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Am J Physiol Gastrointest Liver Physiol 287: G941-G942, 2004; doi:10.1152/classicessays.00014.2004 Free Article
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EDITORIAL FOCUS

ESSAYS ON APS CLASSIC PAPERS

The basis for transport across epithelial cells

Marshall H. Montrose

Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267

ABSTRACT

This essay looks at the historical significance of two APS classic papers that are freely available online:

Ingraham RC and Visscher MB. Further studies on intestinal absorption with the performance of osmotic work. Am J Physiol 121: 771–785, 1938 (http://ajplegacy.physiology.org/cgi/reprint/121/3/771).

Visscher MB, Fetcher ES Jr, Carr CW, Gregor HP, Bushey MS, and Barker DE. Isotopic tracer studies on the movement of water and ions between intestinal lumen and blood. Am J Physiol 142: 550–575, 1944 (http://ajplegacy.physiology.org/cgi/reprint/142/4/550).

AT THE BEGINNING of the 20th century, intestinal absorption was a mysterious process that seemed to be explained by the recently developed models for diffusion and osmosis. These processes provided a rationale for the net movement of salty fluids, which faithfully followed concentration and/or osmotic gradients between the gut lumen and the blood under the simple conditions that had been examined. Into this somewhat pastoral scene erupted Maurice Visscher (Fig. 1) and colleagues, who proceeded to delve deeper into the transport of materials across the gut wall (both experimentally and conceptually) than had ever been attempted before. Among their many publications in the American Journal of Physiology and elsewhere, two publications have been selected as APS classic papers.



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  		Fig. 1. M. B. Visscher.

 
The first publication, from 1938 (1), offers an analysis of the net movement of fluid and ions from the gastrointestinal tract, using loops of ileum from anesthetized dog as the experimental model. The work was inspired both in its design and interpretation. First, the systematic substitution of luminal ions and osmolytes revealed that both chloride and sodium could be moved from the gut lumen against a concentration gradient. They noted for the first time that changes in luminal pH accompanied absorption under some circumstances and had numerous hints of the types of linked cotransporters and exchangers (e.g., Na+/H+ exchange and Cl–/HCO3– exchange) that would be discovered by others in later years. However, the most striking finding was a clear dissociation between the net transport of sodium, chloride, and fluid volume. Careful thought about the set of observations led the authors to the inexorable conclusion that bidirectional fluxes were needed to explain how to dissociate fluid and ion flux in mechanisms that can work against existing ion gradients. In other words, they had to postulate that the gut was able to simultaneously mediate fluid movement from the blood to the lumen, as well as from the lumen to the blood. They advanced the idea further by developing a simple model in which "selective transport of materials against high concentration gradients is the result of the circulation of fluid through differentially permeable membranes" (1). Thus this work also led to the concept of physically separate processes mediating absorption and secretion. This work is one foundation for developing modern concepts of diversity among the ion-transporting epithelial cells, with crypts containing secretory cells and intestinal villi (or cells at the colonic surface) having absorptive cells. This leads to the somewhat shameful admission that more than 65 years later, we are still fine tuning their discovery. Colonic crypts have the striking ability to both secrete and absorb (2, 6), ruining our comfortable assumptions but giving new excitement about exactly which cells are able to perform the opposing tasks defined by Ingraham and Visscher.

Maybe one of the strongest impacts of the 1938 article was to give Visscher the intellectual insight that net fluxes across the intestinal wall could really only be interpreted if one knows the two opposing fluxes (from lumen to blood and from blood to lumen) that together create the net flux. This concept formed the basis for another APS classic paper.

The second publication, in 1944 (5), presents one of the earliest uses of isotopes to study transport in the intestinal tract. All the more remarkable, it valiantly explores fluxes of (homemade) isotopic chloride and sodium in "heavy water" (deuterium label) to directly study the movement of all the constituents that had fascinated Visscher previously. Isotopic solutions were instilled into ligated loops of dog ileum, and the rates of isotope loss were used to directly measure the lumen-to-blood flux of each constituent. By subtracting the simultaneously measured change of net chemical amounts in the gut lumen, the authors calculated the blood-to-lumen flux. Using this method, they were able to examine how each flux route responded to changes in luminal osmolarity and ion content. The observations contained some remarkable findings for the time, giving compelling evidence for the independence of absorptive and secretory fluxes. For instance, the authors showed that although net chloride absorption increased strongly as luminal NaCl concentration increased, the rate of chloride secretion remained constant. The main surprises from studies of water flux were the rapid fluxes of water both into and out of the gut and the inability to fit the data to any reasonable model in which diffusion was the driving force for water flow. The authors showed that "experimentally derived ratios between total directional rates and net transport rates differ as much as 200-fold from the ratios predicted on the assumption that movement is by diffusion." These results paved the way for future workers to think about the role of membrane proteins and active transport in mediating ion and water transport, providing an alternative mechanism of coupling the energy of ion gradients to drive vectorial fluxes.

There is no better time to highlight the publications of Maurice Visscher and colleagues, which included some of the first isotopic measurements of water fluxes and developed the understanding of how fluid moves between the gut and the lumen. With the awarding of the 2003 Nobel Prize in Chemistry to Peter Agre for discovery of water channel proteins, we have recognition for both the starting point and the current pinnacle of our understanding of water movement across membranes.

This essay has attempted to place these APS classic papers within their scientific setting, but no essay about Visscher's work should neglect to mention his other contributions to the scientific community. Maurice Visscher was president of the APS in 1948–1949. He was a tireless and eloquent advocate of the value of animals in research, constantly wary of the "new antivivisectionists," and was publishing essays on the need for animal research until right before his death in 1983 (3). Maurice Visscher also fought for scientific freedom and civil liberties in a world that grew wary and watchful of scientists when fears of their national loyalty mounted in World War II, and he wrote a chilling account of his personal brush with the House Committee on Un-American Activities (4). Our society and science were enriched by his life and work.

FOOTNOTES


Address for correspondence: M. H. Montrose, Dept. of Molecular and Cellular Physiology, Univ. of Cincinnati, Medical Science Bldg., Rm. 4253, 231 Albert Sabin Way, Cincinnati, OH 45267 (E-mail: mhm{at}uc.edu)

REFERENCES

  1. Ingraham RC and Visscher MB. Further studies on intestinal absorption with the performance of osmotic work. Am J Physiol 121: 771–785, 1938.[Free Full Text]
  2. Singh SK, Binder HJ, Boron WF, and Geibel JP. Fluid absorption in isolated perfused colonic crypts. J Clin Invest 96: 2373–2379, 1995.[ISI][Medline]
  3. Visscher MB. Current attempts to prevent the use of animals in medical research. JAMA 245: 1223–1224, 1981.[CrossRef][ISI][Medline]
  4. Visscher MB. Maurice B. Visscher. A half-century as a scientist-citizen. A past presidential address update. Physiologist 22: 15–21, 1979.[Medline]
  5. Visscher MB, Fetcher ES Jr, Carr CW, Gregor HP, Bushey MS, and Barker DE. Isotopic tracer studies on the movement of water and ions between intestinal lumen and blood. Am J Physiol 142: 550–575, 1944.[Free Full Text]
  6. Welsh MJ, Smith PL, Fromm M, and Frizzell RA. Crypts are the site of intestinal fluid and electrolyte secretion. Science 218: 1219, 1982.[Abstract/Free Full Text]




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