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Potential new way of treating inflammatory diseases identified
September 14, 2007BETHESDA, Md. - Scientists have shown for the first time that platelets, the cells needed for blood clotting, help white blood cells called neutrophils fight inflammation. The discovery was made by Ralph Kettritz, Professor of Medicine at the Medical Faculty of the Charite and investigator at the Max Delbrueck Center for Molecular Medicine, Berlin, Germany, and colleagues. The results of the study could lead to new anti-inflammatory compounds for the treatment of inflammatory vascular injury.
"We found an entirely new mechanism by which neutrophils induce inflammation," Kettritz says. "So far, scientists have shown that platelets form clots and neutrophils can cause symptoms of inflammation, such as swelling, redness, and heat. In this study, we show that platelets and neutrophils sometimes work together to heal a wound or fight an infection."
The new study, to be published in the September 21 issue of the Journal of Biological Chemistry, was selected as a "Paper of the Week" by the journal's editors, meaning that it belongs to the top one percent of papers reviewed in significance and overall importance.
During inflammation - a protective reaction from the tissues following a wound or infection - white blood cells attack bacteria and platelets form clots that close any potential wound. White blood cells called neutrophils are the first to launch an attack against the bacteria. They are attracted by substances, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), that are released at the early stages of inflammation. Once activated, neutrophils engulf and destroy bacteria and damaged tissue.
In addition to neutrophils, two other types of white blood cells, called macrophages and lymphocytes, also engage in the fight against bacteria. These cells are activated by a chemical compound called tumor necrosis factor (TNF) released by the neutrophils. Although there are several ways by which neutrophils release TNF, Kettritz and colleagues found that neutrophils can be stimulated to produce TNF in a totally new and different way.
"Usually, TNF is produced when specific chemicals bind to proteins called receptors on the surface of a neutrophil, which tells the cell that it should make TNF," Kettritz says. "This time, we found that a neutrophil can acquire receptors that are not already present on its surface and use them to stimulate the production of TNF."
The receptors, called GPIIb/IIIa, are sent to neutrophils by platelets. Like a letter sent in an envelope, these receptors are packaged in vesicles called microparticles that, when they reach a neutrophil, bind to its surface and release the receptors. Once released, the receptors are incorporated into the neutrophil's cell membrane.
Kettritz and his team also found that these newly-acquired receptors did not work alone. To stimulate neutrophils to produce TNF, the GPIIb/IIIa receptor works in tandem with the receptor for GM-CSF (the substance produced during the early stages of inflammation). The scientists found that the neutrophil produces TNF both when GPIIb/IIIa binds to a protein outside the cell called fibronectin and when the GM-CSF receptor binds to GM-CSF.
"We have shown for the first time that platelets can, by using microparticles, help other cells - in this case, neutrophils - respond to inflammation," Kettritz says. "We also found for the first time that receptors involved in blood clotting also trigger an inflammatory response."
These results may help devise new drugs against several types of inflammation by targeting the GPIIb/IIIa receptors acquired by neutrophils. In particular, drugs currently used to prevent blood clotting by inhibiting GPIIb/IIIa receptors on platelets may be used against inflammation.
Kettritz and colleagues tested three of these drugs - abciximab, epifibatide, and tirofiban - on cell cultures in which neutrophils had received the GPIIb/IIIa receptors from platelets and confirmed the drugs' effects on inflammation. The scientists showed that all three drugs inhibited the production of TNF, which reduced inflammation in these cells. These results also led the researchers to speculate that some of the beneficial effects of the three drugs on patients with acute coronary syndrome result from their anti-inflammatory properties.
If the drugs' effects are confirmed in clinical trials, they could be used against several types of inflammation that include acute vasculitis, an inflammation of blood vessels that can affect any organ in the body. Also, the drugs have been used successfully to treat acute coronary syndrome, which refers to certain types of heart attack and unstable angina. The new results show that these beneficial effects may be due not only to their anti-clotting properties, but also to their anti-inflammatory qualities.
"The results of this study are very encouraging," Kettritz says. "Although specific drugs that target GPIIb/IIIa receptor actions on neutrophils may need to be developed in the future, these three drugs can now be tested in clinical trials, which could make them - or modified versions of them - new anti-inflammatory drugs."
American Society for Biochemistry and Molecular Biology
During inflammation - a protective reaction from the tissues following a wound or infection - white blood cells attack bacteria and platelets form clots that close any potential wound. White blood cells called neutrophils are the first to launch an attack against the bacteria. They are attracted by substances, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), that are released at the early stages of inflammation. Once activated, neutrophils engulf and destroy bacteria and damaged tissue.
In addition to neutrophils, two other types of white blood cells, called macrophages and lymphocytes, also engage in the fight against bacteria. These cells are activated by a chemical compound called tumor necrosis factor (TNF) released by the neutrophils. Although there are several ways by which neutrophils release TNF, Kettritz and colleagues found that neutrophils can be stimulated to produce TNF in a totally new and different way.
"Usually, TNF is produced when specific chemicals bind to proteins called receptors on the surface of a neutrophil, which tells the cell that it should make TNF," Kettritz says. "This time, we found that a neutrophil can acquire receptors that are not already present on its surface and use them to stimulate the production of TNF."
The receptors, called GPIIb/IIIa, are sent to neutrophils by platelets. Like a letter sent in an envelope, these receptors are packaged in vesicles called microparticles that, when they reach a neutrophil, bind to its surface and release the receptors. Once released, the receptors are incorporated into the neutrophil's cell membrane.
Kettritz and his team also found that these newly-acquired receptors did not work alone. To stimulate neutrophils to produce TNF, the GPIIb/IIIa receptor works in tandem with the receptor for GM-CSF (the substance produced during the early stages of inflammation). The scientists found that the neutrophil produces TNF both when GPIIb/IIIa binds to a protein outside the cell called fibronectin and when the GM-CSF receptor binds to GM-CSF.
"We have shown for the first time that platelets can, by using microparticles, help other cells - in this case, neutrophils - respond to inflammation," Kettritz says. "We also found for the first time that receptors involved in blood clotting also trigger an inflammatory response."
These results may help devise new drugs against several types of inflammation by targeting the GPIIb/IIIa receptors acquired by neutrophils. In particular, drugs currently used to prevent blood clotting by inhibiting GPIIb/IIIa receptors on platelets may be used against inflammation.
Kettritz and colleagues tested three of these drugs - abciximab, epifibatide, and tirofiban - on cell cultures in which neutrophils had received the GPIIb/IIIa receptors from platelets and confirmed the drugs' effects on inflammation. The scientists showed that all three drugs inhibited the production of TNF, which reduced inflammation in these cells. These results also led the researchers to speculate that some of the beneficial effects of the three drugs on patients with acute coronary syndrome result from their anti-inflammatory properties.
If the drugs' effects are confirmed in clinical trials, they could be used against several types of inflammation that include acute vasculitis, an inflammation of blood vessels that can affect any organ in the body. Also, the drugs have been used successfully to treat acute coronary syndrome, which refers to certain types of heart attack and unstable angina. The new results show that these beneficial effects may be due not only to their anti-clotting properties, but also to their anti-inflammatory qualities.
"The results of this study are very encouraging," Kettritz says. "Although specific drugs that target GPIIb/IIIa receptor actions on neutrophils may need to be developed in the future, these three drugs can now be tested in clinical trials, which could make them - or modified versions of them - new anti-inflammatory drugs."
American Society for Biochemistry and Molecular Biology
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