cell injury, cell death, and adaptations

what is pathology?

the causes of disease and the changes in cells, tissues, and organs that are associated with development of disease

what is etiology?

the origin of a disease, including the underlying causes and modifying factors

what is pathogenesis?

steps in disease development

what are the different abnormalitites in cells and tissues?

molecular, functional, morphologic

what are clinical manifestations?

signs and symptoms of disease

what is adaptation?

a new steady state that preserved viability and function

what is reversible injury?

homeostasis is restored

what is irreversible injury?

leads to cell death

what are the types of cellular stress?

oxidative stress
ER stress and UPR
disruption of Ca2+ homeostasis

what is oxidative stress?

cellular damage induced by the accumulation of reactive oxygen species (ROS)
free radicals are unstable and "attack" cellular components

what can free radicals due to oxidative stress cause?

peroxidation of membrane lipids
crosslinking and modification of proteins
DNA damage

what are the types of injury caused by oxidative stress?

chemical and radiation injury
hypoxia
cellular aging
tissue injury by inflammatory cells
ischemia-reperfusion injury

what are sources of ROS?

radiation
metabolic reactions in peroxisome
enzymatic reactions
cell uptake of microbes, nanoparticles, xenobiotics
oxidative phosphorylation in mitochondria
ER stress and unfolded protein response (UPR)

what are levels of ROS determined by?

rates of production and removal

why are ROS levels tightly regulated?

ROS at low concentrations function in signaling pathways

how are ROS levels cleared?

enzymatically or by antioxidants
enzymes: glutathione peroxidase, catalase

how can injuries affect ROS?

increase it by increased rate of production or decreased clearance

what are the effects of radiation toxins reperfusion?

membrane damage, breakdown/misfolding of proteins, mutations/strand breaks in DNA

what is the purpose of chaperones during protein synthesis?

ensure proper folding of newly synthesized proteins

what is the function of UPR?

increases chaperone expression
reduces protein synthesis
increases protein degradation

what is ER stress?

some misfolded polypeptides are generated
misfolded protein in the ER activate the unfolded protein response (adaptive) via sensors like IRE1

how can injuries affect protein synthesis?

can lead to problems with protein folding

what are the effects of high levels of misfolded proteins?

can trigger apoptosis via the mitochondrial intrinsic pathway

what can intracellular accumulation of misfolded proteins be caused by?

abnormalties that increase the production of misfolded proteins or reduce the ability to eliminate them
e.g. mutations in protein that is misfolding or UPR pathway, aging, viral infections, intracellular pH and redox state, hypoxia and ischemia

what can protein misfolding within cells cause?

disease by creating a deficiency of an essential protein (loss of function), by inducing apoptosis, or by gaining a toxic function (gain of function)
e.g. mutations in protein that is misfolding (cystic fibrosis)

what is the ubiquitin-proteasome system?

proteins tagged by ubiquitin ligases
UPS proteolyzes ubiquitinated proteins

what is a proteasome?

an endopeptidase complex
the cell's "trash can"

what are the effects of the disruption of the UPS system?

play key roles in disease
e.g. polyglutamin repeat disease, parkin in parkinson's disease

what is the importance of Ca2+?

important second messenger and a source of cell injury
intracellular Ca2+ is maintained at low [ ] relative to extracellular Ca2+

what are the effects of high intracellular Ca2+?

disrupts multiple signaling pathways and activates enzymes (proteases, phospholipases) that damage cellular components (plasma membrane, cytoskeleton)

what is the cause of ischemia and certain toxins/toxicants increasing cytosolic Ca2+?

release from intracellular stores in the mitochondria and ER
a later release from increased influx across a damaged plasma membrane

what are cellular adaptations to stress?

reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment

what are physiologic adaptations?

the responses of cells to normal stimulation by hormones or endogenous chemical mediators, or to the demands of mechanical stress

what are pathologic adaptations?

the responses to stress that allow cells to modulate their structure and function and escape injury, but at the expense of normal function

what is hypertrophy?

increase cell and organ size
often in response to increased workload
induced by growth factors produced in response to mechanical stress or other stimuli
occurs in tissues incapable of cell division
in other tissues, hypertrophy and hyperplasia may occur together

what is hyperplasia?

increased cell numbers in response to hormones and other growth factors
increased proliferation
occurs in tissues whose cells can divide or contain abundant tissue stem cells
often occurs concurrently with hypertrophy in response to the same stimulus
can be physiologic or pathologic

what is atrophy?

