Researchers target natural heparin's role in promoting infection

HOUSTON--(May 3, 2001)--Heparan sulfate, the natural heparin-like molecule that prevents blood from clotting, has been targeted by scientists at Baylor College of Medicine in Houston as an agent that plays a role in promoting infection.

According to Dr. Pyong Woo Park, an assistant professor in the section of infectious diseases in the departments of medicine and molecular and cellular biology at Baylor and principal investigator of the study, this could be a significant finding for researchers looking for ways to treat infectious pneumonia associated with high mortality rates.

Results of the study, conducted in collaboration with Harvard Medical School, are reported in the May 3 issue of Nature.

"We started by looking at functions of our body's natural heparin, heparan sulfate proteoglycans, and found that they play a role in tissue injury. When the body is exposed to injury, stress or inflammation, heparan sulfate proteoglycans are activated and secreted as one of our normal defenses to these disease conditions," Park said.

The research team found that pseudomonas aeruginosa, a major bacterial pathogen, takes advantage of this defense mechanism to promote lung infection.

Heparan sulfate is a natural mimic of the pharmaceutical product heparin, used as an anticoagulant in patients after invasive cardiovascular procedures. Using gene-targeting techniques, the researchers were able to "knock out" the heparan sulfate proteoglycan gene in mice, and they found that the absence of the natural heparin molecule enabled the animals to resist lung infection.

"After testing several drugs, we found that if we use protamine, a neutralizer of heparin, the drug would prevent infection, and furthermore, infection was also prevented when heparin digesting enzymes were administered as a nasal drug," Park said.

These results suggest that agents that neutralize heparan sulfate or prevent its activation may be targeted for novel and effective therapy against the major public health threat of infectious pneumonia.

Bacterial pneumonia is a serious complication affecting many patient groups, including those with cystic fibrosis, a genetic disorder that affects 30,000-50,000 people in the U.S alone. The majority of cystic fibrosis patients die from lung failure caused by chronic infectious pneumonia.

"One of the major problems with pneumonia and other infections is that pathogens are rapidly developing resistance to available antibiotics and we're starting to run out of effective drugs to combat serious infections. Therefore, it is imperative for us to find new methods of treatment for bacterial infections," Park said.

Experiments remain in preliminary stages, however, researchers hope the findings will one day lead to disease prevention and better therapeutic drugs.

Collaborators in the research included Dr. Merton Bernfield and Dr. Michael Hinkes at Children's Hospital, Harvard Medical School and Dr. Gerald Pier at Brigham & Women's Hospital, Harvard Medical School.