Cell Injury and Death Part 1 Flashcards
A change in stress on a cell/tissue can result in growth ____. They are reversible, functional, and structural responses to changes in physiologic states
Adaptations
The adaptive response may consist of an increase in the size of the cell, called ___, an increase in cell number, ____, a decrease in the size and metabolic activity of cells called _____, or a change in the phenotype of cells called ____.
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
If adaptation is helpful for an organism, it is termed ____. If it is maladaptive, it is termed ____.
Physiologic
Pathologic
Cellular adaptations are controlled by ____ ___.
Feedback loops
____ ____ (cardiac muscle, skeletal muscle, and nerve) cannot make new cells and commonly undergo ____.
Permanent tissues
Hypertrophy
____ ____ in cells detect increased work load, activating signal transduction pathways, which activate ___ ___ that will lead to increase protein expression and induce the production of growth factors. This will ____ the workload and the cell will reach homeostasis again.
Mechanical sensors
Transcription factors
____ Hypertrophy is due to increased functional demands. Example: pregnancy. Estrogenic hormones signal and increase the smooth muscle synthesis and increases size of the uterus. Another example is bulging muscles of bodybuilders
Physiologic
An example of ____ Hypertrophy is enlargement of the heart in response to pressure overload, usually resulting from either hypertension or valvular disease. Initially, cardiac Hypertrophy improves function but overtime this adaptation often causes heart failure
Pathologic
_____ tissue is also at increased risk for development of ischemia as its metabolic demands may overstep its blood supply
Hypertrophied
Picture of cardiac Hypertrophy:
_____ involves the production of new cells from stem cells. ____ hyperplasia can progress to dysplasia and eventually cancer. A notable exception of nonPathologic hyperplasia is ___ ___ ____, which does not increase risk for prostate cancer
Hyperplasia
Pathologic
Benign prostatic hyperplasia (BPH)
An example of physiologic hyperplasia is ___ ____. Another example is the ability of ___ ___ replication in the setting of acute bleeding or premature breakdown of red blood cells. ___ ____ will halt hyperplasia after sufficient growth has occurred using feedback loops.
Liver regeneration
Bone marrow
Growth inhibitors
In Pathologic hyperplasia there is no response to ___ ___. An example is endometrial hyperplasia due to abnormal hormone induced growth
Growth inhibitors
Hyperplasia is a characteristic response to certain ___ ____ such as papillomavirus which causes skin warts. The virus makes factors that interfere with host proteins that regulate ___ ___.
Example is ___ precursor to cancer .
Viral infection
Cell proliferation
HPV
____ is not itself neoplasticism or pre-neoplastic but elevates the risk of acquiring genetic aberrations that drive cancer
Hyperplasia
____ often arises in the setting of decreases stress or decreased stimulation. Decrease in cell number occurs via ____. Decrease in cell size occurs via ___-____ degradation of the cytoskeleton and autophagy of cellular components.
Atrophy
Apoptosis
Ubiquitin-proteasome
Physiologic atrophy is most common in the ____ setting such as the notochord and thyroglossal duct. The thymus atrophies as an individual grows. The decrease in uterus size after birth is another example
Embryologic
Pathologic atrophy are commonly caused by ____ ____ (disuse atrophy), ___ of ____ (denervation atrophy), or ___ ___ supply
Decreased workload
Loss of innervation
Diminished blood
Loss of innervation is when ___ that lead to muscles are damaged and the muscles atrophy
Nerves
A gradual decrease in blood supply (___ ___) to a tissue as a result of slowly developing arterial occlusive disease results in tissue atrophy. Elderly, the brain my undergo progressive atrophy mainly because of reduced blood supply as a result of atherosclerosis, this is called ___ ____.