• decreased organ/tissue size caused by decreased size and number of cells
• due to decreased nutrient supply or disuse
• associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles
• results from a combination of decreased protein synthesis and increased protein degradation
• often accompanied by increased autophagy

what is metaplasia?

• a change in which one adult cell type is replaced by another adult cell type
• change in the phenotype of differentiated cells
• often in response to chronic irritation, which makes cells better able to withstand the stress
• usually induced by an altered differentiation pathway of tissue stem cells
• may result in reduced functions or increased propensity for malignant transformation

what is pure hypertrophy?

usually confined to cell types with a limited capacity to divide

what can hypertrophy progress to?

cell injury if the stress is not relieved or if it exceeds the adaptive capacity of the tissue

what are some examples of hypertrophy?

physiologic enlargement of the uterus during pregnancy
pathologic hypertrophy of the heart in response to increased workload

what is cellular proliferation stimulated by?

hormones or growth factors

what are some examples of physiologic hyperplasia?

hormonal: proliferdation of the glandular epithelium of the femal breast at puberty and during pregnancy
compensatory: residual tissue grows after removal or loss of part of an organ

what are some examples of pathologic hyperplasia?

endometrial hyperplasia
benign prostatic hyperplasia

what is endometrial hyperplasia?

increased uterine epithelial proliferation due to increased estrogenic stimulation

what is benign prostatic hyperplasia?

disruption of androgens and estrogens leads to hyperplasia in the prostate

what are the pathologic and physiolgic causes of atrophy?

decreased workload
loss of innervation
diminished blood supply
inadquate nutrition
loss of endocrine stimulation
aging

what can happen as atrophy worsens?

affected cells may pass a threshold and undergo apoptosis

what is chronic gastric reflux?

normal stratified squamous epithelium of the lower esophagus undergo metaplastic transformation to gastric or intestinal-type columnar epithelium

what does metaplasia typically arise from?

reprogramming of stem cells rather than phenotypic change of differentiated cells

what is direct-acting cell injury?

• combine directly to cellular proteins or organelles
• e.g. mercury poisoning from seafood, chemotherapy drugs

what is latent cell injury?

• chemical must be converted to a reactive metabolite that acts on target cells to exert toxic effect, usually by cytochrome P-450 in the liver
• e.g. acetaminophen poisoning

what is ischemia-reperfusion injury?

• restoration of blood flow to ischemic but viable tissues results, paradoxically, in increased cell injury and necrosis
• contributes significantly to tissue damage, especially after myocardial and cerebral ischemia (stroke)

what are the effects of ischemia-reperfusion injury?

• increased ROS production during reoxygenation
• influx of Ca2+ disrupts Ca2+ homeostasis
• inflammation induced by ischemic injury

what are the effects of inflammation induced by ischemic injury?

may increase with reperfusion due to influx and activation of leukocytes

compare and contrast hypoxia and ischemia

• both deprive cells of oxygen
• blood flow is maintained in hypoxia, but blocked in ischemia
• aerobic metabolism ceases in both, but anaerobic metabolism only fails in ischemic conditions
• ischemia causes more rapid and severe cell and tissue injury

what happens to cells that do not die in hypoxia and ischemia?

activate compensatory mechanisms that help the cell survive in low oxygen conditions

what does persistent or severe hypoxia and ischemia lead to?

• depletion of ATP
• failure of plasma membrane Na/K pump
• decrease of intracellular pH
• increased ROS production
• ER swelling, membrane damage, mitochondrial damage
• inflammation is triggered
• necrosis

what is the process of cell death caused by hypoxia/ischemia?

