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WIREs Syst Biol Med
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Systems physiology of the airways in health and obstructive pulmonary disease

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Fresh air entering the mouth and nose is brought to the blood–gas barrier in the lungs by a repetitively branching network of airways. Provided the individual airway branches remain patent, this airway tree achieves an enormous amplification in cross‐sectional area from the trachea to the terminal bronchioles. Obstructive lung diseases such as asthma occur when airway patency becomes compromised. Understanding the pathophysiology of these obstructive diseases thus begins with a consideration of the factors that determine the caliber of an individual airway, which include the force balance between the inward elastic recoil of the airway wall, the outward tethering forces of its parenchymal attachments, and any additional forces due to contraction of airway smooth muscle. Other factors may also contribute significantly to airway narrowing, such as thickening of the airway wall and accumulation of secretions in the lumen. Airway obstruction becomes particularly severe when these various factors occur in concert. However, the effect of airway abnormalities on lung function cannot be fully understood only in terms of what happens to a single airway because narrowing throughout the airway tree is invariably heterogeneous and interdependent. Obstructive lung pathologies thus manifest as emergent phenomena arising from the way in which the airway tree behaves a system. These emergent phenomena are studied with clinical measurements of lung function made by spirometry and by mechanical impedance measured with the forced oscillation technique. Anatomically based computational models are linking these measurements to underlying anatomic structure in systems physiology terms. WIREs Syst Biol Med 2016, 8:423–437. doi: 10.1002/wsbm.1347 This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Physiology > Physiology of Model Organisms
A fractal model of a bifurcating airway tree that begins being relatively uniformly ventilated (yellow color at top left). As bronchoconstriction proceeds and then dissipates (shown by the direction of the gray arrows), a self‐organized pattern of airway narrowing persists. Similar patterns were observed experimentally using positron emission tomography. (Reprinted with permission from Ref . Copyright 2005 Macmillan Publishers Ltd.)
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Example lung impedance spectra from a type A asthmatic (left) and a type B asthmatic (right). Both types of asthmatics have elevated lung resistance (RL) at all frequencies (open circles) that is reduced by the bronchodilator albuterol (closed circles). Bronchodilation has little effect on lung elastance (EL) in type A asthmatics, but in type B asthmatics, there is a substantial change indicative of a reduction in the amount of central airway shunting. That is, prior to albuterol, the distal airways are significantly constricted so that the oscillations in flow that are applied to the lung to measure impedance become progressively more confined to the central airways as oscillation frequency increases. The albuterol relieves the distal airway constriction so that the flow can move past them and into the alveolar regions of the lung. The result is a major reduction in the apparent stiffness of the system as a whole. (Reprinted with permission from Ref . Copyright 1999 American Thoracic Society)
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Schematic of ASM structure depicting a random assembly and intermingling of actin and myosin filaments, the labile connection of actin filaments to the cell cytoskeleton at focal adhesions via dense bodies, and the net direction of force transmission that results from the vector sum of the individual actin–myosin force vectors.
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(a) Active force in a strip of ASM produced under isometric conditions (black curve) and when 1%, 2%, and 4% length oscillations are imposed, beginning at 120 seconds (gray curve). Note the immediate and rapid decrement in peak force that occurs when the oscillations commence. (Reprinted with permission from Ref . Copyright 2009 American Physiological Society) (b) Steady‐state force‐length loops from activated strips of ASM during length (L) oscillation of various magnitudes about a fixed mean length of L0. Note that the peak force in each loop is virtually independent of amplitude. (Reprinted with permission from Ref . Copyright 1997 American Thoracic Society)
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a) Schematic in cross‐section of an elastic airway of passive radius rp embedded in elastic parenchyma. Fp is the passive hoop stress in the (thin) airway wall. Ptm is the transmural pressure across the airway wall mediated by its parenchymal attachments. With the addition of FA to the hoop stress from active ASM contraction, the airway narrows to a radius r and the transmural pressure increases by ΔPtm. b) Fit of the model to airway resistance vs. time following a bolus i.v. injection of mechacholine in a rat at different values of positive‐end expiratory pressure (PEEP) (top) and in a rabbit ventilated with different tidal volumes (VT) (bottom). (Reproduced with permission from the American Physiological Society)
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Examples of clinical data obtained by spirometry. (a) Volume versus time during a maximal forced expiration shows the beneficial effects of a bronchodilator in increasing FVC. (b) Expiratory flow‐volume curves showing that FEV1 is also increased by a bronchodilator.
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A space‐filling model of the human airway tree created from a 3D computed tomography image from a human subject. The five different lung lobes are shown in different colors. (Reprinted with permission from Ref . Copyright 2014 Springer)
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Airway narrowing caused by contraction of ASM cells (yellow) that thicken and buckle the airway wall (green) and pull inward on the attached alveolar walls, causing local distortion of the parenchyma (black network). The extent to which the area of the airway lumen (white region) decreases, and hence airway resistance increases, depends on the various factors listed.
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Coronal slice images of hyperpolarized helium in the lung obtained by magnetic resonance imaging: (a) healthy subject, (b) subject with chronic obstructive pulmonary disease (COOPD), (c) asthmatic subject, and (d) subject with cystic fibrosis. The values of FEV1 (percent predicted) are indicated on each panel. (Reprinted with permission from Ref . Copyright 2010 Wiley)
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Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
Physiology > Mammalian Physiology in Health and Disease
Physiology > Physiology of Model Organisms

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