HSC Weekly Issue Date: 8/9/2002

HSC researchers awarded two $1 million grants for lung studies

by Lori Oliwenstein

Researchers at the Keck School of Medicine’s Will Rogers Institute Pulmonary Research Center have received two $1 million-plus grant renewals from the National Institutes of Health (NIH) to continue their investigations of how the epithelial cells that line the human lung’s air sacs (or alveoli) transport molecules back and forth, how they defend against invaders and, especially, how they keep those air spaces dry and clean.

"Separating the air from the liquid space allows the air to get very close to the blood in the deep lung," explained Edward D. Crandall, the Hastings Professor and Kenneth T. Norris Jr. Chair in Medicine and chair of the Department of Medicine. "But if there is a malfunction of the alveolar epithelium, as in any lung injury, there is a likelihood that the air space will become filled with liquid—that is called pulmonary edema.

"Normally, the epithelium keeps the air spaces dry by actively pumping salt out of the air spaces—which then pulls any water along with it via osmosis. This pumping is important in keeping the air spaces dry."

Crandall, along with Zea Borok, associate professor of medicine, director of the Keck School’s Pulmonary and Critical Care Medicine Fellowship Program, and co-director, with Crandall, of the Pulmonary Research Center, recently learned that they would be getting a $1.3 million, four-year renewal of a grant to study how all of this occurs, with an emphasis on the role of the Type 1 alveolar epithelial cells (or AT1 cells). (The other major cells in the alveolar epithelium are the Type 2 cells, which are equal in number to AT1 cells, but smaller.)

The renewal, said Crandall, will allow them to exploit their new-found ability to isolate relatively pure populations of AT1 cells—an ability they alone were able to refine—and to grow them in the laboratory.

This, in turn, will allow them to manipulate and observe those cells, and get true insight into their inner workings.

"We’ve been able to get Type 2 cells to grow in the lab for about 20 years," noted Crandall. "And one of our other major contributions in this laboratory was to show that we could get Type 2 cells to differentiate into Type 1 cells in a dish. That discovery led us to the even bigger discovery that there is a pump in those cells that keeps the lungs dry. But nobody had been able to harvest Type 1 cells directly until the past two years when we developed the technology to do it. This was a major advance."

Crandall and Borok plan on perfecting their AT1 isolation and purification techniques and using them to study both the basic properties of these cells and how they respond to injury. In addition, Borok explained, "We are one of several major laboratories working on understanding the process that regulates the transdifferentiation between Type 1 and 2 cells. We can make 1s turn into 2s, and vice versa, in a laboratory dish."

And this is more than just a scientific experiment, noted Borok. "Being able to manipulate the cell types has huge practical implications," she said. "It suggests that with the right combination of growth factors and scaffolding for the cells, we might be able to create actual organs—or, at the very least, help our lungs recover after injury."

Like Crandall and Borok, Kwang-Jin Kim, associate professor of medicine and physiology and biophysics and one of the Pulmonary Research Center’s group leaders, is looking at the ways in which the lung epithelium transports molecules from the air spaces to the bloodstream. But the molecules he is looking at are much larger than the minute ions that his colleagues are considering—proteins such as albumin and immunoglobulins. His work in the field has netted him a four-year, $1.1 million NIH grant renewal.

"In small concentrations, these molecules are normal," said Kim. "But if albumin-like molecules keep building up, they can create problems by pulling water into the air spaces after them. That is why my interest is in understanding how these big serum proteins are removed from the air side of the alveolar epithelium back into the blood."

How they do this is the subject of his NIH grant.

"What we’ve discovered is that most of this large protein transport occurs across the epithelial cell, rather than between the cells," said Kim.

His group identified several albumin- and immunoglobulin-loving cell protein receptors, which grab the proteins, transport them across the cell and release them on the blood side.

"Having found the receptors," Kim said, "it is critical that we start to understand how key proteins move across the epithelial barrier in health and disease. By knowing all the basic features, we will be able to think about better therapeutics and ways to manage some of the most devastating lung diseases."