Why Organs Fail Following Massive Trauma

A new study has found several new biochemical pathways that play a central role in multiple organ failure following severe trauma.

Researchers from eight universities, led by a team from the University of Rochester Medical Center (NY, USA), took blood samples from 22 healthy subjects and from 18 consenting patients who had experienced severe trauma and were in the midst of organ failure. The researchers then used unique, clinically applicable techniques to separate out each immune cell type in the patients' blood into pure samples for study. Next they used microarray technology to generate a long list of genes that change when a patient undergoes massive trauma. They ran that list through a database of genetic information to see which of the genes changed by trauma were listed in the literature as having a role in T cell function. What emerged was a map of the likely functions of hundreds of genes and proteins related to T cell post-trauma dysfunction and their likely partners in signaling pathways.

Results showed that the expression of nearly 5,700 genes related to T cell function is changed in cases of massive trauma, as are 2,800 genes related to the function of macrophages, partnering immune cells necessary to T cell activation. Trauma had the most profound effect on just 338 of the genes, who showed at least a two-fold change in their expression. Post-traumatic genetic changes had two major effects on T cells: a marked increase in regulatory protein pathways that diminished their function, and a decrease in signals that turn them on.

Whether T cells continue to multiply depends on the action of sensitive receptor proteins on their surfaces. Some of the receptors, once activated by signaling molecules, cause the T cell to multiply, while others stop the process or cause the cell to self-destruct. Researchers in the current study identified as many as 20 new receptors on the surfaces of T cells or signaling molecules within T cells that increase their activity in the case of massive trauma to either cause anergy or apoptosis. Each pathway represents a target for the design of new drugs to reverse T cell shutdown.

"Our study proves for the first time that it is possible to identify the genetic and protein changes in specific immune cells that play a significant role in determining whether or not trauma is fatal,” said co-author Carol L. Miller-Graziano, Ph.D., a professor of surgery, and of microbiology and immunology at the University of Rochester. "Beyond trauma, we believe that the techniques established here can provide insights into many diseases that involve human immune system failure.”

The study was published in the October 17, 2006 issue of the Proceedings of the [U.S.] National Academy of Sciences (PNAS).



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University of Rochester Medical Center