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ABSTRACT |
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Abstract
Letter
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The following are the abstracts of the articles discussed in the subsequent letter:
Huang, Yuh-Chin T., Aneysa C. Sane, Steven G. Simonson, Thomas A. Fawcett, Richard E. Moon,
Philip J. Fracica, Margaret G. Menache, Claude A. Piantadosi, and
Stephen L. Young. Artificial surfactant attenuates hyperoxic lung
injury in primates. I. Physiology and biochemistry. J. Appl.
Physiol. 78(5): 1816-1822, 1995.
Prolonged exposure to
O2 causes diffuse alveolar damage and surfactant
dysfunction that contribute to the pathophysiology of hyperoxic lung
injury. We hypothesized that exogenous surfactant would improve lung
function during O2 exposure in primates. Sixteen healthy
male baboons (10-15 kg) were anesthetized and mechanically ventilated for 96 h. The animals received either 100% O2
(n = 6) or 100% O2 plus aerosolized artificial
surfactant (Exosurf; n = 5). A third group of animals
(n = 5) was ventilated with an inspired fraction of
O2 of 0.21 to control for the effects of sedation and
mechanical ventilation. Hemodynamic parameters were obtained every 12 h, and ventilation-perfusion distribution
(
A/
) was measured
daily using a multiple inert-gas elimination technique. Positive end-expiratory pressure was kept at 2.5 cmH2O and
was intermittently raised to 10 cmH2O for 30 min
to obtain additional measurements of
A/. After the
experiments, lungs were obtained for biochemical and histological
assessment of injury. O2 exposures altered hemodynamics,
progressively worsened
A/, altered lung phospholipid composition, and produced severe lung edema. Artificial surfactant therapy significantly increased disaturated
phosphatidylcholine in lavage fluid and improved intrapulmonary shunt,
arterial PO2, and lung edema. Surfactant also
enhanced the shunt-reducing effect of positive end-expiratory pressure.
We conclude that an aerosolized protein-free surfactant decreased the
progression of pulmonary O2 toxicity in baboons.
Piantadosi, Claude A., Philip J. Fracica, Francis G. Duhaylongsod, Y.-C. T. Huang, Karen E. Welty-Wolf, James D. Crapo, and
Stephen L. Young. Artificial surfactant attenuates hyperoxic lung
injury in primates. II. Morphometric analysis. J. Appl.
Physiol. 78(5): 1823-1831, 1995.Diffuse lung injury from
hyperoxia is accompanied by low compliance and hypoxemia with
disruption of endothelial and alveolar epithelial cell layers. Because
both function and content of surfactant in diffuse lung injury decrease in animals and in humans, changes in the extent of injury during continuous hyperoxia were evaluated after treatments with a
protein-free surfactant in primates. Ten baboons were ventilated with
100% O2 for 96 h and five were intermittently given an
aerosol of an artificial surfactant (Exosurf). Physiological and
biochemical measurements of the effects of the surfactant treatment are
presented in a companion paper (Y.-C. T. Huang, A. C. Sane, S. G. Simonson, T. A. Fawcett, R. E. Moon, P. J. Fracica, M. G. Menache, C. A. Piantadosi, and S. L. Young. J. Appl. Physiol. 78:
1823-1829, 1995.) After O2 exposures, lungs were fixed
and processed for electron microscopy. The cellular responses to
O2 included epithelial and endothelial cell injuries,
interstitial edema, and inflammation. Morphometry was used to
quantitate changes in lungs of animals treated with the artificial
surfactant during O2 exposure and to compare them with the
untreated animals. The surfactant decreased neutrophil accumulation,
increased fibroblast proliferation, and decreased changes in the volume
of type I epithelial cells. Surfactant-treated animals also
demonstrated better preservation of endothelial cell integrity. These
responses indicate ameliorating effects of the surfactant on the
pulmonary response to hyperoxia, including protection against
epithelial and endothelial cell destruction. Significant interstitial
inflammation and fibroblast proliferation remained, however, in
surfactant-treated lungs exposed to continuous hyperoxia.
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LETTER |
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Abstract
Letter
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Role of Surfactant and Hyperoxia
To the Editor: The recent companion papers by Huang et al. and Piantadosi et al. at Duke (13, 15) represent a most interesting study into the pathophysiology of hyperoxic lung injury and its attenuation by exogenous surfactant. Their finding that "the interstitial PMN (polymorphonuclear leukocyte) volume in the O2 + surfactant lungs was not significantly different than the value for the O2 group" might suggest a physical rather than a biological cause, especially considering the accompanying fluid shifts, consistent with their morphological evidence for compromised fluid barriers and the "better preservation of epithelial integrity" imparted by exogenous surfactant. It would therefore seem unfortunate that the authors should dismiss physical explanations for their findings because "all these surfactant preparations effectively reduce surface tension" (13), as though this were the only physical role for surfactant in the lung.From the acknowledgments listed, it would appear that the authors (13) might have been advised of only the conventional Hawgood-Clements (H-C; so-called "bubble") model (15) for the role of surfactant in the alveolus, the debate on the validity of which has been largely suppressed until recently (10, 16). This model is based on the assumption that surface-active phospholipid (SAPL) locates only at the air-aqueous interface of a continuous aqueous hypophase assumed to line the alveolus where, for reasons of surface curvature, it must reduce surface tension to "near zero" at end expiration, at least. Such a concept has been described as "absurd" (2) for reasons of basic physics, whereas other shortcomings of this model have been discussed in detail elsewhere (8, 10, 16).
