AIRWAY CONSTRICTION HETEROGENEITY: FROM STRUCTURAL ORIGINS TO
CLINICAL IMPACT
K. R. Lutchen
Biomedical Engineering, Boston University, Boston, MA USA
ABSTRACT
What is the mechanical and structural basis for increased dyspnea and patient
discomfort during diseases in which bronchoconstriction or airway closure may occur? It
is the thesis of this talk that the basis rises beyond the presence of bronchoconstriction
per se. Rather, it may be the heterogeneity of the bronchoconstriction and obstruction in
the lung periphery that can wreak mechanical havoc on the lung, creating huge
increases in the load against which one must breathe. In fact, this mechanisms is more
likely to occur, and with greater impact than simply severe central airway constriction.
Moreover, such peripheral heterogeneities predispose the lung to creating poor
ventilation distribution even if these mechanical loads are overcome. In short, a little bit
of the right form of heterogeneity can go a long way. In this talk I will provide convincing
experimental and modeling evidence that heterogeneity is a “signal” deserving of far
more respect than previously given. I will also convey the distinct defect in an asthmatic
lung in being able to modulate the heterogeneity or mean level of constriction via a deep
inspiration to maximum lung volume.
INTRODUCTION
During lung disease six distinct mechanisms can alter the levels and frequency
dependence of RL and EL for frequencies surrounding breathing. These include 1) the
degree of airway constriction, 2) airway constriction heterogeneities, 3) airway wall
shunting, 4) airway closure, 5) explicit changes in the tissue viscoelastic properties, and
6) airway and tissue nonlinearities.
Moreover, these mechanisms are not all
independent (i.e., excessive uniform airway constriction will exaggerate the influence of
airway wall shunting. This talk addresses two questions. First, Can these mechanisms
cause changes in RL or EL that have significant clinical consequences on breathing
capability?
Second, what changes in lung structure are necessary to invoke these
mechanisms at clinically important levels?
For over 50 years it has been recognized that during breathing transpulmonary
pressure (Ptp) and airway opening flow (Q) should be related by basic force balances
that lead to the equation of motion and incorporate lumped properties for the effective
resistance (R), elastance (E) and, perhaps, inertance (I) of the lungs; i.e.
Ptp = RL*Q + EL*Qdt + IL*dQ/dt
The simplistic notion was that the RL, EL and IL are a consequence of the (serial)
combination of the airway and lung tissue properties. It is the dynamic resistance and
elastance (RL and EL) at typical breathing rates which present the mechanical load
against which sufficient air must be inspired. While it is appreciated that several
mechanisms potentially alter lung dynamic (RL and EL), the relationship between
changes in lung structure necessary to invoke these mechanisms is poorly understood.
CONSTRICTION PATTERN AND THE FREQUENCY DEPENDENCE OF RL AND EL
How can airway constriction pattern impact measurements of R L and EL for
frequencies surrounding breathing (eg., 0.1 - 8 Hz). Otis et al. (5) and Mead (6) were
the first to show that parallel resistance-elastance time constant heterogeneities and
airway wall shunting due to a large homogeneous constriction could both increase the
frequency dependence in dynamic RL and EL. Most important, they suggested that
“heterogeneous” constriction produces an RL at low frequencies higher than the parallel
combination of the individual resistances of airways in a network. In fact, the R L of a
network of parallel pathways will decrease from a higher value at low frequencies to the
parallel combination of the resistances in all pathways at infinite frequency (or about 2-4
Hz for a real lung). Likewise, the effective EL while normal at very low or near static
frequencies, can increase rapidly with frequency. However, it has not been clear how
these mechanisms would alter the RL and EL from 0.1 - 8 Hz when occurring in a
realistic human airway trees.
RESULTS AND DISCUSSION
We have recently implemented a computational human airway tree model
inclusive of distinct wall morphometry for healthy and asthmatics (2,3,4). Our model
predicted that measurements of RL and EL from 0.1 - 5 Hz can be quite distinct
depending on the pattern of constriction. We predict that extreme heterogeneous
constriction in which there is random closure or near closure will produce dangerous
elevations in these RL and EL at typical breathing rates and can do so even without
necessarily a large change in Raw. Moreover, in principle this form of heterogeneous
constriction would greatly compromise the efficacy of ventilation distribution during
normal breathing (2). The task now is to identify if experimental data supports these
predictions.
We have measured the RL and EL from 0.1 - 8 Hz in healthy subjects and mild,
moderate and severe asthmatics before and after a DI both before and after standard
and modified methacholine challenges (7). The modified challenge represents that
performed by Skloot et al (1) in which deep inspirations and maximum flow-volume
maneuvers are prohibited during the challenge. We have also measured in real-time the
airway resistance during tidal breathing and during the deep inspiration (8). Our data
show that severe asthma represents a condition of extreme heterogeneous constriction
in the lung which includes the occurrence of closed or extremely narrowed airways
randomly distributed throughout the bronchial tree and for which deep inspirations are
unable to have a residual re-opening impact. Finally, we will present data that suggests
that airway inflammation promotes a fundamental defect in asthma lies at the level of
airway smooth muscle. Effectively, the muscle transitions to a state of high stiffness and
force generating capacity. This hyperreactive state when stimulated creates a
heterogeneous pattern of functional airway closures. Moreover, the muscle is too stiff to
stretch during deep inhalations. A fixed, and potentially dangerous, defect results not
only in mechanical difficulty in breathing, but in ventilation distribution. The combination
of both can be life-threatening if ventilation-perfusion matching cannot sustain blood gas
levels.
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