR) defined as an exaggerated constriction response of the airways to a variety of stimuli compared to non-asthmatics
This has led to the notion that tidal stretches and deep inspirations (DI) fluidize the cytoskeleton (CSK) of airway smooth muscle (ASM) cells in situ and the lack of the capacity to impose such stretching may be the basis of AHR in asthma [10]
Applying dynamic or static mechanical stresses resulted in similar diameters of intact airways without constriction

Summary

Introduction

A hallmark characteristic of asthma is airway hyperresponsiveness (AHR) defined as an exaggerated constriction response of the airways to a variety of stimuli compared to non-asthmatics. In animals when compared to static conditions, tidal breathing was shown to decrease airway responsiveness [12,13] as well as to relax airways following constriction [14]. This has led to the notion that tidal stretches and DIs fluidize the cytoskeleton (CSK) of ASM cells in situ and the lack of the capacity to impose such stretching may be the basis of AHR in asthma [10]

Objectives

Methods

Results

Conclusion