Lecture 5: Secondary Injury and Neuroinflammation Flashcards
1
Q
Processes in Secondary Injury
A
- Excitotoxicity
- Oxidative stress
- Neuroinflammation
2
Q
Secondary Injury
A
- Delayed and potentially reversible molecular and cellular pathophysiological mechanisms
- Characterised by:
- Neuronal cell death
- Infiltration of peripheral monocytes
- Activation of microglia and astrocytes
3
Q
Excitotoxicity
A
- Increase in extracellular glutamate following unctrolled release with neuronal depolarisation
- Accumulation of intracellular calcium -> degrades cellular structures and eventually cause neuronal degeneration
4
Q
Oxidative Stress
A
- Caused by an increased production of ROS or decreased degredation (role of antioxidants)
- > Disruption of plasma membrane
- > Oxidation of proteins
- > DNA mutations
5
Q
Neuroinflammation
A
- Post-traumatic neuroinflammation is characterised by glial cell activation, leukocyte recruitment and upreg of inflam mediators
- Both protective and detrimental aspects for the progression of secondary brain damage have been associated to diff aspects of the immune response:
6
Q
Microglia
A
- Resident immuhne cell
- Functions:
- Maintenance of tissue homeostasis
- Synaptic remodelling
- Secretion of neurotrophic factors
7
Q
Microglia following injury
A
- Among first responders to CNS injuries
- Mobilised within an hour and continue to accumulate for over a month
8
Q
Microglial activation
A
- ‘Resting’: ramified with short, fine processes to sense changes in local environment
- ‘Activated’: amoeboid, spherical, lacking processes, containing numerous phagocytic vacuoles
9
Q
Microglia Activation States
A
M1: detrimental - Role: phagocytose and remove debris - Cytotoxicity and tissue injury M2: Beneficial - Role: Immune suppression and tissue repair
10
Q
Microglial activation: double edged sword
A
- Microglia can exacerbate tissue damage through:
- Pro-inflam cytokines
- Interferon gamma
- Oxidative metabolites
- MMP-9
- Microglial activation also has beneficial effects due to phagocytosis of cellular debris and release of anti-inflam cytokines to restore tissue homeostasis
11
Q
Astrocytes post injury
A
- Mount a pro-inflam response:
- Clear debris
- Promote tissue repair
- Recruit peripheral leukocytes
- Form a barrier (glial scar) to limit spread of toxic microenvironment created by secondary injury processes
12
Q
Astrogliosis
A
- Inhibitory to axonal growth (due to glial scar)
- This dense physical and chemical barrier inhibits axonal regeneration and prevents functional connections required for axonal growth and repair
13
Q
Recruitment of Peripheral immune cells
A
- Infiltration via: disrupted BBB or release of mediators by activated astrocytes and microglial that induce expression of adhesion molecules on endothelial cells
- Focal TBI -> neutrophils then macrophages and lymphocytes
- Diffuse TBI -> primarily macrophages and lymphocytes
14
Q
Neutrophils in Acute Brain Injury
A
- Phagocytose cellular debris
- Release growth factor for repair
- Also contributes to ongoing tissue injury follow initial insult:
- > releases ROS and proteases eg. MMPs
- > amplify brain inflam response with more extensive activation of resident cells
- Less tissue damage using neutrophil ablation
15
Q
TNF-alpha
A
- Pro-inflammatory cytokine produced by activated microglia and astrocytes