Chronic ischemia
Senile atrophy
Pathological atrophy can also be due to inadequate ____, loss of ___ ___, or tissue ____
Nutrition
Endocrine stimulation
Compression
____ is a cell adaptation that leads to a change in cell type. Most commonly involving a change of one type of surface ____ to another. This process is best thought of as a protective mechanism rather than a ____ change
Metaplasia
Epithelium
Premalignant
___ ____ is a classic example of Metaplasia. The normal esophagus is lined by nonkeratinizing squamous epithelium, acid reflux causes Metaplasia to non-ciliated mucus producing columnar cells (resembles intestinal epithelium)
Barrett’s esophagus
Metaplasia occurs via programming of ___ ___ which then produce the new cell type
Stem cells
The ___ gene plays a crucial role in the development of Barrett’s esophagus
Cdx-2
Barrett’s esophagus will relieve symptoms of acid reflux however if this is not treated, the patient is predisposed to a type of cancer known as _____.
Adenocarcinoma
The most common epithelial Metaplasia is actually ___ to ___ epithelium. This occurs in respiratory tract in response to chronic irritation like cigarette smoke.
Columnar
Squamous
_____ (retinoic acid) deficiency can induce squamous metaplasia in the cornea with highly deleterious effects on vision
Vitamin A
____ in the expiratory ducts of the cell salivary glands, pancreas, or bile ducts, which are normally lined by columnar epithelium may also lead to ___ ___
Stones
Squamous Metaplasia
The more rugged stratified ____ epithelium can survive when the more fragile ___ epithelium might have been destroyed
Squamous
Columnar
As the respiratory tract becomes more durable with squamous cells, the ____ secretion and protection of columnar cells are lost
Mucus
____ ____ metaplasia is the formation of cartilage, bone, or adipose cells in tissues that normally do not contain these elements
Connective tissue
Unlike most epithelial metaplasia, connective tissue metaplasia is ____ associated with increased cancer risk
Not
Bone formation within a muscle called ___ ___ occasionally occurs after intramuscular hemorrhage
Myositis ossificans
____ is disordered cell growth and most often refers to proliferation of pre-cancerous cells.
Example: cervical intraepithelial neoplasm (CIN) is a precursor to cervical cancer
Dysplasia
_____ often arises from long-standing pathologic hyperplasia or metaplasia
Dysplasia
Dysplasia is ____ in theory with alleviation of inciting stress. if stress persists dysplasia progresses to carcinoma, which is _____.
Reversible
Irreversible
____ tissue is rapidly dividing cells that lose there normal progressive maturation. This tissue takes over the area and often progresses to carcinoma
Dysplastic
_____ is failure of cell production during embryogenesis such as unilateral renal agenesis where only one kidney is formed
Aplasia
______ is decrease in cell production during embryogenesis resulting in a relatively small organ such as a streak ovary in Turner syndrome
Hypoplasia
Key concepts:
Cell ____ occurs when a stress exceeds the cells ability to adapt. It can be reversible or irreversible.
Injury
Cell death is often the result of ____ cell injury. ____ is pathologic cell death due to irreversible sell injury. ____ is programmed cell death due to a variety of factors. It may be pathologic or physiologic.
Irreversible
Necrosis
Apoptosis
Common causes of cellular injury:
Hypoxia, free, radical damage, inflammation, infection, nutritional deficiency, trauma, chemicals, or genetic mutations
_____ are highly susceptible to ischemic injury, whereas _____ ____ is relatively more resistant
Neurons
Skeletal muscle
Slowly developing ischemia results in ____ , whereas acute ischemia results in ____.
Atrophy
Injury
There are four systems that are particularly vulnerable to injury:
Membranes
Aerobic respiration
Protein synthesis
DNA and RNA synthesis
The hallmark of cell death is the ___ breaking down
Nucleus
The hallmark of reversible cell injury is cell ____ and membrane ____.
Swelling
Blebbing
_____ is low oxygen delivery to tissues. Decreased oxygen impairs ___ ____, resulting in decreased ATP production. Lack of ATP leads to cellular ___ and injury.
Hypoxia
Oxidative phosphorylation
Edema
Causes of hypoxia include:
Ischemia
Hypoxemia
Decreased O2 carrying capacity of blood
____ is decreased blood flow through an organ. It arises with decreased material perfusion (_____), decreased venous drainage ( ____ syndrome), or shock, which is generalized ____.
Ischemia
Atherosclerosis
Budd-Chiari
Hypotension
_____ refers to low oxygen in the blood. This can result from high altitude, hypoventilation, lung diffusion defect, or ventilation/perfusion mismatch, where blood bypasses oxygenated lung (___ ___) or oxygenated air cannot reach blood (___ ___).
