Podcast
Questions and Answers
What is the most significant biological response associated with the activation of High-mobility group protein B1?
What is the most significant biological response associated with the activation of High-mobility group protein B1?
Which of the following effects is NOT associated with DAMP signaling in post-trauma conditions?
Which of the following effects is NOT associated with DAMP signaling in post-trauma conditions?
Which of the following Toll-like receptors is associated with the recognition of lipopolysaccharides?
Which of the following Toll-like receptors is associated with the recognition of lipopolysaccharides?
What is the role of heat shock proteins in cellular response to injury?
What is the role of heat shock proteins in cellular response to injury?
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Which of the following statements best describes the function of chemokines in inflammation?
Which of the following statements best describes the function of chemokines in inflammation?
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What does the degree of systemic inflammatory response indicate?
What does the degree of systemic inflammatory response indicate?
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Which of the following best characterizes HMGB1's role in the inflammatory response?
Which of the following best characterizes HMGB1's role in the inflammatory response?
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Which response is triggered by HMGB1 binding to TLR4?
Which response is triggered by HMGB1 binding to TLR4?
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What is a common consequence of altered epithelial barrier function due to trauma?
What is a common consequence of altered epithelial barrier function due to trauma?
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Which component is considered a significant outcome of the proinflammatory responses linked to HMGB1 signaling?
Which component is considered a significant outcome of the proinflammatory responses linked to HMGB1 signaling?
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In the context of inflammatory responses, what does SIRS typically relate to?
In the context of inflammatory responses, what does SIRS typically relate to?
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What is the relationship between injury severity and systemic inflammatory response?
What is the relationship between injury severity and systemic inflammatory response?
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What describes the main immune response in cases of trauma compared to infection?
What describes the main immune response in cases of trauma compared to infection?
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What are Damage-Associated Molecular Patterns (DAMPs) primarily responsible for in the context of trauma?
What are Damage-Associated Molecular Patterns (DAMPs) primarily responsible for in the context of trauma?
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In the acute response to trauma, what role does HMGB1 serve?
In the acute response to trauma, what role does HMGB1 serve?
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What is the primary aim of the systemic inflammatory response (SIR) triggered by traumatic injury?
What is the primary aim of the systemic inflammatory response (SIR) triggered by traumatic injury?
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How do endogenous molecules in DAMPs promote an immune response?
How do endogenous molecules in DAMPs promote an immune response?
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In the context of the acute pro-inflammatory response, what is the significance of balancing pro-inflammatory and anti-inflammatory mechanisms?
In the context of the acute pro-inflammatory response, what is the significance of balancing pro-inflammatory and anti-inflammatory mechanisms?
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What is likely the outcome if the innate immune system fails to recognize DAMPs?
What is likely the outcome if the innate immune system fails to recognize DAMPs?
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What is the relationship between DAMPs and necrotic or damaged cells?
What is the relationship between DAMPs and necrotic or damaged cells?
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What term best describes the molecules that actively promote the body's inflammatory response in trauma?
What term best describes the molecules that actively promote the body's inflammatory response in trauma?
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Which laboratory finding is commonly expected in critically ill patients with CIRCI?
Which laboratory finding is commonly expected in critically ill patients with CIRCI?
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What is the primary role of antioxidants in the context of critical illness-related complications?
What is the primary role of antioxidants in the context of critical illness-related complications?
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What is the main function of the hypothalamic CRH in response to injury associated stress?
What is the main function of the hypothalamic CRH in response to injury associated stress?
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What is the role of chemokines in the context of injury-induced inflammation as it relates to the central nervous system?
What is the role of chemokines in the context of injury-induced inflammation as it relates to the central nervous system?
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Which type of endothelium is primarily involved in allowing inflammatory signals to reach the central nervous system?
Which type of endothelium is primarily involved in allowing inflammatory signals to reach the central nervous system?
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Which part of the adrenal gland is primarily responsible for glucocorticoid production?
Which part of the adrenal gland is primarily responsible for glucocorticoid production?
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In the event of severe stress related to critical illness, which of the following electrolyte imbalances may occur?
In the event of severe stress related to critical illness, which of the following electrolyte imbalances may occur?
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Which of the following is NOT a component of pro-inflammatory mediators related to CIRCI?
Which of the following is NOT a component of pro-inflammatory mediators related to CIRCI?
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What neurotransmitter is noted for its regulatory role in central nervous system inflammation during injury?
What neurotransmitter is noted for its regulatory role in central nervous system inflammation during injury?
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Which enzyme is primarily involved in detecting cellular stress and reestablishing protein folding?
Which enzyme is primarily involved in detecting cellular stress and reestablishing protein folding?
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What characterizes necrosis compared to apoptosis in cellular death?
What characterizes necrosis compared to apoptosis in cellular death?
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What role does the vagus nerve play in the inflammatory response?
What role does the vagus nerve play in the inflammatory response?
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How do DAMPs contribute to inflammation in the central nervous system?
How do DAMPs contribute to inflammation in the central nervous system?
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Which statement best describes the properties of the blood-brain barrier (BBB) in relation to injury?
Which statement best describes the properties of the blood-brain barrier (BBB) in relation to injury?
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What is the effect of ACTH on the adrenal cortex?
What is the effect of ACTH on the adrenal cortex?
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What is the role of reactive oxygen species (ROS) in the immune response?
What is the role of reactive oxygen species (ROS) in the immune response?
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The unfolded protein response is primarily triggered by which condition?
The unfolded protein response is primarily triggered by which condition?
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Which of the following conditions illustrates hypoactivity in the HPA axis mechanisms?
Which of the following conditions illustrates hypoactivity in the HPA axis mechanisms?
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What is the effect of cytokines during the inflammatory response in the central nervous system?
What is the effect of cytokines during the inflammatory response in the central nervous system?
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Which statement regarding the secretion of CRH is accurate?
Which statement regarding the secretion of CRH is accurate?
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What can lead to hypoglycemia during critical illness?
What can lead to hypoglycemia during critical illness?
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What is the primary pathway for inflammatory signals to access the central nervous system according to their properties?
What is the primary pathway for inflammatory signals to access the central nervous system according to their properties?
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Which condition best describes the interaction of the central nervous system with peripheral inflammatory signals?
Which condition best describes the interaction of the central nervous system with peripheral inflammatory signals?
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What is a common characteristic of cell death via necrosis?
What is a common characteristic of cell death via necrosis?
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Study Notes
Cellular Injury Detection
- Traumatic injury initiates innate immune system response to limit damage and restore homeostasis.
- Two mechanisms exist: acute pro-inflammatory and anti-inflammatory responses.
- The degree of systemic inflammation correlates with injury severity and predicts organ dysfunction/mortality.
- SIRS (systemic inflammatory response syndrome) can result from sterile or infected trauma.
- Clinical features of SIRS include fever, increased heart and respiratory rate, and elevated white blood cell count.
Damage-Associated Molecular Patterns (DAMPs)
- DAMPS are endogenous molecules released from damaged cells.
- HMGB1 (High Mobility Group Protein B1) is a crucial DAMP.
- HMGB1 triggers pro-inflammatory responses, including cytokine release from macrophages/monocytes/dendritic cells, neutrophil activation, and changes to epithelial barrier function (increased permeability).
- HMGB1 plays a role in traumatic brain injury and hemorrhagic shock.
- Proteins from mitochondria create inflammasomes that activate STING (Stimulator of interferon genes).
Heat Shock Proteins (HSPs)
- HSPs are intracellular proteins that respond to oxidative stress and tissue injury.
- HSPs have roles in chaperoning and regulating protein folding, targeting of misfolded proteins, and sequestering partially folded proteins.
- HSPs act as DAMPS. Increased HSP70 expression induces cellular calcium flux, NF-κB activation, and cytokine production.
- Exogenous expression of HSPs can also inhibit NF-κB activation, and reduce dendritic cell T-cell stimulation.
Toll-Like Receptors (TLRs)
- TLRs are plasma-bound receptors (approximately 10) initially triggering immune responses.
- TLR1&2 form a dimer to interact with triacyl lipopeptides.
- TLR3,7,8,9 are found within endosomes.
- These receptors initiate immune responses in response to various stimuli (parasites, yeasts, bacteria, LPS, flagellin, GPI anchors, zymosan, Diacyl Lipopetides, LTA, dsRNA (viruses), CpG DNA (bacteria)).
- Activation of each TLR triggers a cascade activating a number of transcription factors such as AP1, IRF, or NFκB inside the nucleus, stimulating production of interferons, cytokines, and other signalling molecules.
CNS Regulation of Injury
- The central nervous system (CNS) detects inflammation through soluble mediators, neural projections, and DAMPS signals.
- Inflammatory signals reach the CNS through fenestrated endothelium and a leaky blood-brain barrier.
- Acetylcholine from splanchnic nerves plays a role in CNS inflammatory regulation.
- The hypothalamic-pituitary-adrenal (HPA) axis modulates the host response to injury-induced stress. Increased cortisol during acute stress leads to hyperglycemia, hypernatremia, and hypokalemia. Decreased cortisol during severe stress leads to the opposite: hypoglycemia, hyponatremia, and hyperkalemia.
Cellular Stress Responses
- Reactive oxygen species (ROS) are highly reactive molecules produced during oxygen metabolism.
- ROS cause oxidative stress by causing cell injury.
- ROS also act as signaling molecules.
- Inflammasomes activate inflammatory caspases and mature cytokines.
- The body defends against oxidative stress by utilizing antioxidants like superoxide dismutase, catalase, and others.
Cytokines and Immune Responses
- Cytokines are signaling molecules that regulate immune responses during injury.
- Exaggerated cytokine responses lead to inflammatory complications including hemodynamic instability and metabolic derangements.
- Interleukins (IL-1, IL-6, IL-8, IL-10, IL-2, TNFα) are signaling cytokines, regulating tissue repair and contributing to the inflammatory response.
- Cytokines mediate cell responses, including blood flow, activation, and migration.
Eicosanoids
- Eicosanoids like prostaglandins, leukotrienes, and thromboxanes regulate inflammation.
- These are derived from arachidonic acid.
- Eicosanoids exert physiological effects involving various processes such as vasodilation, blood pressure regulation, and bronchoconstriction.
- In inflammatory responses, they mediate pain, fever, and vascular permeability.
Complement System
- Complement systems are involved in inflammation and host responses to injury.
- The major source of complement proteins is the liver
- Complement system pathways include classical, lectin, and alternative pathways.
Apoptosis, Necrosis, and Pyroptosis
- Apoptosis is a regulated form of programmed cell death and is an energy dependent process without promoting inflammatory responses.
- Necrosis is an uncontrolled cell death due to cellular stress and triggers inflammation
- Pyroptosis is a programmed form of cell death, similar to apoptosis, but also involving caspases and resulting in significant inflammation
Cellular Mediator Responses (Inflammation)
- Neutrophils are initial responders to injury, exhibiting cytotoxic effects such as ROS.
- Monocytes (macrophages) are key players in clearance and activation of immune and inflammatory responses following injury.
- Lymphocytes (T and B cells) mediate adaptive immune responses involving cell signaling.
- Dendritic cells act as antigen presenting cells to initiate adaptive immune responses.
- Platelets contribute to hemostasis and inflammatory responses, releasing mediators and cytokines.
- Mast cells mediate inflammation by releasing mediators, including histamine and cytokines.
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