Cellular Reactions to Injury: Apoptosis and Adaptations Flashcards
what is autophagy
- cellular autodigestive system
- transfer of cytoplasmic contents to lysosomes for degradation
purpose of autophagy
rids cells of misfolded proteins, damaged organelles and microbes
autophagy is one of the most important survival responses to
- starvation
- the starving cell reallocates nutrients from unnecessary processes to more essential ones
how are normal endogenous substances produced
at a normal or increased rate, but the rate of metabolism is inadequate to remove it (liver fatty change)
why would normal endogenous substances accumulate
because of defects in enzymes responsible for its metabolism (lysosomal storage disease)
how are abnormal substances accumulated
- endogenous misfolded proteins are a produce by a mutated gene (alpha 1- antitrypsin)
- exogenous ingestion of non-metabolizable materials (Silica, carbon, etc)
what is steatosis (fatty change)
the abnormal accumulation of triglycerides
what organ is steatosis seen in
liver bc it is the major organ involved in fat metabolism
what is the most common cause of steatosis
- alcohol abuse
- nonalcoholic fatty liver disease
- obesity
- diabetes
disorders in cholesterol metabolism leads to what
accumulation of cholesterol which is seen in multiple disease processes
ex. cholesterol granuloma, xanthomas
what happens with atherosclerotic plaques
-cholesterol and cholesterol esters accumulate in smooth muscle cells and macrophages within the intimal layer of large arteries
what is characteristic of advanced atherosclerosis
yellow cholesterol-laden atheromas
what is glycogen
an energy source
where is glycogen stored
in the cytoplasm of healthy cells
disorders in glucose or glycogen metabolism can lead to
excessive intracellular deposits of glycogen
in DM where is glycogen found
in renal, liver, heart muscle cells
glycogen storage disease can cause
massive glycogen accumulation and cause cell injury and death
in DM glycogen can accumulate in renal tubular epithelial cells and cause
nodular glomerulosclerosis
name 2 exogenous pigments
- carbon (coal dust)
2. Tattooing
what is the most common exogenous pigment
carbon (coal dust)
what is carbon (coal dust) pigment
- present as air pollutants
- inhaled and engulfed by macrophages within the alveoli and transported through lymphatic channels to the regional lymph nodes
what can carbon (coal dust) lead to
anthracosis of lung and lymph nodes
what are tattooing pigments
- an exogenous pigmentation
- pigments are engulfed by macrophages but are not degraded
do tattooing pigments evoke an inflammatory response
Not usually
name 3 endogenous pigments
- lipofuscin
- melanin
- hemosiderin
what is lipofuscin
- insoluble brown pigment
- phospholipids in complex with protein
- weak and tear pigments
what is melanin
-brown-black pigment
what is melanin formed by
melanocytes
what is hemosiderin
- golden yellow-to-brown
- granular or crystalline
when does hemosiderin form
when there is local or systemic iron excess to bleeding in some area
what are Russel bodies
globs of immunoglobins that accumulate
what are dutcher bodies
accumulation of protein
appear are pale blue bodies
what is dystrophic calcification
when cells lose their ability to regulate intracellular calcium and crystalline calcium phosphate forms
when does dystrophic calcification occur
-in dead/dying tissues in absence of systemic hypercalcemia
what is metastatic calcification
-calcium salts deposit due to hypercalcemia (ie. increased parathyroid hormone, Paget’s disease)
where does metastatic calcification occur
in normal tissues
what causes biological aging
- decreased cellular replication
- defective protein homeostasis
- environmental and metabolic insults
decreased cellular replication (replicative senescence)
-shortened telomers, short repetitive nucleotide sequences at 3’end of DNA
defective protein homeostasis
- reduced protein translation
- defective chaperone activity
environmental and metabolic insults
-accumulation of DNA, protein, phospholipid damage
what are the diseases of premature aging
- Hutchinson-Guilford progeria
2. Werner Syndrome
what is Hutchinson-Guilford progeria
-a disease of premature aging
what is the mechanism of Hutchinson-Guilford progeria