→ mitochondria is affected
→ decreased ATP → decreased energy-dependent functions
→ increased ROS → damage to lipids, proteins, nucleic acids
→ cell injury
→ necrosis

what is the process of cell death due to ROS?

→ cellular membrane is affected
→ damage to lysosomal membranes → leakage of enzymes
→ damage to plasma membrane → impaired transport functions, leakage of cellular contents
→ necrosis

what is the process of cell death due to radiation mutations?

→ nucleus is affected
→ DNA damage
→ cell cycle arrest
→ activation of BH3-only sensors
→ apoptosis

what is the process of cell death due to mutations, cell stress, and infections?

→ ER is affected
→ accumulation of misfolded proteins
→ unfolded protein response
→ apoptosis

what is the process of autophagy?

→ nutrient depletion sensed by cytoplasmic sensors
→ signals Atgs in the nucleus
→ Atg proteins go to cytoplasmic organelles
→ initiation forms the phagophore
→ elongation
→ maturation of autophagosome
→ autophagosome fuses with lysosome, forming autophagolysosome, where enzymes digest cellular components
→ degradation
→ recycling of metabolites

what is autophagy?

• self-eating
• recycling mechanism during nutrient deprivation
• organelles and portions of cytosol are sequestered in membrane-bound compartments

what is self-eating?

lysosomal digestion of a cell's own components

what is pyroptosis?

cell death mediated by the inflammasome

what is necroptosis?

cell death induced by TNF with necrotic and apoptotic features

what is ferroptosis?

cell death dependent on cellular iron levels

what is the caspase cascade?

• degradation of cellular proteins and nuclear fragmentation
• apototic cells recruit phagocytes that clears apoptotic bodies
• no inflammatory response
• 2 pathways: mitochondrial (intrinsic) pathway, death receptor (extrinsic) pathway

what is the extrinsic pathway of the caspase cascade?

• controlled by death receptors (TNF receptor family and Fas)
• when ligand binds, receptors cross-link via death domain and bind adapter proteins
• leads to the activation of caspase cascade

what is the intrinsic pathway of the caspase cascade?

• most physiologic and pathologic situations
• mitochondrial permeability is controlled by Bcl-2 proteins
• release of pro-apoptotic proteins from mitochondria
• cytosolic cytochrome-c leads to the activation of caspase cascade

what is apoptosis?

• programmed pathway by which cells degrade their own nuclear DNA and nuclear and cytoplasmic proteins causing cellular and nuclear fragmentation and chromatin condensation
• intact plasma membrane
• no inflammatory reaction

what are membrane blebs?

fragments of apoptotic cells break off and form apoptotic bodies

what is the process of apoptosis?

→ start with healthy cell
→ reduced cell size
→ peripheral condensation of chromatin, tightly packed organelles, and membrane blebs
→ cellular fragmentation, nuclear fragmentation, apoptotic body
→ apoptosis
→ phagocytosis of apoptotic cells fragments

what are the cytoplasmic changes due to necrosis?

• glass, homogenous appearance
• vacuolated cytoplasm
• breakdown of plasma and organelle membranes
• swelling of mitochondria with large amorphous deposits
• disruption of lysosomes
• intracytoplasmic myelin figures

what are the nuclear changes due to necrosis?

• breakdown of DNA and chromatin
• pyknosis: DNA condensation and nuclear shrinkage
• karyorrhexis: fragmentation
• karyolysis: digestion of DNA

what is the process of necrosis?

→ breakdown of plasma membrane, organelles, and nucleus
→ large amorphous deposits in mitochondria
→ leakage of contents
→ inflammation (host reaction)
→ necrosis

how can we slow aging?

• exercise and physical activity
• caloric restriction: ~30% decrease in food intake without malnutrition or deprivation of essential nutrients

what are the mechanisms of cellular aging?

• environmental and metabolic insults
• telomere shortening
• abnormal protein homeostasis
• signaling pathways
• persistent low-level inflammation

what is the process of the effects of environmental and metabolic insults?

