Chapter 2: Cellular Responses to Stress and Toxic Insults: Adaptations, Injury, Death Flashcards
Study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlie disease
Pathology
Common reactions of cells and tissues to injurious stimuli; not tissue specific (ex: acute inflammation in response to bacterial infections produces similar reaction in most tissues)
General pathology
alterations and underlying mechanisms in organ specific diseases such as ischemic heart disease
systemic pathology
- cause of disease=______
- sequence of cellular, biochemical, and molecular events that follow the exposure of cells or tissues to an inhurious agent= ______
- structural alterations induced in the cells and organs of the body that are either characteristic of a disease or diagnostic of an etiologic process= ______
- functional consequences of the changes=_____
- etiology
- pathogenesis
- morphologic changes
- clinical manifestations
Etiology can be grouped into what two classes?
Genetic: (inherited mutations and disease associated gene variants or poymorphisms)
Acquired: ex: infectious, nutritional, chemical or physical
The end results of genetic, biochemical and structural changes in cells and tissues are _____
Functional abnormalities which lead to clinical manifestations (symptoms and signs)
How do diseases start?
cell injury–>tissue injury–>organ injury
Increase in cell SIZE that results in an increase in the size of affected organ
hypertrophy
*Hypertrophy is the result of increased production of cellular proteins!
increase in cell NUMBER in organ or tissue in response to stimulus
hyperplasia
decrease in size and metabolic activity of cells; reduction in size of organ or tissue due to a decrease in cell size and number
atrophy
change in phenotype of cells
metaplasia
When limits of adaptive responses are exceeded or if cells are exposed to injurious agents or stress, deprived of essential nutrients or become compromised by mutations that affect essential cellular constituents, _____ results
cell injury
Is cell injury reversible?
Yes, but only upto certain point. If stimulus persists/is severe, cell suffers IRREVERSIBLE injury leading to cell death
Adaptation–>reversible injury–>cell death
Cell death is the end result of progressive cell injury. What are some of the causes of cell death?
ischemia (reduced blood flow), infection, toxin
May also be physiologic: embryogenesis, organ development and maintainence of homeostasis
Two pathways of cell death are?
Necrosis and apoptosis
*Nutrient deprovation triggers an adaptive cellular response called autophagy that also results in cell death
Metabolic derangement of cells and sublethal, chronic injury may be associated with ______ of lipids, proteins and carbs
intracellular accumulations
What is often deposited at sites of cell death?
Ca, leading to pathologic calcification
Reversible changes in size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment
Adaptations
What is the most common stimulus for hypertrophy of muscle?
increased work load
What causes hypertrophy of the heart?
chronic hemodynamic overload resulting from hypertension or faulty valves
Example of hormone induced enlargement of an organ from hypertrophy?
uterus during pregnancy–estrogen induced
First step in cardiac hypertrophy
integrated actions of mechanical sensors (triggered by increased workload), growth factors (TGF-B, IGF-1, FGF), and vasoactive agents (a-adrenergic, endothelin-1, and angiotensin II)
Second step in cardiac hypertrophy:
Signal transduction: PI3 kinase/AKT pathway (excercise induced hypertrophy), GPCR induced by growth factors and vasoactive agents (pathologic hypertrophy)
Third step in cardiac hypertrophy11
activation of transcription factors like GATA4, NFAT, MEF2 which all coordinate to increase the synthesis of proteins that are responsible for hypertrophy
Example of hypertrophy switching contractile proteins:
alpha isoform of myosin heavy chain is replaced by the B isoform which has slower, more energenetically economical contraction (from adult to fetal forms)
Some genes that are expressed only during early development are reexpressed in hypertrophic cells. Example?
gene for atrial natriuretic factor expressed in both the atrium and the ventricle in embryonic heart but is down-regulated after birth but in cardiac hypertrophy, ANF gene expression increases
When the heart is no longer capable of adaptation via hypertrophy, what happens?
