chapter 2: cell response Flashcards
4 aspects of disease process
etiology: cause
pathogenesis:biochem process
morphologic changes: struct alterations in cells/organs
clinical manifestations: conseq of changes
etiology
genetic: multifact
acquired
all forms of disease start with what
molecular or structural alterations in cells
reversible functional and structural responses to changes in physiologic states, some pathologic that allows cell to survive and continue to function
adaption
examples of adaptions
hypertrophy hyperplasia metaplasia pregnancy atrophy pathologic stimuli
cell death happens when and from what
adaption is not achieved
ischemia
ifection
toxins
nutrient deprivation triggers what
autophagy
calcium deposited at sites of cell death is called
pathologic calcification
what is the most common stimulus for hypertrophy
increased workload
uterine hypertrophy process
estrogenic hormones act on SM on estrogen receptors
-increased synthesis of SM cells
3 basic steps in molecular pathogenesis of cardiac hypertrophy
integrated actions of mechanical sensors
-GFs, IGF1, FGF, a adrenergic agonists
signal transduction
- pi3 kinase/AKT pathway (exercised induced hypertrophy)
- GPCR: pathologic hypertrophy
Activation of txn factors
-mef2, nfat, gata4
when does physiologic hyperplasia occur
when need to increase fnct capacity of hormone sensitive organs
need compensatory increase after damage or resection
examples of physiologic hyperplasia
erythropoietin in blood cells
liver regen
glandular epithelium prolif of female breast at puberty
pathologic hyperplasia from
excessive or inappropriate actions of hormones or GF acting on target cells
separate from cancer but can increase chance of cancer
can be from viral infections
pathologic hyperplasia example
endometrial hyperplasia
-abnormal menstrual bleeding
BPH
papillomaviruses
2 mechanisms of hyperplasia
GF driven proliferation of mature cells
increased output of new cells from tissue stem cells
atrpohy: physiologic
embryonic structures going away
atrophy: pathological causes
WINE Blood Pressure
decreased workload
loss innervation
inadequate nutrition
loss endocrine stim
decreased blood
increased pressure
atrophy of the brain
narrows gyri
widens sulci
cellular changes in atrophy
less mitochondria
reduced RER
decreased metabolic demand
mechanisms of atrophy
decreased protein syn
increased protein degradation
some cell debris within autophagic vacuoles resist digestion and persist in cytoplasm called
residual bodies
lipofuscin granules
-brown discoloration of tissue
types of caner in barrett esophagus
adenocarcinomas: glandular
myositis ossificans
bone formation in muscle
after intramuscular hemorrhage
reversible cell injury: 4 categories
reduced oxidative phos
cell swelling from change in ion concent and water influx
alterations in organelles
blebbing of PM
alterations in organelles during reversible cell injury
detachment of ribosomes from ER = decre prot syn
clumping of nuclear chromatin = dna damage
cytoskeletal damage
causes of cell injury
PICO NIG
physical agents
immunologic reactions: autoimmune (end) virus (exog)
chemical agents and drugs
oxygen deprivation
nutritional imbalance
infectious agents
genetic derangements: def of proteins
2 things recognized under light microscope in reversible injury
cellular swelling
fatty change
- hypoxic injury
- cells dep on fat metab
- Lipid vacuoles in cytoplasm
first manifestation of almost all forms of cell injury
cell swelling
cell swelling if see small clear vacuoles in cytoplasm what is it and called
pinched off ER
hydropic change or vacuolar degeneration
morphology of necrosis
NIG DM
nuclear changes
increased eosinophilia in H&E stains
glass appearance
discontinuities in PM and organele membranes
myelin figures
caseous necrosis
tuberculosis infection
cheese like white appearacne
granuloma
fat necrosis
areas of fat destructrion from release of activated pancreatic lipases
chalky-white areas
FAs comine with calcium
immune reactions involving BVs
complex antigens and antibodies in wall of arterires
bright pink amorphous appearance H and E stains
fibrinoid necrosis
necrotic cells and cell debris left over provide site for deposition of calcium salts
dystrophic calcification
depletion of ATP to ______ of mormal levels has widespread effects on critical cellular systems
