Cell Injury, Death, and Adaptation Flashcards
Etiology definition
Origin of a disease - including underlying causes and modifiers
The initiating event and its related risk factors
Why a disease occurs
Pathogenesis definition
Development of disease, from molecular/cellular changes to functional and structural abnormalities
The transition from normal to abnormal
How a disease occurs
Cell injury results from what?
Disruption of one or more components that maintain viability
Induces a cascade of effects
What can happen following cell injury?
It may be reversible
May result in cell adaptation
May lead to cell death
What happens if cell injury is mild/transient?
It is reversible and things can go back to normal
What happens if cell injury is severe/progressive?
Can cause irreversible injury
Cell death
What are the two types of cell death
Necrosis = death Apoptosis = programmed death
What happens if cell death does not occur properly?
Can get sarcomas, carcinomas, cancers
Clinical Expression definition
Several steps removed from morphologic changes that are preceded by the biochemical changes associated with cell injury
What are different causes of cell injury - from the Patient’s persepective?
Hypoxia Infectious agents Physical injury Chemicals/drugs Immune response Genetric abnormalities Nutritional imbalance
Hypoxia
Lack or decrease of Oxygen
T/F - Hypoxia effects all cells equally
False - some cells are more sensitive to hypoxia than others, ie: heart and brain
What are the major targets that cause cell injury/death
Cell membrane
Mitochondria
Cell proteins
DNA/RNA
How can a disruption in cell membrane cause cell injury/death?
Disrupts the balance between electrolytes, cations, protein/enzyme balance
How can a disruption of the mitochondria cause cell injury/death?
Impairs the cell’s ability to get energy
Function drops off rapidly
How can a disruption of cell proteins cause cell injury/death?
Don’t get enzymes and structural proteins needed for function
How can a disruption of DNA/RNA cause cell injury/death?
May take a while for the problem to manifest
Cell lacks an ability to get information
What are the different cell injury mechanisms?
ATP depletion Generation of ROS Loss of Ca+2 homeostasis Altered membrane permeability Mitochondrial damage DNA and protein damage
What is the Hypoxia-Ischemia model of cell damage, and what causes it?
Decreased (hypoxia) or no (anoxia) oxygen due to:
- Impaired absorption of oxygen
- Decreased blood flow (Ischemia)
- Disease of blood or blood vessels
- Inadequate oxygenation of the blood
How does Hypoxia-Ischemia lead to decreased energy production?
What does the decrease in energy lead to?
Decreased oxygen impairs oxidative phosphorylation in the mitochondria
-Reduced ATP reduces the ability of the plasma membrane to maintain homeostasis, leading to a net gain of solute and an isosmotic gain in cytoplasmic water
Decreased energy leads isosmotic gain in water leads to what?
- Cell swelling with formation of cell surface blebs
- Swelling of the mitochondria
- Dilation of the ER
Dilation of the ER leads to what?
Detachment of ribosomes from RER and dissociation of polysomes and a decrease in protein synthesis
Reduced Oxidative phosphorylation leads to what?
Increased glycolysis, producing lactic acid and inorganic phosphates which decreases intracellular pH, leading to chromatin clumping`
Hypoglycemia
Reduced substrate for ATP producing results similar to the Hypoxia-Ischemia model
T/F - ROS are normally generated
True - they’re generated by normal endogenous oxidative reactions in the plasma membrane, mitochondria, cytoplasm, and peroxisomes
Generation of too many ROS are associated with what?
Inflammation Oxygen toxicity Chemicals Irradiation Aging
What are the different types of ROS?
Superoxide (O2*) Hydrogen Peroxide (H2O2) Hydroxyl Radicals (OH*)
Superoxide
O2*
Produced by auto-oxidation in the mitochondria and by cytosplasmic oxidases
Hydrogen Peroxide
H2O2
Produced by auto-oxidation in the mitochondria and by cytoplasmic oxidases
How are Superoxides (O2*) inactivated?
Spontaneously
OR
By superoxide dismutase (SOD) to form H2O2
How is Hydrogen Peroxide inactivated?
By glutathione peroxidase and catalase
Hydroxyl Radicals
OH*
Generated by hydrolysis of water by ionizing radiation and H2O2 by the Fenton reaction that utilizes transitional metals (such as Fe++ or Cu++)
How do ROS damage cells?
Lipid Peroxidation
Protein Fragmentation
Single strand breaks in DNA
Lipid Peroxidation
Oxygen radical comes in and causes the lipids to become radical lipid peroxides
These radical species can react with other species and disrupt the membrane and cause issues with the membrane products
What are the major sites of DNA damage via ROS?
Thymidine and Guanine
What are the Intracellular antioxidant systems to reduce the effects of ROS?
SOD
Catalase
Glutathione Peroxidase
What are the Extracellular antioxidant systems to reduce the effects of ROS?
Vitamins E, A, and C
Glutathione and Cysteine
Serum proteins that reduce/bind iron (transferrin, ferritin) and copper (ceruloplasmin) needed to catalyze the formation of ROS
What maintains Cytoplasmic Ca++
Protein sequestration in the cytoplasm, Mitochondria, and ER
Increased levels of Ca++ will cause what?
