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Focus on body’s tiny ‘first responders’ may improve injury care

While more people survive traumatic injuries than ever before, largely due to the work of first responders and specialized trauma teams, researchers argue that more focus should be directed at the first responders of the body’s immune system to improve care.

Traumatic injuries claim the lives of nearly 200,000 Americans each year and send 27 million to emergency rooms at a cost of $670 billion.

These minuscule first responders can overreact and spiral out of control—leading to death days or weeks after an injury.

Tiny cells and proteins react immediately when the body suffers an injury, to fight its effects on tissues and organs and to clear damage. But these minuscule first responders can also overreact and spiral out of control—leading to death days or weeks after an injury.

For those who survive, that overzealous immune response can worsen long-term disability, such as lasting cognitive defects from a traumatic brain injury or loss of limb function.

A new study that appears in Nature Immunology examines what prior scientific research has revealed about the intricate nature of response and overresponse.

Their conclusion: Immunology and trauma communities need to work more closely together to translate new knowledge into better patient care.

Looking at sepsis

Senior study author Peter A. Ward, a pathologist at the University of Michigan, says he hopes the analysis will prompt a similar response to what has happened in the field of sepsis.

Survival from that syndrome, in which the body’s immune response to infection turns into a disastrous inability to control the inflammatory responses body-wide, has improved in recent years.

Ward attributes those gains to better awareness of the clinical problem of trauma among providers and the public, and to evidence-based supportive care that helps tamp down the inappropriate immune response while boosting other functions and supporting failed organs such as the lungs.

But previous studies have shown sepsis survivors still have a much higher risk of dying after “recovery” than people similar to them who didn’t battle sepsis. The long-term effects of living through a massively overzealous immune response are still being studied.

The same thing appears to be happening in trauma, says Ward. Rapid and advanced trauma care saves the patient from immediate death, but patients still die of complications or live with long-term effects on their brains and organs.

“Post-trauma sepsis is very similar to traditional patterns of infectious sepsis, though the triggers are different,” Ward says. “We need to identify the extent to which some of the approaches that work in sepsis could work in trauma and protect against progression of inflammation.”

Distress signals

The new paper summarizes dozens of findings from basic research laboratories that study the immune response to trauma.

“We found then that a strong driving force of the adverse effects of sepsis was the complement system, which consists of the pro-inflammatory factors that contribute to the multi-organ dysfunction seen in sepsis,” Ward notes.

“We now know that in trauma, no matter what the starting location is in the body, the insult triggers activation of the same cell types, which start to produce the same pro-inflammatory factors.”

For the new paper, the authors gathered evidence from studies of trauma to three common sites: the head, chest, and abdomen.

The effects of trauma on the brain, lungs, and gut—and the immune response to each kind of trauma—differ greatly.

But the bottom line for all is that the release of “distress-signal” proteins (called cytokines, chemokines, and other “danger signals”) by first-responder immune cells can quickly overwhelm the ability of other immune system cells to clear the debris.

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And that can cause those “cleanup” immune cells, such as T cells and B cells, macrophages and monocytes to shut down or even die—which means even fewer cells to respond to the microscopic cries for help coming from the trauma site. The distress-signal molecules also encourage clot formation, which can help stop blood hemorrhage but can also clog vessels and cause more damage.

“Responses that ordinarily are quite contained and limited, and will usually fade gradually, don’t diminish, which results in a spiraling cycle of overwhelming response,” says Ward. That can lead to direct damage to organs nearby or even ones far from the site of the injury.

Plus, other factors can make things even worse, such as infectious bacteria that can invade a body through broken skin, the insult of undergoing repeated operations to repair broken bones and torn tissues, medications that disrupt the body’s natural population of helpful microbes, and any underlying health issues the person had before getting injured.

In the long term

The long-term effects of trauma and sepsis often include a reduced overall immune response, or immunosuppression, because T cells and B cells can’t be replaced once they’ve died. This can put survivors at risk of repeat infection and more, collectively referred to as “immune-suppression.”

Research has not yet shown how to reverse this weakened state, although scientists are looking for options in the lab using animal models.

Another approach to balancing the innate immune response to trauma is to block the distress-signal molecules produced by the complement immune system. But the risk of going too far and interfering with lifesaving pathways that allow the body’s phagocyte cells to vacuum up infected or damaged cells is very real.

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Clinical trials are also in the works to test drugs or antibodies that can inhibit pro-inflammatory proteins produced by the complement system, called C5A, have been studied in detail, but “testing these approaches will be quite tricky, and the clinical trials will need to be carefully crafted,” Ward says.

Source: University of Michigan

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