5-10%
mitochondrial damage from
increased Ca2+
ROS
oxygen deprivation
hypoxia and toxins
cyclophilin D
structural component of MPTP
-cyclosporine targets this to reduce injury to cell
3 major consequences of mitochondrial damage
formation of mitochondrial permeability transition pore
abnormal oxidative phos and ROS
mitochondrial leakage of apoptotic proteins
increased Ca2+ intracellular affect on mitochondria
1) opens MPTP and no ATP
2) activates enzymes: phospholipases,endonucleases, ATPases etc
3) apoptosis: direct activation caspases and increase mitochond perm
generation of free radicals
redox rxns in normal metabolic processes
absorption of radiant energy
rapid bursts of ROS from activated leukocytes
enzymatic metab of exogenous chemicals or drugs
transition metals
NO
redox rxns free radicals
O2*, H202, *OH
uv light and xrays can hydrolyze
water into *OH and H free radical
rapid bursts of ROS from activated leukocyte enzymes
NAPDH oxidase in PM
xanthine oxidase intracellular enzyeme
metab of drugs and chemicals can create
free radicals similar to ROS
CCL4–>CCL3
transition metals and free radicals
iron and copper donate or accept free electorns during intracellular rxns and catalyze free radical fomration
nitric oxide free radicals
can act as free radical and be converted to ONOO- (peroxynitrate anion) and NO2 and NO3-
catalase function
decomposes H202
what enzyme breaksdown O2*
superoxide dismutase
glutathione peroxidase
breaks down H202
-can tell oxidized state of cell
2 phenomena consistently characterized in irreversibility
inability to reverse mitochondrial dysfunction
profound disturbances in membrane function
transaminases in blood is damage to
hepatocytes
alkaline phosphatase in blood is damage to
bile duct epithelium
protective response with cell injury and not enough oxygen getting to tissue
HIF-1
- promotes new blood vessel formation and stimulates cell survival pathways
- enhance anerobic glycolysis
ischemia-reperfusion injury (4)
oxidative stress (ros)
intracellular calcium overload
inflammation (danger signals from dead cells)
activation of complement system (IgM in ischemic tissue gets bound by complement)
chemical toxic inury (2)
direct toxicity
-mercury binding membrane proteins and cyanide posions cytochrome oxidase
conversion to toxic metabolites
-liver cytochrome P450 conversion to free radicals
morphology of apoptosis
cell shrinkage: tightly packed organelles
chromatin condensation: most charact feature
formation of cytoplasmic blebs and apoptotic bodies
sensors of apoptosis
BAD
BIM
PUMA
NOXA
smac/Diablo
mitochondrial protein that can leak out and neutralize inhibitors of apoptosis
-IAPs normally block caspase 3 so smac/diablo allow apoptosis
CD95
FAS
what does FLIP do
inhibits extrinsic apoptosis by binding procaspase 8 and preventing cleavage
viruses use this
apoptotic bodies are coated wtih ___ which are recognized by phagocytes
thrombospondin
receptor and ligand for necroptosis
TNFL and TNFR
process of necroptosis
ligand binds
RIP 1 and 3 and procaspase 8 recruited
downstream effects = ROS
-damge to mitochondria and reduced ATP
necroptosis morphologically
resembles necrosis
loss atp, swellling of cell, lysosomal enzymes, rupture of PM
physiologic necroptosis
bone growth plate
pathologic necroptosis
parkinsons
acute pancreatisis
reperfusion injury
PAR
pyroptosis
cell death with IL-1 release
-inflammasome
autophagy vs microautophagy vs macroautophagy
auto: chaperone mediated, direct translocation across lysoomal membrane
micro: inward invag of lysosomal membrane
macro: sequestration and transporetation of portions of cytoslol in double membrane bound autophagic vacuole
steps of autophagy
Formation of isolated membrane (phagophorre) and its nucleation from the ER
elongation of vesicle: LC3
maturation of autophagosome and fusion with lysosomes
what are Atgsd
genes that code for products required for creation of autophagosome in autophagy
autophagy in alzheimers
formation of autophagosome accelerated
defects in autophagy accelerate neurodegeneration
huntingtons and autophagy
mutant huntintin impairs autophagy
role of autophagy in infectious diseases and example
pathogens degraded by autophagy like shigella
macrophage spefific dletion of Atg5 increases suscepti to what
tuberculosis
abnormal intracellular accumulations
