Cell Injury and Death Part 1 Flashcards by Lily Nunvar

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

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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

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If adaptation is helpful for an organism, it is termed ____. If it is maladaptive, it is termed ____.

Physiologic
Pathologic

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Cellular adaptations are controlled by ____ ___.

Feedback loops

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____ ____ (cardiac muscle, skeletal muscle, and nerve) cannot make new cells and commonly undergo ____.

Permanent tissues
Hypertrophy

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____ ____ 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

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____ 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

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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

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_____ tissue is also at increased risk for development of ischemia as its metabolic demands may overstep its blood supply

Hypertrophied

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Picture of cardiac Hypertrophy:

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_____ 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)

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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

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In Pathologic hyperplasia there is no response to ___ ___. An example is endometrial hyperplasia due to abnormal hormone induced growth

Growth inhibitors

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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

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____ is not itself neoplasticism or pre-neoplastic but elevates the risk of acquiring genetic aberrations that drive cancer

Hyperplasia

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____ 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

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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

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Pathologic atrophy are commonly caused by ____ ____ (disuse atrophy), ___ of ____ (denervation atrophy), or ___ ___ supply

Decreased workload
Loss of innervation
Diminished blood

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Loss of innervation is when ___ that lead to muscles are damaged and the muscles atrophy

Nerves

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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

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Pathological atrophy can also be due to inadequate ____, loss of ___ ___, or tissue ____

Nutrition
Endocrine stimulation
Compression

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____ 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

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___ ____ 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

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Metaplasia occurs via programming of ___ ___ which then produce the new cell type

Stem cells

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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:

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.

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