Department of Physiology, Michigan State University, East Lansing, Michigan 48824
ONE OF THE PERKS OF TEACHING
respiratory physiology to graduate and medical students is the frequent
opportunity to discuss the pathogenic mechanisms underlying acute
lung injury and edema formation with a relatively unbiased audience.
The available textbooks designed for these students do an excellent job
of distilling and summarizing the current state of knowledge in a
manner as unambiguous as possible without burdening the student with
the unavoidable ambiguity and controversy associated with experimental data.
The distillate presented to students is hopefully an accurate
reflection of the large body of literature, much of which has been
published in the American Journal of Physiology-Lung Cellular and
Molecular Physiology, describing cardiogenic and noncardiogenic mechanisms of pulmonary edema. Noticeably absent from most of these
books, however, is a discussion of the important role of the alveolar
epithelium in "backing up" the significantly more leaky capillary
endothelium. As summarized very nicely by West (11), the
interstitial edema resulting from a breach of the capillary wall will
not proceed to alveolar flooding unless the epithelial barrier,
normally an order of magnitude tighter than the endothelium
(2), also becomes breached. Surprisingly, the body of
literature describing the factors that are crucial to the collapse of
the epithelial barrier seems tiny compared with that describing
inflammation and its effects on endothelial barrier function.
Understanding how the river initially overflows its banks is clearly
important, but once the final levee has begun to fall, turning on the
pumps and shoring up the remaining dike become equally if not more critical.
In recent years, the topic of apoptosis in the lung has
received a burst of attention from some of us enamored with the cells of the vascular endothelium, epithelium, and immune system and interstitial cell populations (4). In vivo models have
clearly indicated a physiological role for apoptosis in the
resolution of lung inflammation, in the clearance of excess stem cells
after hyperplastic repair of lung injury, and in the pathogenesis and resolution of pulmonary fibrosis (4). With regard to the
epithelium, the initial demonstration by Fine et al. (3)
that alveolar epithelial cells express functional Fas (CD95, APO1) was
followed rapidly by the finding of Hagimoto et al. (5)
that activation of Fas in vivo could induce epithelial
apoptosis followed by fibrosis.
These observations might lead one to hypothesize that the induction of
cell suicide in the epithelium would be likely to cause acute lung
injury and concomitant collapse of epithelial barrier function. This
expectation is dampened, however, by the realization that the type II
epithelium has an extremely high capacity for repair; moreover, it also
undergoes normal turnover and removal of damaged cells by
apoptosis (10), all the while maintaining high
integrity of barrier function through mechanisms yet to be elucidated.
By analogy, the intestinal epithelium has been shown to be surprisingly
resilient in terms of barrier function, even in the face of ongoing
apoptosis (1).
For these reasons, the paper by Matute-Bello et al. (6) in
this issue of the American Journal of Physiology-Lung Cellular and Molecular Physiology makes an important advance in our
understanding of acute lung injury and edema formation. These
investigators instilled recombinant human soluble Fas ligand (sFasL)
into the lungs of rabbits and thereby produced acute lung injury as
evidenced by apoptosis of alveolar epithelial cells, thickening
of alveolar walls, and increased protein in bronchoalveolar lavage
fluid. Their findings are the first to suggest a link between
Fas-induced apoptosis and collapse of the alveolar epithelial
barrier. Moreover, because the experimental instillate contained sFasL
rather than Fas-activating antibodies, these results argue against
previous suggestions (8, 9) that sFasL may not be
physiologically important as a proapoptotic stimulus.
The results reported are also consistent with the recent findings by
Matute-Bello et al. (7) that patients who die of acute respiratory distress syndrome have higher levels of sFasL in
bronchoalveolar lavage fluid. Together, the available data are
beginning to imply that a lung that is already "primed" by
endothelial damage and the resulting interstitial edema might be
"driven over the edge" by stimuli that are proapoptotic for the
cells of the epithelial levee. Theoretically, these stimuli might
include any proapoptotic signal sufficient to exceed the capacity
of the epithelium for repair. Future efforts to define these stimuli,
their interactions, and ways to block their action will be both
interesting and informative indeed.
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REFERENCES
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. D. Uhal, Dept. of Physiology, 310 Giltner Hall, Michigan State Univ., East Lansing, MI 48824 (E-mail: uhal{at}msu.edu).
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Cheek, JM,
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Fine, A,
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Matute-Bello, G,
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Schneider, P,
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West, JB.
Respiratory Physiology: The Essentials. Baltimore, MD: Williams and Wilkins, 1995, p. 45-47.