It will activate various degradative enzymes, such as:
- Phospholipases
- Proteases
- Endonucleases
- ATPase
What are some ‘other’ causes of cell membrane injury?
Complement C5-C9 membrane attack complex Cytotoxic T and NK cells - perforin Virus Bacterial endotoxins and exotoxins Drugs
Reversible Cell Injury
aka Sub-lethal Cell Injury
Acute in nature
Occurs when the cell cannot maintain normal homeostasis due to cell injury of short duration and minimal intensity
What are some common causes of Reversible Cell Injury?
Toxins
Infectious Agents
Hypoxia
Thermal Injury
What are the morphological changes associated with Reversible Cell Injury
Plasma membrane injury that leads to increased intracellular Na+ that leads to an isosmotic gain in water
Organelles and cells swell, and the organ may appear pale and swollen
What occurs first, Biochemical alterations of morphologic changes?
Biochemical alterations
The degree of cell injury is determines by what?
- Physiological state of the cell
- Intensity of insult
- Duration of insult
- Number of exposures to the insult
What are the different outcomes that can occur from a cell injury?
1) It reverses
2) Results in a cell adaptation
3) Leads to cell death - necrosis or apoptosis
What are different types of cellular adaptations?
Changes in cell number, size, or differentiation
Cellular adaptations associated with abdnormal accumulations
T/F - There is one biochemical event that equates with cell death
False - There is no single biochemical event that equates with cell death
What are the two types of cell deaths
Necrosis
Apoptosis
What gets released after cell death?
Cellular constituents get released into the extracellular environment
What morphologic changes occur in necrosis?
Cell Swelling
Protein denaturation; yielding a glassy, homogenous pink staining cytoplasm
Organelle breakdown may result in vacuoled cytoplasm
Nuclei changes: karylosis, pyknosis, karyorrhexis, or total loss
Inflammation
What are the different morphologic types of necrosis
Coagulative Necrosis
Liquefactive Necrosis
Caseous Necrosis
Fat Necrosis
Coagulative Necrosis
Most common form
Cytoplasmic proteins are coagulated
Nucleus is lost, but the eosinophilic outline of the cell is retained for a short time prior to being removed by inflammatory response
Liquefactive Necrosis
The tissue is totally digested by the release of lysosomal enzymes during the acute inflammatory response
Often associated with focal bacteria or fungal infections (abscesses and wet gangrene)
Also seen in the CNS
Fills with pus
Caseous Necrosis
Associated with M. tuberculosis
The tissue has a white and “cheesy” appearance on gross examination
Microscopically characterized by amorphous pink granular material within a ring of granulomatous inflammation and loss of tissue architecture
Fat Necrosis
Common in trauma to the breast or in cases of pancreatitis
Adipose tissue has a chalky white-yellow gross appearance
What is the type of Necrosis dependent on?
The patterns of enzymatic degredation of cells and ECM
The type of necrotic debris
Bacterial products when present
T/F - Apoptosis is the same as Necrosis
False - It is a morphologically distinct, gene directed form of individual cell death
What are some morphologic features of apoptosis?
Cell shrinkage
Chromatin condensation followed by fragmentation
Apoptotic body formation
Phagocytosis of the apoptotic bodies without a significant inflammatory response
When is apoptosis useful?
Normal cell turnover
Embryogenesis
Immune function
What diseases/pathology cause excessive Apoptosis?
AIDS Ischemia Neurodegenerative diseases Myelodysplasia Toxin-induced liver injury
What diseases/pathology inhibit apoptosis?
Cancer
Autoimmune diseases
Viral diseases
What are the mechanisms of Apoptosis?
1) Intrinsic program - Mitochondria
2) “Death signals” - Fas-ligand binding to Fas receptor (extrinsic)
3) Removal of trophic signals (hormones)
4) ROS, radiation, toxins
5) Effect of Cytotoxic T-cells
What are the two pathways to control and integrate
1) Direct Signaling (Fas-ligand, TNF binding)
2) Regulation of mitochondrial permeability
Bcl-2 gene family
Serve as an ‘on/off switch’ that regulate membrane permeability of the mitochondria (Bcl-2, Bax, Bak)
What do Bcl-2 and Bcl-x products do?
Inhibit apoptosis
What do Bax and Bak gene products do?
Stimulate apoptosis
What happens when Cytochorme-C is released from the outer mitochondrial membrane?
It disrupts Bcl-2, and therefore favors apoptosis
Capspases
Apoptosis signaling pathways converge on an autocatalytic proteolytic cascade of capspaces
Their substrates include: cytoskeletal and nuclear matrix proteins, DNase, and transcription proteins
What does the mitochondrial release of Ca do?
Activates various enzymes the execute apoptosis
- Transglutaminases cross-link cytoplasmic proteins
- Endonucleases cleave DNA at the linker regions between nucleosomes
What removes cell fragments that underwent apoptosis?
Phagocytosis by neighboring cells and macrophages
Little or no inflammation associated
What stimulates each type of cell death?
