| Background:Postoperative cognitive dysfunction(POCD)is a common complication of central nervous system(CNS)in aged patients,which cause the loss of the quality of life,the higher mortality,hiked medical costs.However,the pathological mechanism of POCD has not been clarified so far,and there is no effective treatment for prevent the occurance of POCD.Hence,it is urgent to explore the pathological mechanism of POCD and provide a effective measure for the prevention and treatment of POCD.Emergency evidence have showed that surgery-induced neuroinflammation plays a key role in the occurrence and development of POCD.Peripheral surgery could activate the innate immune system,inducing the activation of peripheral immune cells and the release of pro-inflammatory cytokines.After the immune signal was transferred to brain,the cerebral immune cells could be activated and release cytokines,following with neuronal apoptosis and cognitive damage.Hence,it is necessary to explore the relationship between surgery-induced peripheral inflammation and neuroinflammtion.The physical and pathological effect of mast cells on CNS get more and more attention during recent years.In the brain,mast cells are found in the hypothalamus,thalamus,hippocampus,choroid plexus,meninges and mainly reside on the brain side of BBB.Under physical conditions,a small portion degranulating mast cells release tryptase,histamine,and other mediators to guarantee the normal function of CNS,such as regulating hormones secretion,feeling,mood and cognition.However,the brain mast cells also participate in the pathological process of the neurodegenerative diseases,such as Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,autism,and cerebral ischemia.Due to the brain mast cells mostly lie in close proximity to the brain side of BBB,they can receipt the immune signals in the first time.Once be activated,brain mast cells will released numerous’MC mediators’,such as tryptase,histamine and so on,promoting the occurance and develepment of neuroinflammation.Thus,mast cells are recognized as both sensors and effectors of CNS.However,the exactly relationship between brain mast cells and surgery-induced early neuroinflammation was still unknown.So,the modulated effect of brain mast cells on neuroinflammation was worth to be explored.Part Ⅰ Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosisBackground:Neuroinflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction(POCD).Microglia,the resident immune cells in the brain,has been increasingly recognized to contribute to neuroinflammation.Although brain mast cells(MCs)are the "first responder" in the brain injury rather than microglia,little is known about the functional aspects of MCs-microglia interactions.Methods:Male Sprague-Dawley(SD)rats were injected intracerebroventricular with MC stabilizer Cromolyn(100μg/μl),MC stimulator C48/80(1μg/μl)or sterile saline 30min before open tibial fracture surgery,and the levels of neuroinflammation and memory dysfunction were tested 1 day and 3 days after surgery.In addition,the effect of activated MCs on microglia and neuron were determined in vitro.Results:Tibial fracture surgery induced MCs degranulation,microglia activation and inflammatory factors production,which initiated the acute brain inflammatory response and neuronal death,exhibited cognitive deficit.Site-directed pre-injection of the "MCs stabilizer" disodium cromoglycate(Cromolyn)inhibited this effect,including decrease of inflammatory cytokines,reduced MCs degranulation,microglia activation,neuronal death and improved cognitive function 24h after the surgery.In vitro study,we found that the conditioned medium from lipopolysaccharide(LPS)-stimulated mast cells line(P815)could induce primary microglia activation through Mitogen-Activated Protein Kinase(MAPK)pathway signaling and subsequent production of tumor necrosis factor-a(TNF-α)and interleukin-6(IL-6).In addition,the activated P815 could directly induced neuronal apoptosis and synapses injury with microglia independently.Cromolyn could inhibit P815 activation following improved microglia activation and neuronal loss.Conclusion:These results implicate that activated MCs could trigger microglia activation and neuronal damage,resulting in central nervous system(CNS)inflammation,and communications of MCs with microglia and neuron could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases.Part Ⅱ Cerebral mast cells participate in postoperative cognitive dysfunction by promoting astrocyte activationBackground:Astrocytes,the major glial cell type that has been increasingly recognized as contributing to neuroinflammation,are critical in the occurrence and development of postoperative cognitive dysfunction(POCD).Although emerging evidence showed that brain mast cells(MCs)are the "first responders" in neuroinflammation,little is known about the functional communication between MCs and astrocytes.Methods:In this study,we investigated the potential regulation of astrocyte activation by MCs.Rats received an intracerebroventricular injection of Cromolyn(an MC stabilizer)or sterile saline 30 min before undergoing open tibial fracture surgery,and the levels of neuroinflammation and the degree of memory dysfunction were evaluated at 1 day and 3 days after surgery.In the in vitro study,the effect of activated MCs on astrocytes were further clarified.Results:Surgery increased the number of MCs,the astrocyte activation and the production of inflammatory factors,and resulted in cognitive deficits.Site-directed pre-injection of Cromolyn can inhibit this effect.In the vitro study,the conditioned medium from C48/80-stimulated mast cells(P815)could induce primary astrocyte activation and subsequent production of inflammatory cytokines,which could be inhibited by Cromolyn.Conclusion:These findings indicate that activated MCs could trigger astrocyte activation,which may be involved in neuroinflammation and possibly contribute to POCD.Interactions between MCs and astrocytes could provide potential therapeutic targets for POCD.Part Ⅲ Cerebral mast cells contribute to postoperative cognitive dysfunction by promoting blood-brain barrier disruptionBackground:Postoperative cognitive dysfunction(POCD)is a serious complication after surgery.More and more evidence have showed that neuroinflammation plays a key role in the pathogenesis of POCD.Blood-brain barrier(BBB),a dynamic interference which regulates the toxic and nutrition substance in and out of the central nervous system(CNS),plays a crucial role in maintaining a stable circumstance of the CNS.Recent findings have been suggested that surgery affects the BBB permeability and function adversely.Substantial evidence suggests that mast cells can promote the BBB breakdown.Hence,we hypothesized that activated MCs may induce BBB breakdown and thereby participate in cognitive dysfunction after peripheral surgery.Methods:Male Sprague-Dawley(SD)rats were injected intracerebroventricular with MC stabilizer Cromolyn(100μg/μl)or sterile saline 30min before open tibial fracture surgery,and the levels of neuroinflammation and memory dysfunction were tested 1 day and 3 days after surgery.In addition,the effect of activated MCs on BBB were determined.Results:Surgery increased the number of MCs,the disruption of BBB and the production of inflammatory factors,and resulted in cognitive deficits.Site-directed pre-injection of Cromolyn can inhibit this effect.Conclusion:These findings indicate that activated MCs could promote the broken of BBB,which may be involved in surgery-induced neuroinflammation and possibly contribute to POCD. |
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