defect of packaging and transport–>inadeq removal–>fatty change in liver
defect in protein folding–>a1-antitrypsin
lack of enzyme leading to failure to degrade metab–>storage disease
ingestion of indigestible materials–>carbon and silica
steatosis and casue
abnormal accum of TGs within parenchymal cells
- alcohol abuse
- nonalcoholic fatty liver disease: diabetes and obesity
xanthomas
intracellular accum of cholesterol w/in macrophage (goes with hered hyperlipidemic states)
-clusters of foamy cells in subepithelial of CT of skin and tendons
cholesterolosis
focal accum of cholesterol-laden macrophages in lamina propria of gallbladder
niemann pick disease
lysosomal storage disease
- defect in enzyme directing cholest trafficking
- results cholest in multiple organs
protein accumulation in cell morphology
eosinophilic, rounded droplets, vacoules or aggregates in cytoplasm
causes of excess intracell protien (5)
reabsorption of droplets in prox renal tubules
-renal disease with lost protein through glomerulus
plasma cells secrete too much normal proteins like Igs
-large eosinophilic inclusion called russel bodies
defective intracell transport and secretion critical proteins
-a1 antitrypsin deficiency
accumulation of cytoskeletal proteins
- keratin filaments and neurofilaments
- alcoholic hyaline
- neurofibrillary tangle
aggregation of abnormal proteins
hyaline change intracell
-glassy pink appearance in H&E stain
hyaline change extracellular
long-standing hypertension and diabetes
-wall of arterioles become hylinized
glycogen intracell morph
clear vacuoles within cytoplasm
stain best with carmine or PAS
-rose to violet color
in diabetes glycogen accumulates in
kidney, liver, b cells islets of langerhans, heart muscle cells
katie Lynn breaks hearts
lipofuscin -makeup -derived from sign of color what pts
lipids and phospholipids in complex with proetins
-derived through lipid peroxidation
sign of free radical injury and lipid perox
yellow-brown pigment
-in liver and heart of aging patiens
-patients with severe malnutirtion and cancer cachexia
when black pigment inserted into tissue in pts with alkaptonuria it is called
ochronosis
too much iron caues ___ to accumulate wihtin cells
-local
hemosiderin
-local excess in bruise
systemic overload of iron hemosiderin called
deposited in many organs and tissues
hemosiderosis
causes of hemosiderosis
increased absorption dietary iron due to error of metab
hemolytic anemias
repeated blood transufusions
dystrophic calcification
deposition occuring locally in dying tissues
dystrophic calcification occur in what tissue and what diseases
commonly in aging or damaged heart valves
almost always present in atheromas of atherosclerosis
dystophic calcification morphology
fine white granules or clumps
metastatic calcification
deposition of calcium salts in normal tissue because of hypercalcemia
causes of hypercalcemia
increased PTH: PT tumor or exog PTH related protein from malignant tumor
increased resoption of bone tissue
renal failure
-retention phosphate and 2ndasry hyperPTism
vitamin D related disorders
resorption of bone tissue due to tumor of bone marrow disease
myeloma and leukemia
resoption of bone tissue or accelerated bone turnover
pagets disease
resoprtion of bone diffuse skeletal metastasis
breast cancer
vitamin D disorder sarcoidosis
macrophages activate vit D precursor
Vit D idiopathic hypercalcemia of infacny
williams syndrome
Werner syndrome
premature aging
defective gene product is DNA helicase
genetic instability in somatic cells causes aging what disease
bloom syndrome and ataxia telengiectasia
tumor suppressor genes INK4 and P16 coded by what gene locus
CDKN2a
deficit of protein for folding increases aging rapidly
heat shock protein
rapamycin
inhibits mTOR
increases lifespan in rats
insulin and IGF produced in response to what and does what
GH
-promotes anabolic state
downstream signaling of kinases
-AKT and mTOR
sirtuins
deacetylases, increase longevity, inhibit metabolic activity, reduce apoptosis, increase insulin sensitivtity and glucose metab.
sirtuin ___ contrbutes to metabolic adaption of caloric resrtiction
-promotes genomic integrity by activating DNA repair enzymes through deacylation
6
caloric constriction effect
reduce signal intensity of IGF-1
-reduced cell damage
lower rate of cell growth and metab
