Cardiac arrest affects an estimated 500,000 Americans annually, and fewer than 25% patients will survive to discharge due in large part to overwhelming CNS injury. The post-resuscitation syndrome following cardiac arrest (PCAS) encompasses the damaging effects of tissue ischemia and the delayed effects of ischemic reperfusion injury (IRI). Activation of the innate immune response is a prime mediator of the delayed microvascular damage, increased vascular permeability and progressive tissue damage observed after resuscitation. In particular, blocking leukocyte recruitment to the CNS significantly reduces the extent of brain injury observed after ischemic challenge. In this proposal we investigate the pathological consequences of peripheral inflammation on global cerebral ischemia, focusing on the relationship between lung inflammation, neutrophil priming and delayed CNS injury. These studies are based on our observation that expression of extracellular superoxide dismutase (EC-SOD) targeted to type II pneumocytes blunts neutrophil trafficking into the post-ischemic brain and confers marked neuroprotection. In this proposal we test the hypothesis that expression of EC-SOD within the lung inhibits IRI by reducing the production of damage associated molecular patterns (DAMPs) and levels of TLR4 activation required for endothelial and PMN activation. Successful demonstration that lung-brain coupling modulates delayed cerebral injury through effects on neutrophil priming may suggest new treatment strategies for patients presenting after cardiac arrest.

Public Health Relevance

Despite successful resuscitation, the majority of patients admitted to hospital following cardiac arrest succumb to the neurological injuries caused by ischemia-reperfusion injury. These studies investigate the downstream effects that lung inflammation plays in the CNS ischemic reperfusion injury, focusing on the particular anti-inflammatory effects that existing lung antioxidant systems have on delayed immune mediated injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092455-03
Application #
9240676
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Koenig, James I
Project Start
2015-05-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Mai, Nguyen; Prifti, Landa; Rininger, Aric et al. (2017) Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion. Exp Neurol 297:82-91