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2.06.2012

Stimulation of GHRH Action May Improve Pneumonia Survival

Miller School scientists are part of an international research team that may have found a way to block a second wave of death that can result from pneumonia treatment.

Antibiotics are effective at killing pneumococcus – the cause of about 50 percent of pneumonias – but as the bacterium dies, it releases toxins that can still kill patients.

Adding an agonist that mimics the action of growth hormone-releasing hormone – which ultimately enables growth – may stop that second wave, according to research published in the Proceedings of the National Academy of Sciences.

“This will exponentially improve responses in pneumonia and other diseases involving bacterial toxins,” said Andrew V. Schally, Ph.D., M.D.h.c., D.Sc.h.c., winner of the 1977 Nobel Prize for Physiology or Medicine, Distinguished Medical Research Scientist of the Department of Veterans Affairs, and Distinguished Professor of Pathology at the Miller School, a co-corresponding author.

Rudolf Lucas, Ph.D., vascular biologist at the Medical College of Georgia at Georgia Health Sciences University, also was a co-corresponding author of the study, and other Miller School co-authors were Norman Block, M.D., professor of pathology, urology, oncology and biomedical engineering and the L. Austin Weeks Family Professor of Urologic Research, and Ferenc G. Rick, M.D., Ph.D., research assistant professor of pathology and a member of the Endocrine, Polypeptide and Cancer Institute at the Miami Veterans Affairs Hospital.

The problems start when a bacterium that causes pneumonia, in this case pneumococcus, is inhaled. The infection may result in mucus buildup, cough, fever, chills, shortness of breath and other symptoms. Antibiotics are the front line treatment to kill the infection.

An unfortunate result of bacterial death is the release of pneumolysin, a toxin that can trigger formation of holes in the walls of the millions of tiny air sacs and blood vessels in the lungs. The result: fluid, blood and other products find their way into air sacs that were intended for oxygen exchange.

Pneumolysin naturally binds to cholesterol, a component of all cell membranes, including cells lining the air sacs, or alveoli. Once attached to the membrane, the toxin produces complexes that make holes in the membranes of the air sacs before escaping to do similar damage to nearby capillaries. While the close proximity of capillaries normally enables air sacs to replenish blood with oxygen and to remove carbon dioxide, the now-open exchange enables fluid and cells from the capillaries to get inside air sacs as well as the space in between them. To make matters worse, the toxin also blocks a protective sodium uptake system in the lungs that can help remove fluids. Within a few days, the pneumonia patient is back in jeopardy.

“Despite intensive and aggressive supportive care, these patients may nevertheless consequently still experience a fatal outcome,” said Schally.

Schally, winner of the Nobel Prize for the discovery of hypothalamic hormones and head of the Endocrine, Polypeptide and Cancer Institute at the Miami VA, developed the agonist that may one day make the difference for these patients. His agonist previously was shown to also help protect heart muscle in the aftermath of a heart attack.

Surprisingly, scientists at Georgia Health Sciences University (GHSU) detected receptors for growth hormone-releasing hormone in cells lining the air sacs. Classically, growth hormone-releasing hormone is produced by the hypothalamus and then goes to the pituitary, which makes and releases growth hormone. “We were asking ourselves, what is it doing there?” Lucas said.

They got a clue when they applied the agonist to the growth hormone-releasing hormone in an animal model of pneumonia, as well as human lung cells in culture: Leaking was significantly reduced and beneficial sodium uptake was restored. Conversely, when they applied a hormone antagonist – to block its action – lung cells became leaky even without toxin exposure, further indicating the hormone’s apparent role in the integrity of the lining of the air sacs and capillaries.

Because the problem is acute and affected patients experience dangerous swelling within days, the scientists believe the agonist, or a compound with a similar function, could someday be given to patients in those first few critical days to avoid the second onslaught.

As a result of the findings, extensive collaborative studies are being planned on the use of GHRH agonists to prevent edema in patients with bacterial pneumonia. The next steps include pursuing a National Institutes of Health grant to support more collaborative studies with the University of California, San Francisco, that include an isolated human lung model and a preclinical model where laboratory animals have the same course as patients: They are infected with the bacterium, then given an antibiotic. In the model for the PNAS study, scientists gave the resulting toxin directly.

Trinad Chakraborty, Ph.D., dean of the Faculty of Medicine at the University of Gieesen in Germany, developed the purified toxin used for the studies. Study co-authors Richard White, Ph.D., a GHSU pharmacologist, showed restoration of sodium uptake, and Supriya Sridhar, Ph.D., GHSU research associate, showed air sac damage resulting from applying the hormone antagonist.

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