Exosurf has been well designed to spread rapidly across an air-aqueous interface, reducing surface tension in doing so, thus making it well suited for assisting air inflation of a neonatal lung, which starts as essentially "wet." However, clinical success in treating respiratory distress syndrome does not necessarily validate the H-C model. Surfactants are attracted to many interfaces, including those of solids, and have been much studied in the physical sciences for the many highly desirable properties that they can impart when reversibly bound, i.e., adsorbed to those surfaces in the true physicochemical sense of that word, sometimes termed "chemisorption" (1). Few synthetic surfactants, if any, that reduce the surface tension of water do not adsorb to other interfaces, and this would also appear to apply to SAPL on tissue.
Ultrastructural evidence for a surfactant layer adsorbed to pulmonary epithelium takes three forms: electron microscopy, epifluoresence microscopy, and an appreciable degree of hydrophobicity imparted to pulmonary epithelium when this tissue surface is exposed to surfactant (11). Moreover, at the alveolar level in adult lungs, any surface fluid tends to collect as "pools" at the septal corners, or "pits" elsewhere, rather than wet the surface and form a continuous bubble lining (4). This distribution of water would seem far more likely to arise in the normal alveolus under the influence of homeostatic forces maintaining fluid balance than the continuous liquid lining of the bubble (H-C) model, for which no mechanism for control of its thickness has ever been offered by its proponents. Our efforts, and especially the superb electron micrographs of Ueda and co-workers (17, 19), clearly demonstrate an oligolamellar layer of SAPL lining on epithelium with no intervening aqueous hypophase. Such a coating is confirmed by epifluorescence microscopy (18). Proponents of the bubble model, however, could argue that these are artifacts, because Ueda et al. (19) and ourselves substitute tannic acid for much of the conventional gluteraldehyde as fixative, since aldehydes destroy hydrophobic surfaces (20). Even when using more conventional fixatives for his long and illustrious career devoted to lung morphology, Weibel (21) concludes that "the osmiophilic lining (of surfactant) follows the epithelial surface rather than the interface with air." Recognized by its characteristic interlaminar spacing of 45 Å, oligolamellar SAPL has also been demonstrated "bridging" intercellular junctions in various tissues, as though rendering them "tight" by "caulking" (3, 9).
Adsorbed layers of synthetic surfactants are widely used industrially as barriers to water or hydrated ions, and this would appear to hold for SAPL, where a monolayer can increase resistance to ions as small as hydrogen ions by an order of magnitude (12). There is also much indirect evidence for barrier properties imparted by truly adsorbed SAPL in vivo (7). Pulmonary SAPL can impart water repellency to a surface otherwise exposed to air (6), whereas, in the absence of air, e.g., in the peritoneal cavity, exogenous SAPL has been shown to improve ultrafiltration when added to the dialysate in continuous ambulatory peritoneal dialysis (14).
Hence, there would seem to be a good case for Huang et al. and Piantadosi et al. (13, 15) to consider the fluid barrier derived from the adsorption of SAPL from Exosurf as a possible physical mechanism explaining their results on hyperoxic lung injury. Speaking generally, in considering the vast wealth of knowledge of surfactants available in the physical sciences, it seems unfortunate that only those few aspects related to an air-aqueous interface should have been permitted to enter the respiratory literature.
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REFERENCES |
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References
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1.
Adamson, A. W.
Physical Chemistry of Surfaces (2nd ed.). New York: Wiley, 1967, p. 454.
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S. G. Simonson,
T. A. Fawcett,
R. E. Moon,
P. J. Fracica,
M. G. Menache,
C. A. Piantadosi,
and
S. L. Young.
Artificial surfactant attenuates hyperoxic lung injury in primates. I. Physiology and biochemistry.
J. Appl. Physiol.
78:
1816-1822,
1995
14.
Krack, G.,
G. Viglino,
P. L. Cavalli,
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15.
Piantadosi, C. A.,
P. J. Fracica,
F. G. Duhaylongsod,
Y.-C. T. Huang,
K. E. Welty-Wolf,
J. D. Crapo,
and
S. L. Young.
Artificial surfactant attenuates hyperoxic lung injury in primates. II. Morphometric analysis.
J. Appl. Physiol.
78:
1823-1829,
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16.
Scarpelli, E. M.,
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Surface monolayer theory does not explain surfactant function in vivo.
