February 1, 2002

Liver-lung communication focus of $7 million grant

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Dr. Brian Christman

Liver-lung communication focus of $7 million grant

Dr. Ken Brigham

Dr. Ken Brigham

How does the liver communicate with the lung?

It’s a $7 million question that Drs. Kenneth L. Brigham and Brian W. Christman and their colleagues at Vanderbilt University Medical Center hope to come close to answering.

It’s a well-known fact among health care professionals that the liver plays a role in causing lung inflammation during acute lung injury. But this group of researchers wants to understand the mechanism of communication between the two organs.

Discovering the answer could give clinicians other weapons in the fight against sepsis, an infectious process that claims more than 250,000 lives a year in the United States. It also could improve the outcomes for liver disease patients with acute lung injury.

“Liver-Lung Interactions in the Pathogenesis of Lung Inflammation” is a five-year program supported by a $7.1 million NIH grant through the Heart, Lung, Blood Institute. The program project grant has a unique collaboration with two principal investigators.

Brigham, Ralph and Lulu Owen Professor of Pulmonary Diseases, served as the PPG principal investigator for Vanderbilt when the grant was submitted for approval. He has since accepted a new position as associate chief of Medicine for Research and director of the Lung Research Center at Emory University in Atlanta effective April 1. Christman, associate professor of Medicine, will assume the role as principal investigator at Vanderbilt.

Christman and Brigham have been collaborating for more than 15 years. Typically, PPG research stays with the university, but Brigham will be able to conduct his portion of the project in Atlanta. It is this longstanding and productive teamwork that prompted the NIH to agree to the unusual partnership, which will highlight the use of bioinformatics and communication tools to allow for a seamless transition to foster an ongoing collaboration between both universities.

Brigham and Christman are joined by Dr. John W. Christman, professor of Medicine and chief of Pulmonary Medicine at VA, and Dr. Timothy S. Blackwell, associate professor of Medicine and Cell and Developmental Biology.

Within the entire program there are three projects and three core areas—administration, transgenic mouse and mass spectrometry cores—that support the research efforts of the projects. The collaborative effort will investigate the mechanisms of interactions between the liver and the lungs in sepsis acute lung injury syndromes.

“Clinicians and clinical investigators have long been aware of the terrible prognosis associated with acute lung injury in patients with advanced liver disease,” said Dr. Brian Christman.

“This PPG aims to dissect out several of the key mechanisms underlying liver-lung communication with an overall goal of improving outcomes for these patients. With the growing number of patients with liver disease related to chronic viral hepatitis, there is a critical need for such translational research.”

The underlying theme focuses on the fact that liver injury can signal a prolonged inflammatory response to the lungs that may result in acute lung injury and that eicosanoids play a critical role in regulating the process. Eicosanoids are fatty-acid derivatives that play a key role in mammalian cell signaling. Prostaglandins and related eicosanoids are responsible for tissue responses such as inflammation and wound repair and are increasingly implicated in many of today’s most common diseases.

By taking samples from large animal models, researchers will work on identifying and measuring the chemicals that communicate between the liver and lung. Analysis of tissue samples will discover what genes are expressed, the time sequence and pattern.

“We expect to discover interventions with clinical relevance that can be used as new therapies,” Brigham said. “For instance, we might find a drug that blocks a message from the liver that causes lung injury. Or perhaps we can alter how the lung responds to a message from the liver. We hope that there will be multiple points where we can act.”

The goal of this project is similar to the projects that discovered Protein C. That breakthrough allowed clinicians to move from treating an infection to treating the severe organ and other tissue damage that occurs during severe sepsis.

“Understanding the process of communication between the liver and the lung will help us determine the best approach to therapy—maybe something in addition to Protein C or maybe a substitute,” Brigham said. “Sepsis is such a devastating clinical situation. These are matters of life and death.”

Christman added that the number of hepatitis cases stemming from the 1970s and 1980s is causing epidemic caseloads that need immediate attention.

“Today, we are able to save about 70 percent of patients with acute lung injury, but those with advanced liver disease we are rarely able to save,” Christman said. “We have to discover, try to understand the vocabulary these organs use to communicate.

“I feel that this accomplished group of investigators will be able to create great interaction and synergy toward our goal,” he said. “There has not been much collaboration between the Pulmonary Divisions at Emory and Vanderbilt in the past. We hope the PPG will expand our horizons and bring in more ideas.

“It only seems fitting that one of Dr. Brigham’s last accomplishments at Vanderbilt, after decades of achievement, is the initiation of yet another cycle of multidisciplinary cutting-edge research.”