Journal of Applied Physiology
Vol. 81, No. 4, pp. 1469-1470, October 1996

Invited Editorial on "Strain-induced growth of the immature lung"

Anthony L. Mansell

Department of Pediatrics, Brown University, Providence, Rhode Island 02902-0001

ARTICLE

REFERENCES

ARTICLE

THE HISTOLOGY, MORPHOMETRY, biochemistry, and mechanics of normal mammalian lungs show that the parenchyma grows and develops extensively, if not primarily, after birth. A variety of experimental postnatal disturbances have then produced abnormalities that have often teased parenchymal growth apart from parenchymal development. For example, experimental diabetes mellitus produced lungs that were lighter and contained less DNA but had more collagen, more elastin, and greater surface/volume than controls (5, 6); that is, growth was inhibited but maturation was accelerated. A common thread running through many of the experimental circumstances (weakness of respiratory muscles, atelectasis, increase in metabolic rate, pneumonectomy) that primarily affected parenchymal growth was the possibility of a mechanical cause. Brody and Thurlbeck (2) expressed this unifying concept as the "stretch hypothesis."

There is now a rich literature about the biochemical and molecular machinery by which mechanical forces regulate cell growth in many tissues (10), including lung (8, 9). A number of model systems have been developed, and some are available commercially, for mechanically stimulating tissue-cultured cells. Studies using these model systems have outlined two broad mechanisms involving "mechanogenic second messengers." In one, extracellular matrix molecules, such as fibronectin, carry the external mechanical force through the cell membrane to modify the internal tension of the cytoskeleton. Central attachment of the cytoskeleton to the nucleus then influences cell growth via nuclear events. The other broad mechanism involves activation of cell membrane-associated molecules, such as stretch-activated ion channels, which then activate cytoplasmic second messengers, such as adenosine 3,5-cyclic monophosphate, resulting in cell proliferation. Although these mechanisms are putative, they provide strong support at cellular and molecular levels for the stretch hypothesis.

Support for the stretch hypothesis at organ and tissue levels has remained largely intuitive since Cohn demonstrated, more than fifty years ago, that lung weight in rats diminished ipsilaterally after injection of wax into the pleural cavity, after thoracoplasty, and after phrenic nerve avulsion (4). The subsequently well-studied compensatory growth (pneumonectomy) model (8) has been useful for issues in postnatal lung growth about species, age, hormonal status, and blood flow but has not spoken in detail about mechanical determinants. Deficiencies of the model, in this regard, are largely technical; the thoracotomies cause profound changes in abdominothoracic mechanics and respiratory control and produce inflammatory responses that interfere with instrumentation. Thus the compensatory growth model has not addressed questions about the stretch hypothesis at the organ and tissue level. How do the lungs grow to fit the chest wall? What accounts for the remarkable constancy of end-expiratory pleural pressure at various stages of growth? Can the lungs be made to grow beyond their normal mass and cell number? If so, how persistent is the hyperplastic state and at which stage(s) of growth can it be achieved?

The model developed by Zhang et al. (12), although straightforward in concept, was something of a tour de force technically. A continuous positive airway pressure was imposed for an extended period on the unrestrained animal's respiratory system, resulting in increased absolute volume levels during tidal breathing. To characterize the volume increase, the authors use "strain" instead of the old "stretch," and this switch to more workable and demanding engineering language represents another advance. Testing a more rigorous stress/strain hypothesis for the growth changes found, they compared pressure-volume relationships in air-filled vs. saline-filled lungs. Comparison of recoil pressures under the two conditions, that is, loss of recoil when saline filled, represents the contribution of alveolar surface to the total recoil when air filled (1). If the augmented growth had occurred by simple distention, the authors expected to find less surface per unit volume and, therefore, a smaller air-to-saline difference in recoil. This is just the result that Buhain et al. (3) had produced by a similar experiment in mature dogs, where lung volume was increased by artificial airway obstruction. The fact that air-to-saline recoil did not change here, despite the impressive increase in growth, is evidence that new surface was made. That evidence calls for measurements of surface-to-volume ratios by morphometry in the new model.

Upgrading of the stretch hypothesis to a stress/strain hypothesis bids us to start applying newer concepts of lung architecture to the growing lung. These concepts focus on architecture below the alveolar level, where the lung can be viewed usefully as a passively tensed cable-and-membrane structure (11). In mature lungs, a remarkable uniformity of structure is found here; interseptal angles and the proportion of cabled to uncabled septal borders vary little despite a great variation in airspace dimensions from animal to animal (7). What happens to the apparently delicate balance of this cable-and-membrane structure as new surface is added during stress/strain-induced growth?

REFERENCES

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