When it comes to inflammation, too much of a good thing can be deadly.In some severely injured patients, this normal healing process candevelop into a lethal, whole-body response, including bloodstreaminfection (sepsis) and multiple organ failure. How and why inflammationturns from healing to harming is still mysterious, so doctors can'taccurately predict how each injured patient will fare.
To address these issues, scientists have produced the genomicequivalent of a time-lapse movie, tracking the activity of thousands ofgenes through the course of body-wide inflammation. The researchappears in the August 31 advanced online issue of Nature.
"This work represents a major step in understandinginflammation in severely injured or burned patients. We hope thisknowledge eventually will help physicians better predict patientoutcomes 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 fundedthe research.
The study is the result of a collaborative effort funded by anNIGMS "glue grant." Glue grants bring together scientists from diversefields--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 couldaddress on its own.
To identify all the genes involved in responding to criticalinjury, the Inflammation and the Host Response to Injury glue grantteam injected healthy volunteers with bacterial endotoxin. Thismolecule causes body-wide inflammation similar to sepsis, with oneimportant difference--it is well-defined and lasts only 24 hours. Bycomparing the changes in gene activity caused by endotoxin exposurewith those caused by trauma, the researchers hope to identify themolecular markers that spell sepsis.
The research team zeroed in on white blood cells, which helpfight infection and disease and trigger inflammation. The scientistsanalyzed the activity of tens of thousands of genes from these cells,which were taken from the volunteers at regular intervals over 24hours. Because this research plots the course of the inflammatoryresponse over time, it is particularly valuable, according to Scott D.Somers, Ph.D., NIGMS program director of this glue grant. "In the caseof injury, time is critical. To provide the best treatment, doctorsneed to know how the human body responds in the moments and days afteran injury," he said. "No other study of injury or inflammation hastracked changes to the entire human genome over time."
The research team found that, of the 5,000 or so genes thatfluctuated in response to endotoxin, more than half were turned down,causing the blood cells to be less metabolically active. This seemssurprising, as one would expect genes required for healing to be turnedup and for white blood cells to be more, not less, active. Althoughother research groups have seen similar genetic results in animals,scientists don't yet have an explanation for this counterintuitiveresponse.
Understanding inflammation requires knowing not just whichgenes are involved, but how those genes interact with each other. Toinvestigate this, the group turned to a knowledge base compiled byIngenuity Systems, Inc. of Mountain View, Calif., that includes 200,000published reports on more than 8,000 human, rat and mouse genes andtheir genetic interactions. This tool enabled the group to uncoverabout 300 genes and several genetic pathways not previously known to beinvolved in inflammation.
The Nature article is the second in a planned series of papersthat aim to improve understanding of the human response to injury. Inits first paper, published in March in the Proceedings of the NationalAcademy of Sciences, the research team described the development of amicroarray technique to analyze the entire genome of white blood cellsfrom healthy volunteers and critically injured patients. Next, the teamplans to study gene and protein activity in the white blood cells of alarge group of trauma and burn patients over longer periods of time.
The glue grant team includes scientists from Stanford GenomeTechnology Center in Palo Alto, Calif.; University of Medicine andDentistry of New Jersey-Robert Wood Johnson Medical School in NewBrunswick, N.J.; Ingenuity Systems, Inc. in Mountain View, Calif.;University of Florida College of Medicine in Gainesville; WashingtonUniversity in St. Louis, Mo.; University of Rochester School ofMedicine in Rochester, N.Y.; and Massachusetts General Hospital,Harvard Medical School in Boston.
Materials provided by NIH/National Institute of General Medical Sciences. Note: Content may be edited for style and length.
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