02.08>> Sepsis    
Would you like some tea with that?  

Did you know that in the U.S. over 700,000 people are sickened and over 200,000 of them die each year from a disease called sepsis? And sadly, a small portion of the people with sepsis actually get the disease in the hospital, where they went to be treated for another condition or ailment.

Sepsis occurs when bacteria enter the blood stream, causing an infection and activating the immune system. The infection then spreads, via the blood stream, throughout the entire body. In extreme cases, the immune system cannot stop such widespread infection, but it can try nevertheless. After about 24 hours, the immune system launches an all-out attack against the infection. In doing so, it causes organ failure and can kill you within two or three days.

It is very difficult to manage and prevent sepsis. Within 24 hours of contracting an infection, it can spread throughout the body and induce the septic reaction. The immune system is activated and the patient will get progressively worse before doctors can determine that sepsis is the cause of the illness.

What causes the immune system to begin a suicide mission against the infection? Dr. Haichao Wang of the Feinstein Institute for Medical Research has found one answer to the question. In a previous study, Dr. Wang and his collaborators Dr. Kevin J. Tracey and Dr. Andrew E. Sama identified a late proinflammatory mediator called High Mobility Group Box 1 or HMGB1 that is responsible for the immune response. HMGB1 is a chemical found in white blood cells that does not begin to act until 24 hours after the initial infection.

Dr. Wang identified this protein by conducting in in vitro experiments. The researchers incubated the white blood cells of mice in a culture dish along with a bacterial toxin called lipopolysaccharide or LPS. (Note: remember LPS. It shows up below.) At different time intervals (from 6 to 18 hours) after incubation, small amounts of fluid were removed from the dish and analyzed for possible mediators. HMGB1 is one primary protein released by activated white blood cells.

To make sure this protein was specific for the bacterial toxin, Dr. Wang demonstrated HMGB1 release only from the white blood cells of mice sensitive to LPS. The cells of LPS-resistant mice did not produce HMGB1 in spite of stimulation with bacterial toxin.

The next step was to determine if HMGB1 was released by mice in response to an LPS challenge. To do this, the levels of HMGB1 protein were measured in mice given bacterial endotoxin. The protein appears in the circulation 12 to 16 hours, and peaks approximately 32-72 hours after LPS challenge, according to Dr. Wang. HMGB1 has also been observed in human patients with sepsis, and significantly elevated levels have been found in patients who died from severe sepsis.

The Good News

To find ways to combat HMGB1, Dr. Wang and his team immunized mice with HMGB1 antibodies. If the HMBG1 antibodies could prevent an infection, the animals would recover from the infection and have a better chance of survival. Dr. Wang found that immunizing mice prevented the septic reaction and a large number of animals survived.


Green Tea Salvia

Top: Danggui (Angelica sinensis). Bottom row: Green Tea (Camellia sinensis), Danshen (Salvia miltiorrhiza).

But it is hard to produce HMGB1 antibodies, so Dr. Wang and his colleagues went in search of a chemical that would inhibit the release of HMGB1 from immune cells. This would allow doctors time to identify the infection and destroy it with antibiotics.

The researchers turned to traditional Chinese herbal medicine. They tested many chemicals found in more than two-dozen herbal teas and medicines. To test each chemical, the scientists induced a bacterial infection in mice and then watched to see if the characteristic septic reaction took place. Dr. Wang found that the chemical in several medicinal herbs, Danggui (Angelica sinensis), Danshen (Salvia miltiorrhiza) and Green Tea (Camellia sinensis), effectively inhibited HMGB1 so that the immune system did not launch an overzealous attack against the infection and the mice survived most of the time.

“This is a potentially very important finding,” said Dr. Wang. “We’re looking at saving potentially 50,000 lives a year in American hospitals.” There is still much more work ahead, as the chemical enters pre-clinical trials in humans, but Dr. Wang is optimistic. “Who knew,” said Dr. Wang, “that the tea Eastern peoples have been drinking for thousands of years could be the answer we were looking for.”

Dr. Wang recommends drinking green tea. “It may have other health effects,” says Dr. Wang. He also explained that the dose of herb given to the mice is the equivalent of drinking about 10 cups of green tea. Since green tea has caffeine in it, he recommends drinking decaffeinated tea particularly for those people with kidney or other health problems.

Dr. Haichao Wang is Director of the Laboratory of Emergency Medicine at the Feinstein Institute for Medical Research and Chief of the Basic Science Research Program at North Shore University Hospital, both in Manhasset, New York, as well as an Associate Professor of Emergency Medicine at the New York University School of Medicine in New York City. Dr. Wang received his Bachelor’s and Master’s degrees in China and came to the United States 20 years ago to earn his Ph.D. He was trained as a basic scientist in China and became interested in traditional Chinese medicine when he moved to the US.


Dr. Haichao Wang
Dr. Haichao Wang

Dr. Wang's Research Team
Dr. Wang's Research Team [enlarge]

A Green Tea Summary [enlarge]
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What A Year! is a project of the Massachusetts Society for Medical Research.

And it is funded by a grant from The William Townsend Porter Foundation.


To Learn More

  • Chen, Xiaotian, Wei Li, and Haichao Wang. "More tea for septic patients? --Green tea may reduce endotoxin-induced release of high mobility group box 1 and other pro-inflammatory cytokines." Medical hypotheses 2006;66:660-663.
  • Li, Wei, Jianhua Li, Mala Ashok, Rongquian Wu, Dazhi Chen, et al. "A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1." Journal of Immunology. 2007;178:3856-3864.
  • Li, Wei, Mala Ashok, Jianhua Li, and Huan Yang. "A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1." Plos One. 2007;2:1-11.
  • Wang, Haichao, Ona Bloom, Minghuang Zhang, Jaideep Vishnubhakat, Michael Ombrellino, et al. "HMG-1 as a late mediator of endotoxin lethality in mice." Science 1999;285:248-251.
  • Wang, Haichao, Wei Li, Jianhua Li, Beatriz Rendon-Mitchell, Mahendar Ochani, et al. "The aqueous extract of a popular herbal nutrient supplement, Angelica sinensis, protects mice against lethal endotoxemia and sepsis." Journal of Nutrition. 2006;136:360-365.
  • Wang, Hong, Hong Liao, Mahendar Ochani, Marilou Justiniani, Xinchun Lin, et al. "Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis." Nature medicine. 2004;10:1216-1221.

For Information On Sepsis:

Rebecca Kranz with Andrea Gwosdow, Ph.D. Gwosdow Science Associates



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