Apoptosis = Physiologic and pathologic Necrosis = hypoxia and toxins
What is the morphology of Apoptosis v Necrosis?
Apoptosis
- Single cells
- Shrinkage
- Condensed chromatin
- Intact plasma membrane
- Apoptotic bodies
Necrosis
- Multiple cells
- Lysed plasma membrane
- Organelle disruption
What are the mechanisms of DNA destruction in Apoptosis v Necrosis?
Apoptosis
- ATP dependent
- Gene activation and endonuclease mediated DNA fragmentation
Necrosis
- ATP independent
- Random, Diffuse, Free radicals, Membrane injury
What are the tissue reactions of Apoptosis v Necrosis?
Apoptosis
- Minimal inflammaiton
- Phagocytosis of Apoptotic bodies
Necrosis
-Inflammation
Chronic (sub-lethal) cell injury leads to what?
Adaptations
What are the different types of cellular adaptations?
Atrophy = diminishment of cells and functionality Hypertrophy = Increase in size Hyperplasia = Increase in number Metaplasia = Intracellular accumulations
What occurs alongside cell atrophy?
Concurrent decrease in organ size and/or funciton
What can cause Atrophy?
Decreased workload Loss of innervention Decreased blood supply Inadequate nutrition Decreased hormonal stimulation Aging Local pressure
What is the morphologic appearance of atrophic cells
Shrunken
Reduction in structural components
Hypertrophy
Increase in cell size and is associated with an increase in functional capacity
What can accompany cellular hypertrophy?
Tissue and/or organ size may increase
AND
It may be accompanied by an increase in cell number (hyperplasia)
What are the different etiologies of hypertrophy?
Response to trophic signals (hormonal)
Response to increased functional demand
What are the types of trophic signaling that lead to cellular hypertrophy?
Normal/Physiologic (ie smooth muscle hypertrophy in pregnant uterus)
Abnormal/Pathologic (ie, exogenous anabolic steroids leading to muscle hypertrophy, and increased TSH leading to a goiter)
What are some examples of hypertrophy to response of increased functional demand?
Muscle hypertrophy - skeletal muscles get bigger with exercise or myocardial cell hypertrophy due to increased pumping workload
Hyperplasia
Increase in the number of cells in a tissue or organ
May involve the proliferation of epithelial and.or stromal cells
May increase the risk for subsequent neoplastic transformation
Hyperplasia is stimulated by what
Trophic factors (hormones and cytokines/GF)
What are some examples of hormones stimulating hyperplasia
Endometrial glandular cells during the normal menstrual cycle
Gynecomastia (hyperplasia of breast in men) secondary to estrogen treatment of prostate cancer
Erythrocyte hyperplasia can follow extopic production of erythropoeitin renal cell carcinoma
Metaplasia
One adult cell type is replaced by another adult cell type in response to chronic stress
Intestinal metaplasia
Replacement of normal epithelium with goblet cells and other intestinal mucosa-type cells
-due to prolonged exposure to reflux gastric contents
Squamous metaplasia
Conversion of normal columnar epithelium to stratified squamous epithelium
Examples include
-respiratory tract in response to smoking
-Ductal epithelium of various glands due to vitamin A deficiency
-Cervix in response to various agents
Mechanisms of intracellular accumulations include what?
Abnormal metabolism
Lack on an enzyme
Abnormal protein folding or transport
Ingestion of indigestible matieral
What are the different types of lipid accumulation
Steatosis
Cholesterol
What things can accumulate in cells
Normal constituents (H2O, lipids, proteins, carbs)
Abnormal substances - either endogenous or exogenous
Pigments
Calcium
Steatosis
An abnormal accumulation of triglycerides within parenchymal cells of the liver, heart, kidney, and skeletal muscle
What is the etiology of Steatosis
Obesity Diabetes EtOH Anorexia Toxins Protein malnutrition
Gross appearance of Steatosis
Enlarged, yellow liver
Microscopic appearance of Steatosis
Hepatocytes contain clear cytoplasmic vacuoles that displace the nucleus
Cholestrol accumulation
Accumulates primarily in macrophages (foam cells)
Cholesterol accumulation in skin
In the subepithelial macrophages forming a Xanthoma
Cholestrol accumulation in vessels
In Atheromas of atherosclerosis
Protein accumulation histology
Eosinophilic cytoplasmic droplets, vacuoles, or aggregates
What are some examples of protein accumulation
a1-anti-trypsin deficiency - impaired folding due to a gene mutation
Mallory bodies - impaired secretion due to improper folding or precipitation
Neurofibrilary triangles in Alzheimer’s disease
What are the different types of pigment accumulation?
Exogenous pigement
Endogenous pigment
What are examples of exogenous pigments
Carbon accumulated in macrophages
Tattoos
What are examples of endogenous pigments
Lipofuscin
Melanin
Hemosiderin
Bilirubin
Lipofuscin
“Wear-and-tear” brown-yellow granular pigment
A lipoprotein complex due to ROS peroxidation of membranes
Melanin
Balck-brown pigment
Produced by melanocytes by accumulated in adjacent epidermal cells and in macrophages
