“While the biological sequence of events is triggered by cardiac arrest, the death and disability associated with this event is the result of a broader systemic injury caused by the initial loss of blood flow and subsequent tissue inflammation once blood circulation is restored,” said University of Rochester Medical Center neurologist Marc Halterman, M.D., Ph.D., the principal investigator of the study. “In fact, it is the cumulative effect of this systemic injury on the brain – and not the heart – that ultimately leads to mortality in the disorder.”
Each year, some 400,000 Americans suffer cardiac arrest. Despite improvements in pre-hospital resuscitation and the widespread use of induced hypothermia, which can help protect tissue from damage due to lack of blood flow, fewer than 30,000 (7.6 percent) cardiac arrest patients will ultimately survive to hospital discharge.
Within minutes of resuscitation, a complex sequence of events unfolds throughout the body involving the cardiovascular, immune, and respiratory systems. The tissue damage caused by the cessation and restoration of blood flow combined with pro-inflammatory factors released from the gastrointestinal tract triggers a robust systemic inflammatory response.
These molecular cues in turn activate circulating neutrophils, which serve as the immune system’s “first responders” channeling them to sites of injury where they inadvertently cause further damage. Scientists speculate that this chain of events causes the immune system to go into overdrive and immune cells, including neutrophils, eventually work their way into the central nervous system where they attack and kill brain cells.
“While we typically associate neutrophils with the immune system’s first line of defense against invading pathogens, in the aftermath of a cardiac arrest they may actually act more like the enemy within by adding fuel to the fire,” said Halterman.
The attack on the brain is delayed and peaks days after arrest; consequently, scientists speculate that by focusing on the early steps in this response they may be able to find a way to head neutrophils off at the pass by preventing their activation and mobilization into tissue that is attempting to recover from the initial effects of the loss of blood flow. The new research will focus primarily on the lungs as a potential site of therapeutic intervention where the activation of neutrophils could be modified or prevented.
Because of the complex, multi-system nature of the project, the research will bring together a team of scientists, including Michael O’Reilly, Ph.D. and Arshad Rahman, Ph.D. with the Department of Pediatrics, and Minsoo Kim, Ph.D. with the Department of Microbiology and Immunology. The National Institute of Neurological Disorders and Stroke (NINDS) will fund work on the project. The initial studies were supported pilot funds from the Schmitt Program on Integrative Brain Research to Halterman and O’Reilly. Additional support will be provided through a recent fellowship from the NINDS awarded to Nguyen Mai, an M.D./Ph.D. student in Halterman’s lab, who played a key role in collecting the preliminary data required for the grant applications.
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