Hypoxemia
Vascular shunt
Collapsed lung
Decreased O2 carrying capacity arises with ____ loss or dysfunction. _____ refers to decreased hemoglobin or red blood cells.
Hemoglobin
Anemia
In carbon monoxide poisoning, CO binds to ____ more avidly than oxygen
Hemoglobin
_____ is when the iron in heme is oxidized and cannot bind oxygen
Methemoglobinemia
Low oxygen leads to low ATP which results in decreased action of ___ ___, resulting in sodium and water buildup in the cell leading to cellular edema
Na/K pumps
Low ATP causes reduced action of ____ ___ resulting in calcium buildup in the cell, which activate cellular enzymes, and poisons the mitochondria
Calcium pumps
Low ATP disrupts anaerobic glycolysis leading to ___ ___ buildup, low pH (acidosis), which denatures ___ and precipitates of ___.
Lactic acid
Proteins
DNA
The initial phase of injury is reversible. The hallmark of reversible injury is ___ ____ with the loss of microvilli and membrane blebbing
Cellular swelling
Eventually the damage becomes irreversible, the hallmark of irreversible injury is ___ ___.
Membrane damage
Plasma membrane damage results in ___ ___ leaking into the serum (cardiac troponin). Additional ___ enters the cell and poisons the ____.
Cytosolic enzymes
Calcium
Mitochondria
Mitochondrial membrane damage results in loss of ___ ___ ___. Cytochrome C leaking into cytosol activates ____.
Electron trainsport chain
Apoptosis
Lysosome membrane damage results in ____ ___ leaking into the cytosol, which are activated by the high intracellular calcium
Hydrolytic enzymes
The result of irreversible injury is ___ ___.
Cell death
Review of reversible and irreversible injury:
Increases cytosolic calcium:
___ ____ are chemical species with an unpaired electrons in their outer orbit. Formation of free radicals occurs during oxidative phosphorylation.
Free radicals
Cytochrome C oxidase (complex IV) transfers electrons to oxygen. Partial reduction of oxygen yields a ____. Hydrogen peroxide, and ___ ____ are products of subsequent proton coupled reactions
Superoxide O2•-
Hydroxyl radicals •OH
Pathologic generation of free radicals:
1. ____ ___: water is hydrolyzed to hydroxyl free radicals.
2. _____: NADPH oxidase, generates super oxide ions, during oxygen dependent killing by neutrophils.
3. _____: Fe2+ and hydrogen peroxide, generates hydroxyl radicals via the Fenton reaction
4. ______: p450 system of liver metabolize is drugs, generating, free radicals
Ionizing radiation
Inflammation
Metals (copper, and iron)
Drugs and chemicals
Free radicals, cause cellular injury via _____ of lipids, and ____ of DNA and proteins
Peroxidation
Oxidation
Oxidized, phospholipids and proteins are not readily ___ ___, so they accumulate and aggregate.
Broken down
Oxidative modification of amino acids and proteins causes protein _____ and _____.
Cross-linking
Fragmentation
Reactive oxygen species are removed by converting ___ to ____ by SOD. ____ is decomposed to water by glutathione peroxidase catalase.
Superoxide O2•-
Hydrogen peroxide (H2O2)
Hydrogen peroxide
Diagram of reaction oxygen species damage:
_____ such as glutathione and vitamins A, C, and help eliminate free radicals. Enzymes ___ ____ and ___ ___ in the mitochondria remove free radicals. Enzyme ____ in the peroxisomes also help.
Antioxidants
Superoxide dismutase
Glutathione peroxidase
Catalase
Review:
Reversible injury histology:
Reversible injury histology:
Mitochondrial swelling electron microscopy:
Key concepts review:
The hallmark of cell death is loss of the nucleus, which occurs via nuclear condensation (_____), fragmentation (____), and dissolution (____).
Pyknosis
Karyorrhexis
Karyolysis
____ refers to death of large groups of cells followed by acute inflammation. Due to some underlying pathologic process, it is ___ ____. Divided into several types based on gross features.