- mutation in LMNA gene (encodes lamin A protein)
- defective lamin A precurson protein termed Progerin
- Progerin accumulates in nucleus (no longer round, irregular shaped)
what are the characteristics of Hutchinson-Guilford progeria
- see features of aging (male pattern baldness, atheroscelrosis/coronary artery disease)
- typical lifespan less than 10 yrs
what is Werner Syndrome
- a disease of premature aging
- a mutation in WRN gene, which codes for a protein with multiple DNA-dependent enzymatic activities
- increased cancer risk
- typically die in 5th decade
what is the function of the WRN gene
plays a role in telomere length maintenance and processing of DNA damage
what are characteristics of Werner Syndrome
-early cataracts, hair loss, skin atrophy, osteoporosis and atherosclerosis
what is apoptosis
- programmed cell death in which activated enzymes degrade the DNA/proteins
- ATP-dependent process
- involves single cells or small groups of cells
where does apoptosis occur
in both physiologic and pathologic situations
what is the function of apoptosis
- role in developing and maintaining health by eliminating old, unhealthy or unnecessary cells
- apoptotic cells break up into apoptotic bodies, membrane-bound vesicles of cytosol and organelles
what happens to apoptotic bodies
are rapidly extruded and phagocytosed
does apoptosis produce inflammation
NO!
what are 4 types of physiologic apoptosis
- embryogenesis
- hormone-dependent tissue
- maintaining adequate cellular number
- elimination of self-reactive (harmful) lymphocytes
- elimination of “no longer needed” cells
define embyogenesis
Implantation, organogenesis, developmental involution
define hormone-dependent tissue
endometrial cell breakdown (menstrual cycle), ovarian follicular atresia (menopause), regression of the lactating breast
maintaining adequate cellular number includes
antigenic selection of lymphocytes in bone marrow and thymus
when does elimination of “no longer needed” cells occur
at the end of the inflammatory response
what is pathologic apoptosis
not physiologic apoptosis
eliminates cells that have been irreversibly damaged avoiding inflammation and additional damage to surrounding tissue
what are the causes of pathologic apoptosis
- DNA damage
- Protein misfolding
- infections
DNA damage
- direct or indirect (ROS) damage caused by radiation, drugs, hypoxia
- intrinsic cell destruction is started to avoid DNA mutation
protein misfolding
improper protein expression of mutated genes leads to accumulation of misfolded proteins causing ER stress and apoptotic cell death
infections
mediated by infections agent (virus) or host immune response (cytotoxic T lymphocytes)
what are morphologic changes associated with Apoptosis
- cell shrinkage
- chromatin condensation
- formation of apoptotic bodies
- macrophage phagocytosis
what are the biochemical features of apoptosis
- activation of caspases
- DNA and protein breakdown
- membrane alteration and recognition by phagocytes
what triggers apoptosis to begin
activation of caspases (cleavage of pro-enzymatic inactive state)
what are caspases
family of cysteine proteases cleaving after aspartic acid residues
what are 2 functional groups of caspases
- initiators (caspases 8,9)
- executioners (caspases 3,6)
what can DNA be cleaved by in agarose DNA gels
Ca++ and Mg++ dependent endonucleases btwn nucleosomal subunits
what will viable cells look like in DNA gels
intact DNA
what will apoptotic cells look like in DNA gels
ladder pattern of DNA fragments, which represent multiples of oligonucleosomes
what does necrotic cells look like in DNA gels
diffuse smearing of DNA
describe how membrane alterations can contribute to apoptosis
- Phosphatidylserine on the cell membrane move from the inner to outer leaflet where they are recognized by a number of receptors on phagocytes
- Adhesive glycoproteins are expressed on some apoptotic bodies, recognized by phagocytes
describe the main mechanism of Apoptosis
- intrinsic mitochondrial)
- extrinsic (death receptor-mediated)
- cytotoxic CD8+ T-cell (perforin/granzyme-mediated)
Through distinct mechanisms, pathways converge to activate caspases, the actual mediators of cell death
what are the main players of viable cells in the mitochondria that aid with apoptosis
