Lecture 1/2 - Cell Injury, Death, and Cell Adaptations Flashcards
Fundamental concepts in cell injury
- Clinical signs and symptoms are several steps removed morphologic changes that are preceded by the biochemical changes associated with cell injury
- Cell injury is common to all pathologic processes
- Cell injury results from a disruption of one or more of the cellular components that maintain cell viability
- Cell injury may be reversible or result in cell adaptation ofdeath
Oxygen deprivation
hypoxia
ischemia
anemia
infectious agents
bacteria
viruses
fungi
parasites
physical changes
trauma electricity pollutants burns UV light radiation
chemical agents and drugs
tobacco
alcohol
posions
Rx/ OTC drugs
immunologic reactions
allergies and autoimmune disease
genetic derangement
chromosome abnormalities
gene mutations
nutritional imblanace
malnutrition
vitamin deficiecy
obesity
What are the causes of cell injury from the cell’s perspective?
cell injury results from a disruption of one of more of the cellular components that maintain cell viability
-Divergent factors can act at the same point on the cell to induce cell injury
The structures and processes that maintain cell viability include:
plasma membrane
mitochondria
macromolecular synthesis
nucleus
There are several basic biochemical themes in cell injury, what are they?
ATP depletion generation of ROS (oxidative stress) loss of calcium homeostasis altered plasma membrane permeability mitochondrial damage DNA and protein damage
Cell injury by impaired energy production - decreased oxygen (hypoxia) or no oxygen (anoxia) is due to:
impaired absorption of oxygen
decreased blood flow (ischemia)
disease of blood or blood vessels
inadequate oxygenation of the blood
decreased oxygen impairs oxidative phosphorylation in the…
mitochondria
reduced ATP reduces the ability of the plasma membrane to maintain homeostasis. This leads to …
a net gain of solute and an isosmotic gain in cytoplasmic water
an isosmotic gain in water leads to:
- cell swelling with formation of cell surface blebs
- swelling of mitochondria
- dilation of the endoplasmic reticulum that leads to: detachment of ribosomes from RER and dissociation of polysomes an decrease in protein synthesis - can lead to increased lipid deposition
reduced oxidative phosphorylation leads to increased ________
glycolysis
increase glycolysis produces
lactic acid and inorganic phosphates that decrease intracellular pH leading to chromatin clumping
what is hypoglycemia
reduced substrate for ATP production can result in the same basic patterns
From wiki: is a medical emergency that involves an abnormally diminished content of glucose in the blood.[1] The term literally means “low blood sugar” It can produce a variety of symptoms and effects but the principal problems arise from an inadequate supply of glucose to the brain, resulting in impairment of function (neuroglycopenia)
ROS are free radicals that are generated by
normal endogenous oxidative reactions in the plasma membrane, mitochondria, cytoplasm and peroxisomes
Generations of ROS is associated with:
Inflammation oxygen toxicity chemicals irradiation aging
Types of ROS (3 of them)
- Superoxide (O2-) - inactived spontaneously or by superoxide dismutase (SOD) to form H2O2
- Hydrogren peroxide (H2O2) - detoxified by glutathione peroxidase and catalase
- Hydroxyl radicals (OH) - generated by hydrolysis or water by ionizing radiation or by transitional metals such as Fe++ or Cu++
ROS damage cells by:
- lipid peroxidation
- protein (cytoplasmic and membrane bound) cross-linking
- react with thymiddine and guanine to induce single strand DNA breaks
intracellular and extracellular antioxidant systems act to reduce the effects of ROS by blocking their initiation or by inactivating them. These include:
- Intracellular - SOD, catalase and glutathione peroxidase
- Extracellular - vitamins E, A, and C and serum proteins that bind free iron (transferrin, ferritin) and copper (ceruloplasmin)
Cytoplasmic Ca++ is maintained by protein sequestration in the…
cytoplasm, mitochondria, and endoplasmic reticulum
increase cytoplasmic Ca++ is a final common pathway of what?