Necrosis
Never physiologic
____ necrosis is necrotic tissue that retains structure. an injury denatures, structural proteins, and enzymes blocking ____ of the dead cells. A localized area of coagulative necrosis is called an ____.
Coagulative
Proteolysis
Infarct
____ necrosis is when necrotic tissue becomes liquefied via proteomic enzyme lysis of cells and proteins
Liquefactive
Brain infarction characterized by microglial cells ____ infarcted tissue
Liquify
Neutrophils liquefy tissue in ____ formation
Abscess
Pancreatic digestive enzymes liquify ____ in pancreatitis
Tissue
____ necrosis is coagulative necrosis that resembles mummified tissue often caused by ischemia of lower limbs. If super imposed infection of dead tissues occurs, then liquefactive necrosis ensues AKA ___ ___
Gangrenous
Wet gangrene
____ necrosis is soft and friable necrotic tissue with cheese like appearance. It is a combination of coagulative and liquefactive necrosis. It is a characteristic of granulomatous inflammation due to tuberculosis or fungal infection.
Caseous
____ necrosis has a chalky white appearance due to deposition of calcium. Characteristic of trauma to fat and pancreatitis mediated damage of Peripancreatic fat.
Fat
In fat necrosis fatty acids join with calcium via a process called _____. this is an example of _____ ____
Sponification
Dystrophic calcification
____ necrosis is damage to blood vessel walls. Leaking of proteins into vessel, wall results in a bright pink staining of the wall. Characteristic of malignant, hypertension, and immune related vasculitis.
Fibrinoid
Review of types of necrosis:
Key concepts:
Necrosis is considered to be an ____ type of cell death. Apoptosis is ____ cell death.
Unregulated
Regulated
______ is the result of the activation of specific pathways in the cell that results in the loss of membrane, integrity and release of cytoplasm to the extracellular environment with inflammation. It is a necrotic type of death that can be regulated.
Necroptosis
Why would a cell purposefully become necrotic?
The thought is that inflammation can be advantageous in some instances, for example, in influenza a infected cells, death by necroptosis both limits the replication of the virus, as well as mobilizes, innate and adaptive immune responses
Picture:
Apoptosis is a normal process in ___ ___ which scopes tissue and organs. Apoptosis also removes cells that have served their purpose.
Early development
Removal of excess ___ results from competition of finite supply of survival factors released by target cells
Neurons
Apoptosis of inter-digit cells is specified by ___ signaling
BMP
Removal of auto-reactive lymphocytes is carried out through ____ signaling between cells
Juxtacrine
Apoptosis in early development refines the ____ ____, ___ formation, and maturation of the ___ ___.
Neuronal circuitry
Digit
Immune system
Picture of viable versus apoptotic cells
Apoptotic cells are stained with the fluorescent DNA binding dye , ____. You can see chromosome condensation and fragmentation in apoptotic cells.
Hoechst
You can also stain apoptotic cells with fluorescent _____ green dye on top of Hoechst. You can see the fragmented mitochondrial network
Mitochondrial
____ are enzymatic effectors of apoptosis. They are proteases that hydrolyze a large number of target proteins
Caspases
The functions of some proteins (like lamins) are ____ by caspase and others (like MST1 and some DNases) are ___ by caspase cleavage
Destroyed
Activated
Caspases are classified by either ____ or ___
Initiator
Effector
Caspases are ____-_____ acid proteases that are responsible for executing apoptosis
Cysteine-aspartic
Caspases are synthesized in an inactive form and activated by ____. ____ Caspases are activated first and subsequently activate ____ Caspases
Proteolysis
Initiator
Effector
Initiator Caspases are activated by two major pathways:
1. _____ signaling pathway: apoptosomes assemble in the cytoplasm and activate initiator caspase 9
2. ____ signaling pathway: DISCs assemble on plasma membrane receptors and activate Caspases 8 and 10
Intrinsic
Extrinsic
The intrinsic pathway is typically activated in response to ___ ___ or prolonged or intense ___ such as DNA damage, hypoxia, survival factor deprivation, or oncogene activity
Cell injury
Stress
____ is a centrally important sensor of cellular stress and an important activator of the intrinsic pathway
p53
The extrinsic pathway is typically activated in response to events occurring ____ of the cell and involves ___-___ signaling
Outside
Receptor-Ligand
Extrinsic pathway:
Prominently represented are members of the ___ ___ family of signaling molecules and receptors
Tumor necrosis
Extrinsic pathways are extensively used by cells of the ___ ___ to carry out their functions in ridding the body of pathogens
Immune system
____ are sensitive to cellular damage and stress and a hallmark response to irreversible injury is the ___ ___ ___ ___ ____ (MOMP) and release of cytochrome C from the intermembrane space
Mitochondria
Mitochondrial outer membrane pore opening
Released cytochrome C forms a complex with ____ and ____ in the cytoplasm called the apoptosome.