-cytochrome c
Bcl family of pro- and anti-apoptotic proteins
what are the main players of viable cells in the cytoplasm that defend against apoptosis
Bcl-2 and Bcl-x
what are Bcl-2 and Bcl-x
are anti-apoptotic proteins present in cytoplasm and mt and prevent mitochondrial protein leakage
when are Bcl damage sensor proteins activated
in the presence of ER stress of DNA damage
what activates pro-apoptotic Bax and Bak
-damage sensors
what forms when pro-apoptotic Bax and Bak are activated
oligomers and insert into mitochondrial membrane allowing leakage of contents
what does Bcl-2 and Bcl-x anti-apoptotic proteins do
-prevent pores leakage of contents by preventing formation of pores
when is cytochrome c released
when Bax-Bak activation and anti-apoptotic Bcl blockage
death receptor-mediated (extrinsic) pathway is involved in
elimination of self-reative lymphocytes
describe the death receptor-mediated pathway
- activated T-lyphocytes express Fas ligand
- target cell (self-reactive thymocyte) will express Fas death receptor CD95
- Fa ligand binding to Fas receptor binds to and activates caspase 8
- TNF receptor type 1 (expressed on most cell types) binding to soluble mediator TNF also activates extrinsic pathway for apoptosis
what do cytotoxic T cells release
- perforins, punching holes in target cells
- granzymes which can activate caspases
how are apoptotic cells removed
- lipid components of the cellular membrane (phosphatidulserine) hcange their configuration making itself available to macrophage receptors
- formation of apoptotic bodes break cells up into small fragments allowing for easy phagocytosis
- secretion of soluble factors that recruit phagocytes (thrombospondin by apoptotic bodies)
why is it crucial that the clearance of apoptotic cells is fast
crucial in avoiding secondary necrosis, inflammation and further tissue damage
what is growth factor withdrawal
an intrinsic (mitochondrial) initiation pathway of apoptosis
when does growth factor withdrawal occur
in the absence of survival signals (eg. growth factors) decreased synthesis of Bcl-2 and Bcl-x and activation of pro-apoptotic members the Bcl family leads to apoptosis
examples that can lead to growth factor withdrawal
- Hormone-sensitive cells without relevant hormone
- Lymphocytes without antigenic/cytokines stimuli
- Neurons deprived of nerve growth factor
what happens when DNA damage (genotoxic stress) occurs
p53 protein accumulates and signals the cell to arrest the cell cycle in G1 phase (to allow time for repair)
what happens if DNA damage is irreversible
p53 triggers apoptosis by activating transcription of Bcl pro-apoptotic proteins (eg. Bax, Bak)
what can lead to genotoxic stress
-exposure to radiation, toxins (chemotherapeutic drugs), free O2 radicals
where are p53 mutations often seen
in cancer (ie. uterine serous carcinoma)
mutated p53 is incapable of
inducing apoptosis therefore cells with damaged DNA are allowed to survive, proliferate and undergo malignant transformation
what is uterine serous carcinoma
aggressive type of endometrial cancer associated with rapid progression of disease and a poor prognosis
both USC and precursor lesions demonstrate what
- strong p53 overexpression by immunohistochemistry
- suggests alterations of the p53 gene in their pathogenesis
what are misfolded proteins tagged with
Ubiquitine and targeted for proteolysis
if misfolded proteins accumulate in the ER what happens
they trigger the unfolded protein response which increases ubiquitination, degradation and decreased translation of defective proteins
what happens if accumulation of misfolded proteins is excessive in the ER (ER stress)
caspases are activated and aptoptosis ensues
intracellular accumulation of abnormally folded proteins can causes what neurodegerative diseases
- Alzheimer
- Huntington
- Parkinson
how can defects in apoptosis DECREASE cell survival
increase risk of:
- Neurodegenerative diseases
- Ischemic injury
- Death of virus-infected cells
how can defects in apoptosis INCREASE cell survival
- p53 is the most common genetic abnormality found in human cancers
- Failure to eliminate harmful cells (self-reacting lymphocytes) and dead cells (source of self-antigens)
- Thus, defective apoptosis may be the basis of autoimmune disorders