cell injury
high levels of Ca++ will activate various degradative enzymes including:
phospholipases
proteases
endonucleases
ATPase
What are other causes of cell membrane injury? (5 of them)
- Complement - C5-C9 membrane attack complex
- Cytotoxic T cells - perforin
- Viral
- Bacterial endotoxins and exotoxins
- Chemicals
Biochemical alterations occur prior to
morphologic changes
degree of cell injury is partly determined by…
- cell type and its physiological state
- the intensity, duration, and/or number of exposures to an etiological agent
cell injury may result in..
- reversible cell injury
- cellular adaptations associated with changes in cell number, size or differentiation
- cellular adaptations associated with abnormal accumulations
- cell death (necrosis or apoptosis)
reversible cell injury is acute in nature in occurs when the cell cannot maintain what?
normal homeostasis due to cell injury of short duration and minimal intensity
common etilogies of reversible(sub-lethal) cell injury include:
toxins
infectious agents
hypoxia
thermal injury
what are the two types of morphology with reversible cell injury?
hydropic change and fatty change
- Plasma membrane injury leads to increase intracellular Na+ that leads to an isosmotic gain in water
- organelles and cells swell, and the organ may appear pale and swollen
What are the concepts of cell death?
- There is NO SINGLE biochemical event that equates with cell death
- There are two morphologic forms of cell death - necrosis and apoptosis
- Cell death leads to the release of cellular constituents into the extracellular environment
Morphologic changes in necrosis include: (5 of them)
- Cell swelling
- Protein denaturation yielding a glassy homogenous pink staining cytoplasm
- Organelle breakdown may result in vacuolated cytoplasm
- Nuclei changes include: karyolysis, pyknosis, karyorrhexis, or total loss
- Inflammation - acute or granulomatous
The type of necrosis is dependent upon what?
patterns of enzymatic degradation and by bacterial byproducts when present
What is the most common from of necrosis?
coagulative
(cytoplasmic proteins are coagulated)
- The nucleus is lost, but the eosinophilic outline of the cell is retained for a short time prior to being removed by the inflammatory response
Which type of necrosis is described: tissue is totally digested by the release of lysosomal enzymes during the acute inflammatory response?
liquefactive necrosis (“pus”, purulence)
Which type of necrosis is often associated with focal bacterial or fungal infections (eg. abscesses and wet gangrene), it is also seen in the CNS
liquefactive necrosis
Which type of necrosis is associated with M. tuberculosis infection?
caseous necrosis
Which type of necrosis displays gross features of the tissue having a white and “cheesy” appearance?
YUMMMMMMM this makes me want a cheeseburger
caseous necrosis
Which type of necrosis is described: microscopically charactererized as amorphous pink granular material within a ring of granulomatous inflammation and loss of tissue architecture
caseous necrosis
which type of necrosis is common in trauma to the breast or in cases of pancreatitis?
fat necrosis
which type of necrosis has a gross appearance of chalky white-yellow
fat necrosis
which type of necrosis give a “soap bubble” histologic appearance because of its dead adipocytes
fat necrosis
What is another name for programmed cell death?
apoptosis
What are the general concepts of apoptosis?
- morphologically distinct, gene directed, form of individual cell death
- it has a physiologic role
- diseases may arise from an increase or from a decrease in the rate of apoptosis
Morphologic features of apoptosis include: (4 of them)
- Cell shrinkage
- Chromatin condensation followed by fragmentation
- Apoptotic bodies formation
- Phagocytosis of the apoptotic bodies without a significant inflammatory response
What are the SIGNALING mechanisms of apoptosis?
intrinsic program "death signals" (e.g. Fas- ligand binding to Fas receptor) removal of a trophic signal (hormones) ROS, radiation and toxins effect of cytotoxic T cells
What are the CONTROL AND INTEGRATION mechanisms of apoptosis?
(two pathways)
- direct signaling (e.g. Fas ligand, TNF binding)
2. regulation of mitochondrial permeability
In the control and integration mechanisms of apoptosis what is the role of the Bcl-2 gene?
Bcl-2 gene family serve as on and off switches that regulate the membrane permeability of the mitochondria (Bcl-2, Bax, Bak)
- Bcl-2 and cl-x gene products INHIBIT apoptosis
- Bax and bax gene products STIMULATE apoptosis
What is released from the outer mitochondrial membrane and serves to disrupt the inhibitory function of Bcl-2, favoring apoptosis?
cytochrome-c
mechanisms of apoptosis category execution - what are caspases?
apoptosis signaling pathways converge on an autocatalytic proteolytic cascade of caspases.
Their substrates include: cytoskeletal and nuclear matrix proteins, DNAse and transcription proteins
In apoptosis the mitochondria release Ca that activates which two enzymes?
- transglutaminases cross link cytoplasmic proteins
2. Endonucleases cleave DNA at the linker regions b/w nucleosomes
In apoptosis how are dead cells removed?
- phagocytosis by neighboring cells and macrophages
- little or no inflammation
How is apoptosis difference than necrosis in relation to STIMULI?
apoptosis: physiologic or pathologic
necrosis: hypoxia or toxins
How is apoptosis difference than necrosis in relation to: MORPHOLOGY?
apoptosis: single cells, cell shrinkage, condensed chromatin, intact plasma membrane, apoptotic bodies
necrosis: multiple cells, cellular swelling, lysed plasma membrane, organelle disruption
How is apoptosis difference than necrosis in relation to: MECHANISMS OF DNA DESTRUCTION?
Apoptosis: ATP DEpendent process, gene activation and endonuclease mediated DNA fragmentation
Necrosis: ATP INDEPENDENT process, random, diffuse, free radicals, membrane injury
How is apoptosis difference than necrosis in relation to: TISSUE REACTION?
apoptosis: minimal inflammation, phagocytosis of apoptotic bodies
necrosis: inflammation
Chronic cell injury leads to cell adaptations, the etiological factors are the same as those that cause reversible cell injury or cell death, but differ in….
duration and intensity
cell adaptations include:
- alterations in cell size (atrophy vs. hypertrophy)
- alterations in cell number (hyperplasia)
- alterations in cell differentiation (metaplasia)
- intracellular accumulations
What is the definition of atrophy
a decrease in cell size and function
*there is often concurrent decrease in organ size and/ or function
What is the etiology of atrophy?
- decreased workload
- loss of innervation
- decreased blood supply
- inadequate nutrition
- decreased trophic signals
- aging
- local pressure
what is the morphologic appearance of atrophy?
- atrophic cells are shrunken
- there is a reduction in structural components
what is the definition of hypertrophy?
an increase in cell size
- associated with an increase in functional capacity
- tissue and/ or organ size may increase and may be accompanied by an increase in cell number (hyperplasia)
in reference to hypertrophy, what is a NORMAL (physiologic) response to trophic signals (hormone stimulation)?
smooth muscle hypertrophy in the pregnant uterus
in reference to hypertrophy, what is an ABNORMAL (pathologic) response to trophic signals (hormone stimulation)?
- exogenous anabolic steroids induced muscle hypertrophy
- overproduction of TSH due to iodine deficiency induces thyroid follicle hypertrophy (goiter)
increased functional demand (muscle hypertrophy) skeletal muscle cells hypertrophy in response to…
exercise
When and why do myocardial cells hypertrophy?
due to increased workload of pumping against impaired aortic outflow or systemic hypertension
What is the definition of hyperplasia?
an increase in the number of cells in a tissue or organ
- may involve the proliferation of epithelial and/ or stromal cells
- cell proliferation is stimulated by trophic factors (hormones and cytokines)
- may increase the risk for subsequent neoplastic transformation
what is the etiology of hyperplasia? (in relation to hormones)
hormones can stimulate hyperplasia:
- endometrial glandular cells during the normal menstrual cycle
- gynecomastia (hyperplasia of the breast in men) can be iatrogenic in its etiology (i.e. secondary to estrogen treatment for prostate cancer
- erythrocyte hyperplasia can follow ectopic production or erythropoietin
What is the etiology of hyperplasia? (in relation to growth factors)
growth factors can stimulate hyperplasia:
- wound healing represents hyperplasia of CT cells as well as associated epithelial cells
- lymph node hyperplasia is due to lymphocyte hyperplasia resulting during chromic inflammation and an immune response
- epidermal cell hyperplasia leads to a callus due to repeated friction
- chronic inflammation can induce hyperplasia of overlying epithelial cells
definition of metaplasia
one adult cell type is replaced by another adult cell type in response to chronic stress
intestinal metaplasia relates to replacement of
normal epithelium with goblet cells and other intestinal mucosal type cells
what is Barrett’s esophagitis?
the normal stratified squamous epithelium of the esophagus being replaced due to prolonged exposure to reflux gastric contents
squamous metaplasia is conversion of
normal columnar eptiehlium to stratified squamous epithelium
what are some examples of squamous metaplasia
- Resp. tract in response to chronic smoking
- ductal epithelium of various glands in response to vitamin A deficiency
- cervix in response to various agents
categories of cell accumulations include:
-excess of normal cellular constituent such as water, lipids, proteins, and carbohydrates and pigments that may be exogenous or endogenous
the mechanisms of intracellular accumulations include:
- abnormal metabolism
- lack of enzyme
- abnormal protein folding or transport
- ingestion of indigestible material
what is a steatosis
it is a fatty liver
- an abnormal accumulation of triglycerides within paenchymal cells of the liver, heart, kidney, and skeletal muscle
what is the etiology of lipid accumulation (steatosis)
obesity diabetes alcohol anorexia toxins protein malnutrition
what is the gross appearance of a fatty liver?
enlarged yellow (3-6 kg) liver
what is the microscopic appearance of a fatty liver?
hepatocytes contain clear cytoplasmic vacuoles that displace the nucleus
where does cholesterol primarily accumulate?
macrophages (foam cells)
- skin - in subepithelial macrophages forming a xanthoma
vessels - in atheromas of atherosclerosis
what is the histology of proteins
eosinophillic cytoplasmic droplets, vacuoles, or aggregates
what are examples of proteins?
- alpha 1 anti trypsin deficiency - impaired folding due to gene mutation
- mallory bodies - impaired secretions due to improper folding or precipitation
- neurofibrillary tangles in Alzheimer’s disease - accumulations of microtubule associated proteins and neurofilaments
what is the morpholog of glycogen/ glucose?
clear cytoplasmic/ nuclear vacuoles, PAS (+)
what is a glycogen storage disease?
abnormal glycogen metabolism due to enzyme deficiency
what are some examples of exogenous pigments?
- carbon is accumulated in makcrophages, (anthracosis vs. pneumoconiosis)
- tattoos - pigment is accumulated locally
what is lipofuscin?
“wear and tear” brown-yellow granular pigment
-lipoprotein complex due to ROS peroxidation of membranes
definition of melanin?
black-brown pigment produced by melanocytes but accumulated in adjacent epidermal cells and in macrophages
what is hemosiderin?
- a yellow brown pigment represents aggregates of ferritin micelles
- ## its accumulation arises from excess iron locally due to hemorrhage and can lead to hemosiderosis
what is hemochromatosis
genetic disease associated with cell death due to uncompensated hemosiderin accumulation
what is bilirubin?
- brown yellow pigment
- end produce of heme metabolism
- accumulates in heptaocytes and bile ducts due to hemolysis, obstructed bile flow and or hepatocellular disease