Regressive changes occur in myocardial fibers–lysis and loss of myofibrillar contractile elements–can lead to myocyte death resulting in cardiac failure
Drugs used to inhibit the signaling pathways in the heart to prevent damage target which transcription factors?
NFAT, GATA 4, and MEF2 genes
_____ due to the action of hormones or growth factors occurs in several circumstances: when there is a need to increase functional capacity of hormone sensitive organs; when there is need for compensatory increase after damage or resection
Pathologic hyperplasia
proliferation of glandular epithelium of female breast at puberty and during pregnancy is example of ____
hormonal hyperplasia
*this process is usually accompanied by enlargement (hypertrophy)
cells of the liver can proliferate so that organ grows back to normal size after resection is example of ____
compensatory hyperplasia
Bone marrow undergoing hyperplasia after acute bleed or after hemolysis uses which growth factor to stimulate the growth of red cell progenitors?
Erythropoietin
Most forms of pathologic hyperplasia are caused by _____. Example?
excessive or inappropriate actions of hormones or growth factors acting on cells
Ex: endometrial hyperplasia resulting from disturbance of balance between estrogen and progestrone resulting in increase in estrogen–PATHOLOGIC
Benign prostatic hyperplasia is another example of pathologic hyperplasia induced in responses to hormonal stimulation by ____
androgens
Is hyperplasia the same as cancer?
No. While hyperplasia is distinct from cancer, pathologic hyperplasia constitutes a basis for which cancerous proliferations may arise—example: endometrial hyperplasia can lead to endometrial cancer
Hyperplasia is a characteristic response to what kind of infections?
viral infections]
ex: paillomavirus which cause skin warts and several mucosal lesions composed of masses of hyperplastic epithelium (viruses make factors that interfere with host proteins that regulate cell proliferation)–can be precursor to cancer like other hyperplasias
Hyperplasia is the result of ?
growth factor-driven proliferation of mature cells and, in some cases, by increased output of new cells from tissue stem cells
Examples of physiological atrophy
notochord and thyroglossal duct; decrease in size of uterus after parturition
6 main causes of pathologic atrophy:
- Decreased workload (atrophy of disuse)
- Loss of innervation (denervation atrophy)
- Diminished blood supply
- Inadequate nutrition
- Loss of endocrine stimulation
- Pressure
Name the cause of atrophy: when fractured bone is immobilized in a plaster cast or when a patient is restricted to bed rest resulting in skeletal muscle atrophy
atrophy of disuse
Name the cause of atrophy: damage to nerve leads to atrophy of muscle fibers supplied by those nerves
Loss of innervation
Name cause of atrophy: brain undergoes progressive atrophy bc of reduced blood supply (ischemia) as a result of artherosclerosis (senile atrophy–also affect heart)
Diminished blood supply
Name cause of atrophy: Protein-calorie malnutrition (marasmus) associated with utilization of skeletal muscle proteins as a source of energy after other reserves like adipose tissue have been depleted
Inadequate nutrtion
–leads to muscle wasting=cachexia; also seen with chronic inflammatory diseases and cancer mediated by TNF
Name cause of atrophy: Loss of estrogen stimulation after menopause results in physiologic atrophy of the endometrium, vaginal epithelium and breast
Loss of endocrine stimulation
Name cause of atrophy: an enlarging benign tumor causing atrophy in surrounding uninvolved tissues
Pressure
- due to ischemic changes caused by compromise of blood supply by pressure exerted by expanding mass
What are the fundamental cellular changes associated with atrophy?
decrease in cell size and organelles, reduction of metabolic needs of cell sufficiently to permit its survival
What happens early in the process of atrophic cells/tissues?
they have diminished function but CELL DEATH IS MINIMAL! But atrophy caused by gradually reduced blood supply may progress to the point at which cells are irreversibly injured and die by apoptosis
What is the mechanism of atrophy?
