Lung Biology Programme, Research Institute, The Hospital for Sick Children; Canadian Institutes of Health Research Group in Lung Development; and Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada
DESPITE MUCH RESEARCH and many
medical advances, pulmonary edema remains one of the more common causes
for admission to the hospital and intensive care units. Although many
illnesses lead to pulmonary edema, the underlying pathophysiological
mechanisms are one of two processes that may operate individually or in
concert. Pulmonary edema occurs when the safety mechanisms of the lung (reviewed in Ref. 14) are overwhelmed by either
high transvascular pressure gradients, as in cardiogenic edema, or
increases in the microvascular permeability to solutes, as in the
premature and adult acute respiratory distress syndromes. The excess
fluid first accumulates in the interstitial spaces of the lungs
(15), with few or no associated clinical symptoms. The
interstitium can only accommodate a few hundred milliliters of excess
fluid (14) so the fluid soon floods the airspaces, which
in a 70-kg adult approximates 5,000 ml. This airspace flooding is
associated with profound respiratory distress because the acini can no
longer effectively exchange gases.
It is important to study the mechanisms involved in airspace
fluid clearance because little is gained if one removes the cause of
the edema and the lungs cannot clear the alveolar fluid. Increased work
of breathing, hypoxemia, and pulmonary hypertension would lead to
adverse clinical outcomes. This was best illustrated by studies
(10, 18) of adult patients with cardiogenic and
noncardiogenic edema where survival was associated with evidence of the
active absorption of airspace fluid. Airspace fluid clearance is not only important in pulmonary edema but also during birth when the airspaces are filled with fetal lung liquid (reviewed in Ref. 11). All infants are born with "alveolar flooding,"
yet the vast majority of newborn infants uneventfully survive their
"salt water drowning" and do not develop respiratory distress syndrome.
How is airspace fluid cleared? Historically, it was assumed that
Starling forces were responsible for fluid clearance. However, in vivo
studies subsequently showed that the lung could clear fluid from its
airspaces against unfavorable transepithelial hydrostatic and colloid
osmotic pressure gradients (9), raising the possibility of
active transport
processes.1 In
vitro experiments with primary cultures of adult type II cells (5, 8) and late-gestation fetal distal lungs
(13) showed that the epithelium actively transported
Na+ via amiloride-sensitive pathways. In vivo
pharmacological (12) and genetic (6)
experiments documented the critical physiological importance of distal
lung epithelial Na+ transport in airspace fluid clearance
at the time of birth. Studies in the adult lung (3, 10)
have indicated that the fluid clearance rate in humans is ~18%/h,
with variable rates in other mammals (dog, 4%/h; sheep, 8%/h; rabbit,
15%/h; mouse, 27%/h).
New observations reported in this issue of the American
Journal of Physiology-Lung Cellular and Molecular Physiology
(17) suggest that liquid can very rapidly move out of a
fluid-filled acinus. Wang et al. (17), using an optical
"real-time" method, provide direct and indirect evidence that
liquid very rapidly leaves a fluid-filled acinus when the remainder of
the lung is filled with air. The half-life of fluid movement was only
5 s, and changes in lung volume or intracellular Ca2+
concentration modulated the rate of fluid movement. The authors acknowledge that they are not studying active transport by the distal
lung epithelium. As outlined above, the time frame of fluid movement is
inconsistent with active transport processes, and their experiments
showed that inhibitors of epithelial active ion transport did not alter
the rate of fluid movement. It should also be noted that the authors
were measuring the removal of fluid from the injected acinus and were
not measuring the movement of fluid out of the lung. As such, despite
the novelty of their observations, the clinical relevance of their
findings needs further study because if there is only a shift of fluid
from one acinus to another acinus, there would not be any benefit to
the patient.
