A multi-scale approach to airway hyperresponsiveness: from molecule to organ

Lauzon, Anne-Marie; Bates, Jason H. T.; Donovan, Graham; Tawhai, Merryn; Sneyd, James; Sanderson, Michael J.
May 2012
Frontiers in Physiology;May2012, Vol. 3, p1
Academic Journal
Airway hyperresponsiveness (AHR), a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics and force production of actin-myosin contractile proteins during cross-bridge and latch-state cycling; at the cellular scale, Ca2+ signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a frame-work for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy.


Related Articles

  • Asthma: alternative anti-inflammatory agents needed for patient subgroup.  // PharmaWatch: Monthly Review;Mar2005, Vol. 4 Issue 3, p26 

    The article presents a study conducted by the European Network for Understanding Mechanisms of Severe Asthma, concerning the role of the neutrophil in the pathogenesis of asthma. It has suggested that severe asthma is a different disease to mild-moderate disease. The presence of neutrophilic...

  • Author's response: Airway anatomy in COPD: many dimensions to consider. Smith, Benjamin M.; Hoffman, Eric A.; Barr, R. Graham // Thorax;Jun2015, Vol. 70 Issue 6, p585 

    A response from the authors of the article related to multi-ethnic study of atherosclerosis (MESA) chronic obstructive pulmonary disease that was published in the 2014 issue of the periodical.

  • Cough Variant Asthma: Lessons Learned from Deep Inspirations. Lougheed, M.; Turcotte, Scott; Fisher, Thomas // Lung;Feb2012, Vol. 190 Issue 1, p17 

    The pathophysiology of cough variant asthma is poorly understood. In particular, the mechanisms that cause different symptoms in typical asthma (in which wheeze predominates) compared with cough variant asthma (in which cough predominates) have not been determined. Traditional explanations...

  • Seasonal effect on exercise challenge tests for the diagnosis of exercise-induced bronchoconstriction. Goldberg, Shmuel; Mimouni, Francis; Joseph, Leon; Izbicki, Gabriel; Picard, Elie // Allergy & Asthma Proceedings;Sep/Oct2012, Vol. 33 Issue 5, p416 

    Exercise challenge test (ECT) may help in the diagnosis of asthma. Asthma is season dependent (relative summer nadir).This study was designed to prospectively show that ECT sensitivity decreases when performed in summer and/or out of personal asthma season. We performed two ECTs in 49 patients...

  • Ventilation Defect Formation in Healthy and Asthma Subjects Is Determined by Lung Inflation. Scott Harris, R.; Fujii-Rios, Hanae; Winkler, Tilo; Musch, Guido; Melo, Marcos F. Vidal; Venegas, José G. // PLoS ONE;Dec2012, Vol. 7 Issue 12, p1 

    Background: Imaging studies have demonstrated that ventilation during bronchoconstriction in subjects with asthma is patchy with large ventilation defective areas (Vdefs). Based on a theoretical model, we postulated that during bronchoconstriction, as smooth muscle force activation increases, a...

  • Continuing the debate about measuring asthma in population studies. Peat, J. K.; Toelle, B. G.; Marks, G. B.; Mellis, C. M. // Thorax;May2001, Vol. 56 Issue 5, p406 

    The reasons for measuring atopy and airway hyperresponsiveness (AHR) and the methods of validating measurements of in asthma in population studies continue to of be debated. The debate has centred around standards against which to validate asthma measurements but the absence of a "gold standard"...

  • Evaluation of airway inflammation by quantitative Th1 /Th2 cytokine mRNA measurement in sputum of asthma patients. Truyen, E.; Coteur, I.; Dilissen, E.; Overbergh, I.; Dupont, L. J.; Ceuppens, J. L.; Bullens, D. M. A. // Thorax;Mar2006, Vol. 61 Issue 3, p202 

    Background: Asthma is a chronic inflammatory disorder of the airways driven by I cell activation. Th2 cells and their cytokines are thought to play a role in the pathophysiology of allergic as well as non-allergic asthma. Methods: Airway cells were obtained by sputum induction from 15 healthy...

  • A novel tissue inhibitor of metalloproteinase-1 (TIMP-1) polymorphism associated with asthma in Australian women. Lose, F.; Thompson, P. J.; Duffy, D.; Stewart, G. A.; Kedda, M.-A. // Thorax;Aug2005, Vol. 60 Issue 8, p623 

    Background: Airway remodelling is a characteristic feature of chronic asthma and there is evidence that an airway imbalance between levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) is associated with airway remodelling. On this basis, we...

  • Biopharmaceutical Therapeutics for Asthma Remodeling. Das, A. M.; Griswold, D. E.; Torphy, T. J.; Li, L. // Current Pharmaceutical Design;Sep2006, Vol. 12 Issue 25, p3233 

    Current asthma therapy is aimed at controlling disease symptoms. A subset of asthma patients remains symptomatic despite optimal therapy indicating that an unmet medical need exists for these patients. Innovative therapeutics are needed to treat the unmet need in asthma and biopharmaceutical...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics