1-Metabolic

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Questions and Answers

What is the most significant biological response associated with the activation of High-mobility group protein B1?

Increase in apoptotic signaling pathways.

Decrease in cellular proliferation rates.

Inhibition of inflammatory response.

Activation of cytokines and chemokines. (correct)

Which of the following effects is NOT associated with DAMP signaling in post-trauma conditions?

Decrease in epithelial barrier function.

Procoagulant activity enhancement.

Increased activation of neutrophils.

Inhibition of chemotaxis in macrophages. (correct)

Which of the following Toll-like receptors is associated with the recognition of lipopolysaccharides?

TLR 4 (correct)

TLR 2

TLR 1

TLR 5

What is the role of heat shock proteins in cellular response to injury?

They are expressed in response to oxidative stress. Signup and view all the answers

Which of the following statements best describes the function of chemokines in inflammation?

They mediate the chemotaxis of leukocytes towards sites of inflammation. Signup and view all the answers

What does the degree of systemic inflammatory response indicate?

It directly predicts the likelihood of subsequent organ dysfunction. Signup and view all the answers

Which of the following best characterizes HMGB1's role in the inflammatory response?

It is a damage-associated molecular pattern (DAMP) that activates inflammation. Signup and view all the answers

Which response is triggered by HMGB1 binding to TLR4?

Release of pro-inflammatory cytokines. Signup and view all the answers

What is a common consequence of altered epithelial barrier function due to trauma?

Increased permeability leading to fluid loss. Signup and view all the answers

Which component is considered a significant outcome of the proinflammatory responses linked to HMGB1 signaling?

Increased procoagulant activity on platelet surfaces. Signup and view all the answers

In the context of inflammatory responses, what does SIRS typically relate to?

The physiological response to sterile trauma. Signup and view all the answers

What is the relationship between injury severity and systemic inflammatory response?

They are directly proportional. Signup and view all the answers

What describes the main immune response in cases of trauma compared to infection?

In both cases, similar pro-inflammatory responses are activated. Signup and view all the answers

What are Damage-Associated Molecular Patterns (DAMPs) primarily responsible for in the context of trauma?

Activating innate immune cells in response to cellular injury Signup and view all the answers

In the acute response to trauma, what role does HMGB1 serve?

It is the most characterized DAMP involved in inflammation Signup and view all the answers

What is the primary aim of the systemic inflammatory response (SIR) triggered by traumatic injury?

To limit damage and restore homeostasis in the body Signup and view all the answers

How do endogenous molecules in DAMPs promote an immune response?

By recruiting and activating antigen-presenting cells Signup and view all the answers

In the context of the acute pro-inflammatory response, what is the significance of balancing pro-inflammatory and anti-inflammatory mechanisms?

It ensures proper tissue repair and immune regulation Signup and view all the answers

What is likely the outcome if the innate immune system fails to recognize DAMPs?

Development of chronic inflammation Signup and view all the answers

What is the relationship between DAMPs and necrotic or damaged cells?

DAMPs can be released passively or through overexpression in stressed cells Signup and view all the answers

What term best describes the molecules that actively promote the body's inflammatory response in trauma?

Alarmins Signup and view all the answers

Which laboratory finding is commonly expected in critically ill patients with CIRCI?

Hyperkalemia Signup and view all the answers

What is the primary role of antioxidants in the context of critical illness-related complications?

Protecting host cells from oxidative stress Signup and view all the answers

What is the main function of the hypothalamic CRH in response to injury associated stress?

To promote ACTH release from the anterior pituitary Signup and view all the answers

What is the role of chemokines in the context of injury-induced inflammation as it relates to the central nervous system?

They help in the localization and recruitment of immune cells. Signup and view all the answers

Which type of endothelium is primarily involved in allowing inflammatory signals to reach the central nervous system?

Fenestrated endothelium Signup and view all the answers

Which part of the adrenal gland is primarily responsible for glucocorticoid production?

Zona fasciculata Signup and view all the answers

In the event of severe stress related to critical illness, which of the following electrolyte imbalances may occur?

Hyperkalemia and hyponatremia Signup and view all the answers

Which of the following is NOT a component of pro-inflammatory mediators related to CIRCI?

Insulin Signup and view all the answers

What neurotransmitter is noted for its regulatory role in central nervous system inflammation during injury?

Acetylcholine Signup and view all the answers

Which enzyme is primarily involved in detecting cellular stress and reestablishing protein folding?

Inositol requiring enzyme 1 (IRE1) Signup and view all the answers

What characterizes necrosis compared to apoptosis in cellular death?

Loss of plasma membrane integrity Signup and view all the answers

What role does the vagus nerve play in the inflammatory response?

It mediates the inflammatory reflex through acetylcholine. Signup and view all the answers

How do DAMPs contribute to inflammation in the central nervous system?

By acting as endogenous signals of cell stress or injury. Signup and view all the answers

Which statement best describes the properties of the blood-brain barrier (BBB) in relation to injury?

The BBB displays increased permeability during inflammatory responses. Signup and view all the answers

What is the effect of ACTH on the adrenal cortex?

Promotes cortisol secretion from the zona fasciculata Signup and view all the answers

What is the role of reactive oxygen species (ROS) in the immune response?

Facilitating pathogen killing by phagocytes Signup and view all the answers

The unfolded protein response is primarily triggered by which condition?

Cellular stress disrupting protein folding Signup and view all the answers

Which of the following conditions illustrates hypoactivity in the HPA axis mechanisms?

Adrenal insufficiency Signup and view all the answers

What is the effect of cytokines during the inflammatory response in the central nervous system?

They can both propagate and inhibit inflammation depending on their type. Signup and view all the answers

Which statement regarding the secretion of CRH is accurate?

CRH is secreted from the paraventricular nucleus of the hypothalamus. Signup and view all the answers

What can lead to hypoglycemia during critical illness?

Severe stress and metabolic dysregulation Signup and view all the answers

What is the primary pathway for inflammatory signals to access the central nervous system according to their properties?

Via leaky tight junctions of the blood-brain barrier. Signup and view all the answers

Which condition best describes the interaction of the central nervous system with peripheral inflammatory signals?

It can be overwhelmed by excessive peripheral inflammation. Signup and view all the answers

What is a common characteristic of cell death via necrosis?

Occurs in response to ischemia and trauma Signup and view all the answers

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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