APAF-1
Caspase 9
___ ____ model of caspase activation refers to the close clustering of caspase 9 in the apoptosome stimulates their protease activity, they rapidly ____ specific sites on each other, fully activating themselves
Induced proximity
Cleave
Activated caspase 9 subsequently activates ____ Caspases by proteolysis, resulting in a chain reaction of caspase activation- a caspase ____.
Effector
Cascade
Intrinsic pathway of activation:
____ family proteins are central regulators of MOMP. When ____ is over expressed, cell death was suppressed, leading to cancer.
Bcl
Bcl2
___ and ___ of the Bcl2 family promote cell death by forming an oligomeric complex in the outer mitochondrial membrane which is the basis of MOMP
Bax
Bak
There are 30 Bcl2 family members that have been discovered.. they all have 1 to 4 ___ domains.
BH
Pro survival Bcl2 members exhibit ___ BH domains (BH1234). Pro apoptotic members exhibit ___ BH domains (BH123).
4
3
A group of Bcl2 family members that are pro apoptotic but do not form pores in the outer mitochondrial membrane contain only the ___ BH domain and are called _____ proteins
Third
BH3-only
BH3-only proteins serve as ____ that promote the ability of Bax and Bak to oligomerize and form pores
Initiators
BH3-only proteins are ___ and Bax and Bak are ____ of apoptosis. Pro survival proteins are ____ against apoptosis
Initiators
Effectors
Guardians
A key feature is that the initiator BH3-only and the pro survival Bcl family members are ____ ____. Together with the fact that cells express multiple members of both categories, this allows for numerous inputs to factor into the decision of whether the cell should survive or undergo apoptosis
Mutually inhibitory
BH3-only and ____ are initiators of apoptosis
t-Bid
Extrinsic pathway:
____ ____ factor receptor (TNFR) family and tumor necrosis factor (_____) Paracrine signaling
Tumor necrosis
TNF-alpha
Extrinsic pathway:
___ - ____ ligand Juxtacrine signaling
____ - _____ juxtacrine signing
FAS - FAS
TRAIL - TRAILR
Extrinsic pathway:
Ligand binding triggers assembly of ___ ___ that serve as docking sites for adaptor proteins that bind ___ and bring them close in contact, which activates them via ___ ____
Receptor complexes
Caspases
Induced proximity
Extrinsic pathway:
_____ is the complex that forms and activates caspase. ____ and ____ are modular recognition elements that DISC uses to bind constituent proteins
DISC (death inducing, signaling complex)
DDs (death domains)
DEDs (death effector domains)
The extrinsic and intrinsic pathway can be linked. ____ can be a target of the extrinsic pathway becoming activated when cleaves by caspase 8. Activated Bid inhibits the anti-apoptotic effects of ____ at the mitochondrial membrane, tilting the scales toward ___. This effect has been referred to as the ___ ___ ___.
Bid
Bcl2
Apoptosis
Mitochondrial amplification loop
FAS-FAS signaling by immune cells:
Induce (_____) an adjacent target cell to become apoptotic. Signaling back to itself to trigger apoptosis (_____)
Murder
Suicide
______ is a protease that can directly cleave and activate both Bid and initiator and effector Caspases independently of ____, allowing for particularly robust apoptotic response
Granzyme B
DISC
___ links cell proliferation, cell health, and regulated cell death pathways
p53