→ ROS?
→ accumulation of mutations in DNA
→ decetive DNA repair
→ decreased cell functions, cell loss

what is the process of the effects of telomere shortening?

→ decreased cellular replication
→ cell loss

what is the process of the effects abnormal protein homeostasis?

→ decreased proteins, damaged proteins
→ decreased cell functions

what is the process of the effects of signaling pathways?

→ decreased TCR and insulin/IGF signaling
→ altered transcription
→ decreased cell functions

what are the results of persistent low-level inflammation?

chronic diseases

what are telomeres?

• short, repeated sequences of DNA at the ends of chromosomes
• ensure complete replication of chromosome ends
• protect chromosome ends from fusion and degradation
• progressively shortened with each division of somatic cells

what happens when telomeres are completely eroded?

choromosome ends are recognized and broken DNA, leading to cell cycle arrest and cellular senescence/proliferative arrest

what are telomeropathies?

inherited deficiencies in telomerase activity including aplastic anemia, pulmonary and liver fibrosis, premature graying of hair, and characteristic changes in skin pigmentation and nails

what is telomerase?

• maintains telomere length in germ cells and stem cells, but not somatic cells
• reactivated in many cancer cells

how does DNA damage contribute to cellular aging?

mutations in mitochondrial and nuclear DNA accumulate with age and cause telomere dysfunction and cellular senescence (proliferative arrest)

what is telomere dysfunction and cellular senescence?

cells (other than stem cells) have a limited capacity for replication and become arrested in a terminally nondividing state after a fixed number of divisions

how do specific signaling pathways contribute to cellular aging?

certain environmental stresses, such as caloric restriction, alter signaling pathways that influence aging, including insulin-like growth factor (IGF-1) and molecular target of rapamycin (mTOR) signaling

how does persistent inflammation contribute to cellular aging?

accumulation of damaged cellular components can activate the pathways that cause low-level inflammation

what is aging?

• progressive decline of physiologic, cellular, and molecular homeostatic mechanisms after the reproductive years
• age is one of the strongest independent risk factors for many chronic diseases
• a consequence of alterations in genes and signaling pathways that are evolutionarily conserved from yeast to mammals
• due to imperfect DNA repair, mutations accumulate over time and those that are deleterious in those pathways contribute to cellular aging

what is pathologic calcification?

the result of abnormal deposition of Ca2+ salts: fine white granules or clumps and gritty deposits

what is metastatic calcification?

• associated with hypercalcemia (high blood Ca2+) in otherwise normal tissues

• principally affects the interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa

• generally does not cause clinical dysfunction

what are the effects of metastatic calcification?

• increased secretion of parathyroid hormone due to either primary parathyroid tumors or hyperplasia, or production of parathyroid hormone-related protein by malignant tumors

• destruction of bone due to the effects of accelerated turnover, immobilization, or tumors

• high vitamin D levels: vitamin D intoxication and sarcoidosis (in which macrophages activate a vitamin D precursor)

• renal failure: phosphate retention leads to secondary hyperparathyroidism

what is dystrophic calcification?

• deposition of crystalline calcium phosphate in membrane-bound vesicles
• found in injured/dead tissue, such as areas of necrosis
• seen in plaques in atherosclerosis and necrotic cells in tuberculosis
• often an incidental finding of past cell injury, but can also cause dysfunction

what are intracellular depositions?

abnormal intracellular accumulations caused by inadequate removal and degradation or excessive production of an endogenous substance, or deposition of an abnormal exogenous material

what are fatty change (steatosis) intracellular depositions?

• abnormal accumulation of triglycerides within parenchymal cells, most common in liver
• cholesterol and cholesteryl esters: occur due to increased intake or decreased catabolism of lipids, seen in atherosclerosis
• due to abnormal metabolism

what are protein intracellular depositions?

• caused by increased uptake or synthesis, misfolding, reduced degradation
• due to defect in protein folding transport