Mechanical forces, including those involved in lung
interdependence (reviewed in Ref. 7), and surface tension
forces at the air-liquid interface may be responsible for movement of
the injected fluid. One could argue that the movement of fluid from the
injected acinus to an adjacent acinus is the fluid equivalent of
"pendulluft," a phenomenon where air moves from on acinus to an
adjacent acinus (7). Although neither surfactant nor
surface tension forces were assessed during the present study
(17), the authors appropriately asked whether or
not surface tension forces at the air-liquid interfaces are involved in
the phenomenon they observed. Indeed, the work of Espinosa et al.
(2) may be relevant; they indicate that bulk fluid
movement can occur in response to gradients in surface tension, a
phenomenon termed the "Marangoni effect." Their work suggests the
interesting possibility that the high surface tension at the airway
surface (4) draws the fluid out of the airspaces and up
into the airways (2) where it could then either enter an
adjacent acinus or be absorbed by respiratory bronchiolar and bronchial
epithelia. Indeed, the smallest airways are lined by Clara cells, which
are known to transport Na+ at ~10 times the rate of
alveolar type II epithelium (16).
The present observations (17) are relevant to
previous work investigating the sequence of events during the formation
of interstitial and alveolar edema. In a classic paper, Staub et al.
(15) determined the sequence of events leading from
interstitial to airspace edema. As edema formation occurs, the gas
volume of the alveolus decreases in a nonlinear relationship with the
distending pressure and the absolute size of the alveolus decreases as
it becomes fluid filled (Fig. 1). A
decrement in acinar size with fluid filling is consistent with the data
provided by Wang et al. (Fig. 2 in Ref. 17). As such, the
argument provided by Wang et al. (APPENDIX A in Ref.
17) may need revision as they speculate that the
fluid-filled alveolus A has a greater diameter than the partially filled alveolus B.
ARTICLE
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REFERENCES
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Fig. 1.
Schematic representation of the sequence of fluid
accumulation during acute pulmonary edema. A: normal
alveolar walls and no excess fluid in perivascular connective tissue
spaces. Br, bronchus; PA, pulmonary artery. B: initial fluid
leak. Fluid flows to the interstitial space (at subatmospheric
pressure) around the conducting vessels and airways. C:
tissue space filled, alveolar edema increases, and fluid begins to
overflow into the alveoli, notably at the corners where curvature is
great. D: quantal filling. Individual alveoli read critical
configuration at which existing inflation pressure can no longer
maintain stability. Alveolar gas volume rapidly passes to a new
configuration with a much reduced curvature (bottom right).
The volume deficit is absorbed by additional fluid filling or alveolar
collapse depending on associated conditions such as alveolar surface
tension and availability of fluid. [Reproduced from Staub et al.
(15).]
The state-of-the-art optical imaging developed by Wang et al. (17) represents a major advance. Their ability to provide "real-time" measurements of fluid movement within the distal regions of the lung is an important new approach that will supplement the existing gravimetric and histopathological techniques in studying the resolution of pulmonary edema.
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ACKNOWLEDGEMENTS |
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I thank Dr. A. Charles Bryan for insight regarding potential Marangoni flow within the lung.
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FOOTNOTES |
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My research is supported by the Canadian Institutes of Health Research Group in Lung Development, the Heart and Stroke Foundation of Ontario, and the Ontario Thoracic Society.
Address for reprint requests and other correspondence: H. O'Brodovich, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada (E-mail: hugh.obrodovich{at}sickkids.on.ca).
1 This speculation was also supported on a theoretical basis. Because the reflection coefficient of the alveolar epithelium for Na+ is 1 (1), a phenomenon arising from the 4-Å effective molecular radius of the intercellular junction, electrolytes become osmotically relevant in transepithelial fluid and solute movement. Because each 1 mosmol/l generates 19 mmHg pressure, the approximate 1.5 mosmol/l protein-induced osmotic pressure becomes trivial relative to the 280 mosmol/l electrolyte-induced osmotic pressure. Electrolytes, and not colloids, are therefore the quantitatively most important osmotic particle when airspaces with normal epithelium are filled with fluid.
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REFERENCES |
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