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Inflammatory response could hinder spinal cord repair

Posted on | November 4, 2009 | 161 views |

By Emily Caldwell, Research Communications

The inflammatory response following a spinal cord injury appears to be set up to cause extra tissue damage instead of promoting healing, new research suggests.

Scientists analyzing this response in mice discovered that the types of cells recruited to the site of the injury are dominated within a week by those that promote inflammation. When chronic, inflammation can prevent healing, and these inflammatory cells are believed to remain at the injury site indefinitely.

Meanwhile, similar cells that are typically involved in a later phase of injury repair and that are anti-inflammatory were found to promote effective growth of axons that connect nerve cells. However, these cells disappear shortly after an injury, making it unlikely that they get a chance to complete their work under naturally occurring circumstances.

All of the responding cells in question are macrophages, but the study revealed that they have slightly different characteristics that define their functions. The research suggests that changing the balance of how these cells are activated in favor of the anti-inflammatory macrophages could be a potential treatment strategy for spinal cord injury.

Scientists have not yet discovered a way to repair nerve cells that are damaged or killed when the spinal cord is injured. An estimated 1.3 million people in the United States are living with a spinal cord injury.

“If these pro-inflammatory macrophages are a big part of the reason cells are dying, and we can figure out how to shut off that death cascade that they start, we might be able to minimize the amount of tissue damage,” said senior study author Phillip Popovich, a professor of neuroscience and molecular virology, immunology and medical genetics at Ohio State.

“If that could be achieved by injecting a drug or giving a patient a pill for a set number of days after injury, that could improve a lot of function and quality of life for people who suffer a spinal cord injury.”

The research appears in the Oct. 28 issue of the Journal of Neuroscience.

Popovich, also director of Ohio State’s Center for Brain and Spinal Cord Repair, has known about the presence of macrophages after spinal cord injury for a long time. What he didn’t know was exactly what they did, how they did it or whether there could be more than one function among these cells.

In this study, he and colleagues compared the spinal cords of mice with injury to the spinal cords of uninjured mice. The mouse injuries resembled the most common contusion/compression spinal cord damage in humans that occurs when a vertebral bone or a disc bumps into the cord, causing a lesion and bleeding.

The researchers used chemicals to stain the spinal cords with markers that would indicate what types of cells were active at the injury site. They named the pro-inflammatory macrophages M1 cells and anti-inflammatory macrophages M2 cells.

Immediately after the injury, the researchers observed an intermingling of M1 and M2 cells at the site of the spinal cord injury. In just a few days, all of the anti-inflammatory M2 cells had disappeared. The pro-inflammatory M1 population persisted for a month after injury — the longest period scientists have ever observed.

Once they knew how these cells were distributed at an injury site, the researchers created in vitro models in which they examined the effects of M1 and M2 macrophages on neurons, the cells that make up most of the spinal cord and brain.

The M1 macrophages killed neurons or stimulated a sprouting type of growth among their axons, which function as arms on neurons that reach out to connect with other cells or to send and receive signals. This type of sprouting of axons is associated with misguided circuits and can actually cause chronic pain.

The M2 cells, on the other hand, promoted long-distance axon growth without causing toxicity. This is the kind of axon growth required to regenerate spinal cord tissue and is the type of axon growth that is normally inhibited by proteins and cells that accumulate in the spinal cord after injury.

Researchers still must determine whether changing the balance of macrophages in an injured spinal cord to favor the activation of M2 cells would be beneficial in a human body.

Popovich conducted the work with Kristina Kigerl, John Gensel, Daniel Ankeny, Jessica Alexander and Dustin Donnelly, investigators in the Center for Brain and Spinal Cord Repair. The National Institutes of Health and National Institute of Neurological Disorders and Stroke supported this research.

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