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Ueda, S.,
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Ueda, S.,
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Ueda, S.,
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Brian A. Hills Paediatric Respiratory Research Centre Mater Children's Hospital South Brisbane, Queensland 4101, Australia |
To the Editor: We thank Hills for his comments and his interest
in our work. He offers a unique perspective on the results of our study
with O2 injury in the anesthetized ventilated primates (2,
4, 5, 7). Because our studies have been focused on the role of a
natural and an artificial surfactant in reducing O2
toxicity, we do not feel that an extended response to comments about
the basic physiology of lung surfactant would be appropriate. We
subscribe to what appears to be the majority view of surfactant as an
important component in determining the mechanical behavior of mammalian
lungs. Its profound lowering of surface tension upon compression of an
interfacial film and substantial hysteresis has been found in many
experiments over the past several decades. With regard to the
morphology and continuity of the alveolar epithelium, in particular of
the surface-lining layer, we would add to Hills' comments the
observations of Manabe (6), Williams (8), and of Bastacky et al. (1).
We interpret these studies as showing that the alveolar lining layer is
continuous; although there are complex forms in the hypophase, these
freeze-fracture images are consistent with a monolayer at the
air-liquid interface.
The mechanisms responsible for the results of our studies, i.e., that
an artificial surfactant protected primates against O2
injury but that a natural surfactant had less benefit, are not entirely
clear (2, 4, 5, 7). Hills' questions may be taken to imply that the
protection was due less to surface forces than to some other property
of the artificial surfactant. This conclusion, in fact, was stated in
the discussion of the investigation (5), and we believed that effects
other than surface forces were likely contributing to the protection
against O2 toxicity. To explore that possibility, other
studies have been done with the individual components of the artificial
surfactant (Exosurf; Glaxo Wellcome), including the detergent
Tyloxapol. We found that Tyloxapol, a material unable to reduce surface
tension to very low levels, was an independently effective agent,
capable of protecting against lethal O2 toxicity in rats
when administered by instillation (3).
A physical or chemical interaction of the artificial surfactant (or its
components) with reactive O2 species is an appealing prospect for explaining the protective effects of artificial surfactant in pulmonary O2 toxicity in the baboon.
We would thus be in agreement with the broad interpretation by Hills
that a physical characteristic of the surfactant, other than its
surface-tension-lowering properties, might have been important in our
findings.
REPLY
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Abstract
Letter
References
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REFERENCES |
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Top
Abstract
Letter
References
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1.
Bastacky, J.,
C. Y. Lee,
J. Goerke,
H. Koushafar,
D. Yager,
L. Kenaga,
T. P. Speed,
Y. Chen,
and
J. A. Clements.
Alveolar lining layer is thin and continuous: low-temperature scanning electron microscopy of rat lung.
J. Appl. Physiol.
79:
1615-1628,
1995
2.
Fracica, P. J.,
C. A. Piantadosi,
F. G. Duhaylongsod,
J. D. Crapo,
and
S. L. Young.
Natural surfactant and hyperoxic lung injury in primates. II. Morphometric analysis.
J. Appl. Physiol.
76:
1002-1010,
1994
3.
Ghio, A. J.,
P. J. Fracica,
S. L. Young,
and
C. A. Piantadosi.
Synthetic surfactant scavenges oxidants and protects against hyperoxic lung injury.
J. Appl. Physiol.
77:
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1994
4.
Huang, Y.-C. T.,
T. A. Fawcett,
R. E. Moon,
P. J. Fracica,
S. P. Caminiti,
F. J. Miller,
S. L. Young,
and
C. A. Piantadosi.
Natural surfactant and hyperoxic lung injury in primates. I. Physiology and biochemistry.
J. Appl. Physiol.
76:
991-1001,
1994
5.
Huang, Y.-C. T.,
A. C. Sane,
S. G. Simonson,
T. A. Fawcett,
R. E. Moon,
P. J. Fracica,
M. G. Menache,
C. A. Piantadosi,
and
S. L. Young.
Artificial surfactant attenuates hyperoxic lung injury in primates. I. Physiology and biochemistry.
J. Appl. Physiol.
78:
1816-1822,
1995.
6.
Manabe, T.
Freeze-fracture study of alveolar lining layer in adult rat lungs.
J. Ultra Res.
69:
86-97,
1979.
7.
Piantadosi, C. A.,
P. J. Fracica,
F. G. Duhaylongsod,
Y.-C. T. Huang,
K. E. Welty-Wolf,
J. D. Crapo,
and
S. L. Young.
Artificial surfactant attenuates hyperoxic lung injury in primates. II. Morphometric analysis.
J. Appl. Physiol.
78:
1823-1831,
1995.
8.
Williams, M. C.
Freeze-fracture studies of tubular myelin and lamellar bodies in fetal and adult rat lungs.
J. Ultra Res.
64:
352-361,
1978.
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Claude A. Piantadosi Yuh-Chin Tony Huang Stephen L. Young Division of Pulmonary and Critical Care Medicine Department of Medicine Duke University Medical Center Durham, North Carolina 27710 |
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