When it comes to inflammation, too much of a good thing can be deadly

When it comes to inflammation, too much of a good thing can be deadly. In some severely injured patients, this normal healing process can develop into a lethal, whole-body response, including bloodstream infection (sepsis) and multiple organ failure. How and why inflammation turns from healing to harming is still mysterious, so doctors can't accurately predict how each injured patient will fare.

To address these issues, scientists have produced the genomic equivalent of a time-lapse movie, tracking the activity of thousands of genes through the course of body-wide inflammation. The research appears in the August 31 advanced online issue of Nature.

"This work represents a major step in understanding inflammation in severely injured or burned patients. We hope this knowledge eventually will help physicians better predict patient outcomes and tailor treatments accordingly," said Jeremy M. Berg, Ph.D., director of the National Institute of General Medical Sciences (NIGMS), the component of the National Institutes of Health that funded the research.

The study is the result of a collaborative effort funded by an NIGMS "glue grant." Glue grants bring together scientists from diverse fields--in this case surgery, critical care medicine, genomics, bioinformatics, immunology and computational biology--to solve major, complex problems in biomedical science that no single laboratory could address on its own.

To identify all the genes involved in responding to critical injury, the Inflammation and the Host Response to Injury glue grant team injected healthy volunteers with bacterial endotoxin. This molecule causes body-wide inflammation similar to sepsis, with one important difference--it is well-defined and lasts only 24 hours. By comparing the changes in gene activity caused by endotoxin exposure with those caused by trauma, the researchers hope to identify the molecular markers that spell sepsis.

The research team zeroed in on white blood cells, which help fight infection and disease and trigger inflammation. The scientists analyzed the activity of tens of thousands of genes from these cells, which were taken from the volunteers at regular intervals over 24 hours. Because this research plots the course of the inflammatory response over time, it is particularly valuable, according to Scott D. Somers, Ph.D., NIGMS program director of this glue grant. "In the case of injury, time is critical. To provide the best treatment, doctors need to know how the human body responds in the moments and days after an injury," he said. "No other study of injury or inflammation has tracked changes to the entire human genome over time."

The research team found that, of the 5,000 or so genes that fluctuated in response to endotoxin, more than half were turned down, causing the blood cells to be less metabolically active. This seems surprising, as one would expect genes required for healing to be turned up and for white blood cells to be more, not less, active. Although other research groups have seen similar genetic results in animals, scientists don't yet have an explanation for this counterintuitive response.

Understanding inflammation requires knowing not just which genes are involved, but how those genes interact with each other. To investigate this, the group turned to a knowledge base compiled by Ingenuity Systems, Inc. of Mountain View, Calif., that includes 200,000 published reports on more than 8,000 human, rat and mouse genes and their genetic interactions. This tool enabled the group to uncover about 300 genes and several genetic pathways not previously known to be involved in inflammation.

The Nature article is the second in a planned series of papers that aim to improve understanding of the human response to injury. In its first paper, published in March in the Proceedings of the National Academy of Sciences, the research team described the development of a microarray technique to analyze the entire genome of white blood cells from healthy volunteers and critically injured patients. Next, the team plans to study gene and protein activity in the white blood cells of a large group of trauma and burn patients over longer periods of time.

The glue grant team includes scientists from Stanford Genome Technology Center in Palo Alto, Calif.; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School in New Brunswick, N.J.; Ingenuity Systems, Inc. in Mountain View, Calif.; University of Florida College of Medicine in Gainesville; Washington University in St. Louis, Mo.; University of Rochester School of Medicine in Rochester, N.Y.; and Massachusetts General Hospital, Harvard Medical School in Boston.