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Questions and Answers
What are the two types of programmed cell death that have inflammatory characteristics?
Pyroptosis and ferroptosis
What triggers different pathways in cells for decision making regarding stress response?
Adaptation is always the optimal response to environmental stress.
False
What is a significant inflammatory cytokine released during pyroptosis?
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Which of the following might be considered a non-optimal response to stress?
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What key components will be discussed in the Biology of Disease course?
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What is pathology?
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What are the proximal causes of death?
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Which of the following is a major distal factor of death?
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Which organelle is primarily responsible for ATP generation?
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Oxidative stress can lead to cell injury.
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What process is referred to as programmed cell death?
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What is the main difference between apoptosis and necrosis?
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Which enzyme is involved in the apoptotic process?
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Cell injury may be caused by extremes of ______ tension or pH.
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What initiates the unfolded protein response (UPR)?
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Match the type of cell death with its characteristic:
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Study Notes
Pathology: The study of disease and injury
- Pathology studies the causes (aetiology), development (pathogenesis) and effects of disease on cells and tissues.
- Disease is a disturbance of homeostasis, caused by cell damage.
Causes of Death
- Proximal causes of death are failures in critical systems: brain, heart, and lungs.
- Distal factors are the original problems leading to these failures, such as infections, cancers, or injuries.
- Leading causes of death globally include ischemic heart disease, stroke, and other age-related conditions, which primarily affect the brain, heart, and lungs.
- Major distal factors include inflammatory diseases, infectious diseases, and cancers.
Cell Injury
- Virchow proposed that cell injury is the foundation of disease.
- Cell injury can be caused by various factors, including oxygen and pH extremes, ATP depletion, toxins, drugs, cold, heat, nutrient deprivation, trauma, aging, and infections.
- Injury caused by infection can be direct due to toxins from the infectious agent or indirect as a result of the immune response to infection.
Cellular Targets of Cell Injury
- Cell injury commonly targets essential cellular components:
- Mitochondria (ATP generation)
- Cell membranes (ionic and osmotic balance)
- Cytoskeleton
- Protein synthesis
- Genetic material
Oxidative Stress
- Oxidative stress is a common consequence of many types of injury.
- Cells rely on oxygen for energy production, but they have systems to protect against free radical damage.
- Free radicals are molecules with unpaired electrons, such as reactive oxygen species (ROS) and nitric oxide (NO).
- ROS are generated by normal metabolism, ionizing radiation, and xenobiotics.
- ROS can cause DNA damage, protein oxidation, and lipid membrane disruption.
- While ROS have a short lifespan, they are highly reactive and can lead to cell injury.
- Neutrophils and macrophages use ROS to kill microorganisms, but this can also damage host cells.
Impaired Energy Homeostasis
- Reduced oxygen supply results in ATP depletion, leading to:
- Decreased activity of the Na+/K+ pump, causing cell swelling due to water accumulation.
- Increased glycolysis, which produces lactic acid and lowers pH, decreasing cellular enzyme activity.
- Influx of calcium, activating proteases, phospholipases, endonucleases, and ATPases.
- Ribosome detachment, hindering protein synthesis.
- This ultimately leads to cell death, primarily through necrosis.
Cell Responses to Stress and Injury
- Cells can adapt to varying levels of stress to maintain homeostasis.
- Adaptation is often reversible, allowing cells to return to normal when the stress is removed.
- Adaptive responses include hypertrophy (increased cell size), hyperplasia (increased cell number), and atrophy (reduced cell complexity).
- When cells can't adapt, they suffer damage, which can be either reversible or irreversible.
- Reversible injury often manifests as cell swelling or fatty deposits.
Cell Adaptation (Protective Responses to Stress)
The Heat Shock Response
- The heat shock response is a fundamental protective mechanism for cells.
- Stress triggers the release of heat shock factors (HSFs) from their inactive complexes.
- HSFs translocate to the nucleus and activate transcription of heat shock proteins (HSPs).
- HSPs are chaperone proteins that refold damaged proteins, helping cells maintain function under stress.
- HSPs contribute to preconditioning, making cells resistant to further stress after minor injury.
The Unfolded Protein Response
- The endoplasmic reticulum (ER) is responsible for protein synthesis and folding.
- The unfolded protein response (UPR) ensures the folding process keeps up with protein production.
- The UPR activates signaling pathways to increase chaperone synthesis, enhance protein degradation, and slow down protein translation.
- It is usually reversible and part of "host cell shut-down," a primitive response to injury that suppresses RNA and DNA synthesis and inhibits enzyme activity.
The Stress Kinase Pathways
- These pathways are activated by various stressors, including osmotic and oxidative stress, heat, UV radiation, and DNA damage.
- They activate transcription factors, such as AP1, which reprogram transcription.
- Important examples include the Jun N-terminal Kinase (JNK)/stress-activated protein kinase pathway (SAPK) pathway and the P38 kinase pathway.
- These pathways modulate cell responses, but they don't have a deterministic role; the ultimate outcome (protein synthesis shutdown, necrosis, or apoptosis) depends on additional factors.
Cell Death (Failure Responses to Stress)
- If injury is severe or persistent, cells reach a point of no return and die.
- Cell death can occur through necrosis or apoptosis.
Apoptosis (Programmed Cell Death)
- Apoptosis is a programmed death process that requires the cell to maintain energy control.
- It is crucial for tissue development and repair.
- Apoptotic cells detach from neighbors, shrink, form blebs and buds, and fragment.
- Specific proteases called caspases cleave proteins, and the dying cell exposes signals for phagocytosis by neighboring cells, mainly macrophages.
- Apoptosis is considered "silent" death, as it rarely causes inflammation.
Necrosis (Uncontrolled Cell Death)
- Necrosis is an uncontrolled death process, characterized by loss of cell volume homeostasis, cell swelling, and membrane rupture.
- Intracellular contents leak into the extracellular space, attracting neutrophils and triggering inflammation.
- Necrosis tends to affect groups of cells and can spread.
Other Forms of Cell Death
- Besides apoptosis and necrosis, other forms of programmed, inflammatory cell death exist, such as pyroptosis, ferroptosis, and NETosis.
- These are initiated by the body to kill cells while recruiting an immune response.
- Pyroptosis is particularly inflammatory, releasing IL1β.
Cellular Decision Making
- Cells respond to various stressors through multiple pathways.
- They must decide between adaptation or death, guided by the type and severity of the stress.
- Cells rely on incomplete information, sensing stress levels but not always identifying the source.
- Contextual cues, such as the presence of viral infection pathways, improve decision-making.
- Cells make decisions probabilistically, sometimes resulting in non-optimal outcomes and pathogenic consequences.
Course Overview
- The course covers the innate and adaptive immune systems and how they protect the body from infection
- The course analyzes inappropriate immune responses
- Major groups of infectious pathogens will be examined and their interactions with hosts
- The vascular response to injury, ischemia, infarction, and atherosclerosis will be discussed, highlighting their contribution to mortality
- The course will cover tissue growth and cancer, another major cause of death
- Each module of the course builds upon the previous topics to highlight the interconnectedness of pathology.
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Description
Explore the foundational concepts of pathology, including the causes and effects of disease on cells and tissues. This quiz will cover proximal and distal causes of death, along with major contributing factors like infections and cancers. Test your knowledge on the intricate relationship between cell injury and various disorders.
