Abstract
Resolution agonists, including lipid mediators and peptides such as annexin A1 (ANXA1), are providing novel approaches to treat inflammatory conditions. Surgical trauma exerts a significant burden on the immune system that can affect and impair multiple organs. Perioperative cerebral injury after cardiac surgery is associated with significant adverse neurological outcomes such as delirium and postoperative cognitive dysfunction. Using a clinically relevant rat model of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA), we tested the pro-resolving effects of a novel bioactive ANXA1 tripeptide (ANXA1sp) on neuroinflammation and cognition. Male rats underwent 2 h CPB with 1 h DHCA at 18°C, and received vehicle or ANXA1sp followed by timed reperfusion up to postoperative day 7. Immortalized murine microglial cell line BV2 were treated with vehicle or ANXA1sp and subjected to 2 h oxygen–glucose deprivation followed by timed reoxygenation. Microglial activation, cell death, neuroinflammation, and NF-κB activation were assessed in tissue samples and cell cultures. Rats exposed to CPB and DHCA had evident neuroinflammation in various brain areas. However, in ANXA1sp-treated rats, microglial activation and cell death (apoptosis and necrosis) were reduced at 24 h and 7 days after surgery. This was associated with a reduction in key pro-inflammatory cytokines due to inhibition of NF-κB activation in the brain and systemically. Treated rats also had improved neurologic scores and shorter latency in the Morris water maze. In BV2 cells treated with ANXA1sp, similar protective effects were observed including decreased pro-inflammatory cytokines and cell death. Notably, we also found increased expression of ANXA1, which binds to NF-κB p65 and thereby inhibits its transcriptional activity. Our findings provide evidence that treatment with a novel pro-resolving ANXA1 tripeptide is neuroprotective after cardiac surgery in rats by attenuating neuroinflammation and may prevent postoperative neurologic complications.
Highlights
Resolution of inflammation was once believed to be a passive process, but we know that it involves a cascade of coordinated events that is initiated as inflammation begins [1, 2]
No deaths were reported after cardiopulmonary bypass (CPB)/deep hypothermic circulatory arrest (DHCA) in this study
After CPB/DHCA, we found a significant increase in brain levels of key pro-inflammatory cytokines such as TNF-α and MPO (Figure 1)
Summary
Resolution of inflammation was once believed to be a passive process, but we know that it involves a cascade of coordinated events that is initiated as inflammation begins [1, 2]. Defective resolution and non-resolving inflammation contribute to a chronic and maladaptive state that characterizes several diseases ranging from atherosclerosis to rheumatoid arthritis [3]. Endogenous mediators, including lipids biosynthesized from omega-3 fatty acids, gases such as carbon monoxide, and certain proteins, promote resolution of inflammation, and restore homeostasis without causing unwanted side effects by optimizing the body’s natural chemistry to safely regulate inflammatory molecules [4]. Novel treatment strategies for inflammatory conditions use “resolution agonists” to modulate and enhance these endogenous mediators and signaling pathways [5, 6]. Annexin A1 (ANXA1), a 37-kDa glucocorticoid-regulated protein, is an exemplary resolution agonist that signals through the G protein-coupled receptors FPR2/ALX and FPR1 to regulate calcium influx into the cell [7]. ANXA1 exerts potent anti-inflammatory actions by regulating leukocyte diapedesis, efferocytosis, and pro-inflammatory mediators following infection or injury [8, 9]
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