Results from decreased protein synthesis and increased protein degradation in cells which occurs via the ubiquitin-proteasome pathway: Nutrient deficiency and disuse may activate ubiquitin ligases which attach the ubiquitin peptide to cellular proteins for degradation in proteasomes
The process in which the starved cell eats its own components in an attempt to reduce its nutrient demand to match the supply is called ______
autophagy
In autophagy, the cell debris in the autophagic vacuoles that resist digestion and persist in the cytoplasm as membrane bound is called ________
residual bodies
This is an example of a residual body and when it is present in sufficient amounts, they impart a brown discoloration to the tissue (brown atrophy)
Lifofuscin granules
This is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type
Metaplasia
The most common epithelial metaplasia is _____
columnar to squamous
Ex: respiratory tract in response to chronic irritation
Examples of metaplasia:
- Smoking: ciliated columnar in trachea/bronchi–>stratified squamous
- Stones in excretory ducts of salivary glands, pancreas, or bile ducts: secretory columnar–>stratified squamous
- Vit. A deficiency: induces squamous metaplasia in respiratory epithelium
Metaplasia allows for better adaptation to enviornment, but what is the caveat?
The original cell served an important function that the new cell type cannot do. For example: in resp. tract, although the epithelial tract becomes tough, important mechanisms of protection against infectionn–mucous secretion and ciliary action of columnar epithelium–are lost
Example of squamous TO columnar metaplasia:
Barret esophagus in which the esophageal squamous epithelium is replaced by intestinal-like columnar cells due to gastric acid; cancers may arise in these areas (glandular adenocarcinomas)
Formation of cartilage, bone, or adipose tissues that normally do not contain these elements is called ____. Example?
connective tissue metaplasia
example: myositis ossificans after intramuscular hemmorage results in bone formation in muscle–result of cell/tissue injury
What is the mechanism of metaplasia? does it result from a change in phenotype of an already differentiated cell type?
No. It is the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue
- alter the activity of transcription factors that regulate differentiation (example: retinoic acid)
Hallmarks of reversible cell injury?
- reduced oxidative phosphorylation leading to low ATP
- cellular swelling caused by changes in ion concentrations and water influx
- changes in intracellular organelles like mitochondria and cytoskeleton
cell death characterized as “accidental” and unregulated resulting from damage to cell membranes and loss of ion homeostasis; lysosomal enzymes enter cytoplasm and digest the cell, cellular contents leak through the damaged plasma membrane into extracellular space where they elicit host reaction (inflammation)
Necrosis
Cell death characterized by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity and rapid removal of cellular debris and NO leakage of cellular contents so NO INFLAMMATION!
Apoptosis
Is necrosis pathological or physiological? What about apoptosis??
Necrosis is ALWAYS pathologic; apoptosis serves many normal functions and is not necessarily associated with cell injury
What is necroptosis?
A form of necrosis that is also a form of programmed cell death regulated by a series of signaling pathways
What are the 7 main categories of injurious stimuli leading to cell injury?
- Oxygen deprivation (hypoxia)
- Physical agents
- Chemical agents and Drugs
- Infectious agents
- Immunologic reactions
- Genetic derangements
- Nutritional imbalances
Causes of hypoxia:
ischeia (reduced blood flow), inadequate oxygenation of blood due to cardiorespiratory failure, and decreased oxygen-carrying capacity of blood as seen in anemia orCO poisoning or after severe blood loss
What are physical agents capable of causing cell injury?
mechanical trauma, extremes of temperature (burns and deep cold), sudden changes in atmospheric pressure, radiation and electric shock
Chemicals that may produce cell injury
glucose or salt in hypertonic concentrations, O2 at high concetrations, poisons like arsenic, cyanide or mercuric salts, air pollutants, insecticides, herbicides, CO, asbestos, alcohol and even therapeutic drugs
Infectious agents that can cause cell injury
submicroscopic virus, tapeworms, rickettsiae, bacteria, fungi, and higher forms of parasites
Immunologic reactions that cause cell injury
injurious reactions to endogenous self antigens leading to autoimmune disease, immune rxn to external agents like viruses
How do genetic defects cause cell injury?
Because of deficiency of functional proteins like enzyme defects in inborn errors of metabolism or accumulation of damaged DNA or misfolded protein leading to cell death.
