This figure represents the multiple scale interactions that
occur in the pulmonary system. The entire lung (top left) is comprised
of many small-scale structures such as the alveoli (top right). The
mechanical properties of the alveoli are determined by the surfactant
uptake to the air-liquid interface, a molecular-level response (bottom). This,
in turn, influences the overall mechanical behavior of the organ (center).
The center figure shows that without surfactant, the entire lung is much
less compliant. This has many implications for the overall stability
and viability of the organ, and is related to frequently fatal diseases such
as infant and acute respiratory distress syndrome.
- Donald P. Gaver
|
|
At birth, pulmonary airways are liquid-filled and must be inflated from a
collapsed state to initiate gas exchange. For healthy infants, a modest
inspiratory effort introduces air into the bronchial tree so that the
atmosphere can directly communicate with alveoli, the primary site of gas-
exchange with blood. Gestationally mature lungs release surfactant from
alveolar type II pneumocytes into the lining fluid. Surfactant reduces the air-
liquid surface tension and thus decreases the effort necessary to inflate the
lung. However, premature infants may lack the ability to produce adequate
surfactant, increasing the surface tension.
Surfactant insufficiency coupled
with the extremely small size of the lung results in an extraordinarily large
inspiratory effort necessary to inflate the premature lung, leading to airway
atelectasis (extensive collapse of portions of the lung), deranged pulmonary
mechanical responses, poor ventilation/perfusion relationships and
insufficient alveolar ventilation. These premature airways can be opened by
the application of high pressure using a mechanical ventilator, however this
damages the epithelial cells that line the airway walls, resulting in
respiratory distress syndrome (RDS). Surfactant replacement therapy (SRT),
first successfully implemented the late 1980's, has dramatically reduced the
number of fatalities associated with this disease. Nevertheless, RDS remains
the fourth leading cause of death of premature infants in the United States.
|
Recent experiments indicate that during compression of an interface the
pulmonary surfactant can fold into a multilayer. This multilayer occurs at
high primary layer surface concentrations, and results in meta-stability of
sub-equilibrium surface tensions. These observations are corroborated by
observances using atomic force microscopy (AFM) that show that if surfactant
proteins (SP-B and SP-C) are included, a "folding transition" can occur that
reduces surface tension and provides a reservoir for surfactant to the
interface upon expansion. This response does not occur if SP-B or SP-C are non-
existent.
We thus hypothesize that these proteins provide an advantageous
energy landscape for the production of multi-layers, which are instrumental in
creating meta-stable low dynamic surface tensions.
We will investigate
molecular transport mechanisms, and their effect on surfactant transport in
the lung. These models will relate to surfactant spreading, airway reopening
and closure. This project will couple molecular dynamics simulations of
surfactant/protein adsorption (molecular) to the surface energy that drives
fluid flow (macroscale). The goal of our project will be to use fluid
mechanical principles coupled to molecular dynamics simulations to determine
the interrelationships between surfactant molecular processes and pulmonary
lining fluid flow. This will be useful in explaining the importance of
surfactant proteins B-C on adsorption characteristics that are critical to
proper lung function, and will allow us to simulate ventilation scenarios in
surfactant deficient lungs and determine methods for reducing micromechanical
stresses that may damage pulmonary tissue.
|
