Published: Sept. 4, 2003
Updated: Nov. 3, 2004
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By Duke Medicine News and Communications
Durham, NC -- New insights into how the body eliminates dead cells could lead to new approaches for treating conditions including lupus and cancer, or for preventing infections following trauma. Researchers at Duke University Medical Center and the Durham Veterans Administration Hospital say the specialized cells that clear dead cells from the body have a much more complicated -- and important -- role than scientists previously understood.
Most human cells die through a process known as apoptosis, or "programmed cell death," and are rapidly removed from the body. In contrast, necrotic death occurs when cells die from injury or disease. Increased amounts of DNA from dead cells can be measured in the blood following a wide range of medical events including trauma, heart attacks, blood clots to the lung and chemotherapy treatment. Best known as the molecule of heredity, DNA may perform other activities when it is released from dead cells and appears in the blood.
Dead cells are cleared from the body by macrophages, scavenger cells of the immune system. When macrophages do not remove dead cells, the contents of the dead cells, including the DNA, can trigger a response from the immune system, which may eventually weaken the body and leave it susceptible to infection, a common complication following trauma. For people with lupus, the contents of the dead cells, especially DNA, may form immune complexes with antibodies that can cause inflammation that is not only painful but also damaging to organs such as the kidneys.
Scientists have long believed DNA from dead cells is present in the bloodstream only when macrophages become overwhelmed with more dead cells than they can remove. In other words, the contents of the dead cells "overflow" from the macrophages. David Pisetsky, M.D., professor of medicine and chief of the division of rheumatology and immunology at Duke University Medical Center, and colleagues recently discovered this may not be the case. The Duke team reports their findings, from studies funded by the Alliance for Lupus Research, in the Sept. 15, 2003, issue of the journal Blood.
The Duke team was surprised while performing a series of experiments to determine whether administration of a large amount of apoptotic and necrotic cells would cause an increased amount of DNA to appear in the blood of mice. In their first experiment, the researchers found that injecting mice with a large quantity of dead cells indeed resulted in increased DNA in the mice's blood.
In the next experiment, they engineered mice lacking macrophages and injected the mice with a large quantity of dead cells. Because macrophages were not present to remove the dead cells, the team expected to find all of the dead cell DNA in the bloodstream. Instead, they found none.
"This result was totally unexpected, and caused us to step back and consider how the macrophages function to remove cell waste," Pisetsky said. Without macrophages, his team eventually theorized, dead cells cannot be broken down efficiently enough for DNA to appear in the bloodstream at a detectable level. Cells not processed by macrophages and removed from the body may accumulate and cause inflammation.
"What we hypothesize is that uptake by macrophages is not just part of the process, but is absolutely crucial to the appearance of DNA from dead cells in the blood," Pisetsky said. "The macrophages can't be bypassed by the dead cells, even if there is more cell DNA than they can process."
According to the researchers, this would mean that DNA from dead cells appears in the blood only when macrophages "fill" to capacity and perhaps then die and release all of their contents, including the DNA from the engulfed cells.
"If we are indeed correct," said Pisetsky, "then macrophages play a much more crucial role than previously thought. This finding could potentially have implications for the treatment of lupus and other inflammatory conditions."
The researchers said macrophages might be reinforced to clear larger amounts of dead cells, thus reducing the amount of DNA and other cellular molecules that pass into the blood and cause inflammation. "This mechanism could apply not only to lupus, but also to conditions like cancer, where we often intentionally kill large numbers of cells with chemotherapy and other treatments," said Pisetsky.
Likewise, bolstering macrophages could help prevent the immune response following trauma, and thereby help the body maintain normal levels of immunity to prevent subsequent infection.
The findings also may lend new insight to the function of current lupus treatment with corticosteroids, the researchers said. "Corticosteroids are one of the standard treatments for inflammation in lupus. We've always thought the steroids worked by reducing inflammation, but it may be that, in fact, they strengthen the macrophages and prevent the inflammatory response from beginning," said Pisetsky.
Joining Pisetsky in this research were Ning Jiang, M.D., of the division of rheumatology and immunology at Duke University Medical Center, and Charles Reich of the division of rheumatology and immunology at the Durham Veterans Administration Hospital.