Examples of nutritional imbalances leading to cell injury:
protein-calorie deficiency leading to death, vitamin deficiencies, anorexia nervosa; nutritional excess can also cause cell injury: cholestrol leading to artherosclerosis, obesity associated with diabetes and cancer
Which method detects the changes associated with cell death/injury first–histochemical/ultrastructural technique or light microscopy?
histochemical/ultrastructural–minutes to hours
light microscopy–hours to days
*morphologic manifestation of necrosis takes more time to develop than reversible damage such as ischemia of myocardium–swelling–in minutes
Reversible cell injury characterized by:
genralized swelling of cell and its organelles, belbbing of plasma membrane, detachment of ribosomes from ER and climbing of nuclear chromatin; leads to decreased ATP,loss of cell membrane integrity, defect in protein synthesis, cytoskeletal damage and DNA damage
Severe mitochondrial damage with depletion of ATP and rupture of lysosomal and plasma membranes are associated with necrosis or apoptosis?
Necrosis
What two important features of reversible cell injury can be recognized under the light microscope?
Cellular swelling fatty change (lipid vacuoles in cytoplasm)--seen in hepatocytes and myocardial cells
cellular swelling affecting many cells in organ causing pallor, increased turgor, and increase in weight of organ; small clear vacuoles in cytoplasm; this pattern of non lethal injury is called ____
hydrophic change or vacuolar degeneration
- cells may also show increased eosinophilic staining which becomes more pronounced with progression to necrosis
Ultrastructural changes of reversible cell injury:
plasma membrnae blebbing/blunting/loss of microvilli
mitochondrial swelling and appearance of small amorphous densities
Dilation of ER with detachment of polysomes–intracytoplasmic myelin figures
nuclear alterations with disaggregation of granular and fibrillar elements
The morphologic appearance of ____ as well as ____ is the result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell
necrosis, necroptosis
Where do the enzymes that digest the necrotic cell come from?
lysosomes of dying cells themselves and from lysosomes of leukocytes involved in inflammatory reaction
The EARLIEST histologic change from myocardial necrosis does not become apparent until ____ later
4-12 hours later
*BUT because of loss of plasma membrane integrity, cardiac specific enzymes and proteins are rapidly released from necrotic muscle and can be detected in blood 2 hrs after necrosis
Necrotic cells show increased _____ atrributable to loss of cytoplasmic RNA (which binds the blue dye, hematoxylin) and in part to denatured cytoplasmic proteins (which bind the red dye eiosin)
eosinophilia in H&E stains
*loss of glycogen particles makes necrotic cells have glassy homogenous appearance than normal cells
In necrotic cells, dead cells may be replaced by large whorled phospholipid masses called _____derived from damaged cell membranes
myelin figures; phospholipid percipitates and is then phagocytosed by other cells and further degraded into fatty acids–calcification of such fatty acids results in calcium soaps–dead cell becomes calcified
In electron microscopy, what are necrotic cells characterized by?
Discontinuities in plasma and organelle membranes, marked dilation of mitochondria with the appearance of large amorphous densities, intracytoplasmic myelin figures, amorphous debris, and aggregates of fluffy material probably representing denatured protein
What 3 nuclear change patterns do you see in necrosis due to non-specific breakdown of DNA?
- Karyolysis: basophilia of chromatin may fade, reflects loss of DNA bc of enzymatic degradation by endonucleases
- pyknosis: nuclear shrinkage and increased basophilia–chromatin condenses into solid, shrunken basophilic mass
- karyorrhexis: pyknotic nucleus undergoes fragmentation
* After a day or two, the nucleus in the necrotic cell disappears
Architecture of dead tissues is preserved for at least some days; firm texture; proteolysis of dead cells is blocked so eosinophilia, anucleate cells may persist for days or weeks
Coagulative necrosis
Ischemia caused by obstruction in a vessel may lead to coagulative necrosis in all organs except ____
The brain
A localized area of coagulative necrosis is called an ______
Infarct