Cellular Responses to Stress & Toxic Insults Flashcards
What is pathology?
- Greek: study of suffering
- Originally started as branch of surgery
–Some surgeons were actually curious about what they were cutting out
What is pathology (seriously)?
•Branch of medical science that:
–Deals with the laboratory examination of samples of body tissue for diagnostic or forensic purposes
- Organs and tissues (anatomic pathology)
- Bodily fluids (clinical pathology)
- DNA/RNA (molecular pathology)
–Studies structural/functional/ biochemical changes in cells/tissues/ organs that underlie disease
•Scientific foundation for all of medicine
–Attempts to explain signs and symptoms manifested by patients
–Provides rational basis for clinical care and therapy
•Serves as bridge between basic sciences and clinical medicine
Pathologists use morphologic, immunologic, microbiologic, and molecular techniques
Pathology and dentistry
•Unless you become a pathologist, your competency in pathology will be demonstrated by your ability to:
–Appropriately recognize and manage abnormalities in your patients
–Understand why you treat patients they way you do
–Communicate with patients and other healthcare professionals
–Pass licensing exams, not get sued, stay out of jail
What is disease?
- Structural or functional disorder (not simply direct result of physical injury) that produces signs or symptoms of affects a specific location
- Diseases have 4 core aspects
–Etiology
–Pathogenesis
–Morphologic changes
–Clinical manifestations
Etiology
- Cause of disease
- Two groups of etiologies
–Genetic: inherited mutations, disease-associated gene variants (polymorphisms)
–Acquired: infectious, nutritional, chemical, physical
•Most common afflictions are multifactorial and arise from effects of external triggers in genetically susceptible individuals
Pathogenesis
•Sequence of cellular, biochemical, molecular events following exposure to injurious agent
–Initial disease cause always several steps removed from disease expression
Morphologic changes
•Structural alterations in cells/tissues characteristic of disease or diagnostic of etiologic process
–Basis for role of biopsy and microscopic evaluation of excised tissue in clinical care
Cell injury occurs when:
- Limits of adaptive responses are exceeded
- Cells are exposed to injurious agents/ stress
- Cells are deprived of essential nutrients
- Cells are compromised by genetic mutations
- Irreversible injury occurs in the context of persistent or severe stress and ultimately leads to cell death
Clinical manifestations
•Signs/symptoms, clinical course, and outcome of disease
–Sign: objective/measurable finding
–Symptom: subjective finding
•Virtually all diseases begin with molecular or structural alterations in cells
–Cell injury leads to tissue and organ injury
–Ultimately determines clinical patterns of disease
- Cells normally confined to narrow range of function/structure
- Normal cell handles physiologic demands within a steady state called homeostasis
- Adaptations: reversible functional/structural responses to changes or stresses
Adaptations of cellular growth and differentiation: hypertrophy
•Increase in cell size
–Results in increase in size of affected organ
–No new cells
- Result of increased production of cellular proteins
- Can be physiologic (exercising) or pathologic (hypertension)
Beyond a certain point cardiac hypertrophy becomes maladaptive and can lead to heart failure, arryhtmia, sudden death
Adaptations of cellular growth and differentiation: hyperplasia
•Increase in number of cells
–Occurs in response to stimulus
–Ends when stimulus removed
- Can be physiologic (breast enlargement at puberty or during pregnancy) or pathologic (endometrial hyperplasia)
- Hypertrophy and hyperplasia frequently occur together
–Both result in increase in size of organ
Adaptations of cellular growth and differentiation: atrophy
•Reduction in tissue/organ size due to decrease in cell size and number
–Reduction in cell size followed by cell death if prolonged adverse stimulus
- Cell size reduction from decreased protein synthesis and increased protein degradation
- Autophagy: starved cell eating its own components
- Can be physiologic (dental lamina) or pathologic
–Decreased workload
–Loss of innervation
–Diminished blood supply
–Inadequate nutrition
–Loss of endocrine stimulation
–Pressure
Autophagy
•Process in which cell eats its own contents
–Recycling of autodigested contents in states of nutrient deprivation
–Physiologic turnover of organelles
–Clearance of intracellular aggregates accumulating during aging, stress or various disease states
- Major form involves delivery of cytoplasmic materials in autophagosome to lysosome for degradation
Adaptations of cellular growth and differentiation: metaplasia
•Reversible change in which one differentiated cell type is replaced by another
–Typically replacing cell type better suited to alterations in local environment
–Underlying stem cells reprogrammed to differentiate along new pathway
- example: Normal columnar cells of trachea/bronchi replaced by stratified squamous epithelium (more rugged) in smokers
Causes of cell injury
•Oxygen deprivation (hypoxia)
–Common, important cause of cell injury
•Physical agents
–Trauma, temperature changes
- Chemical agents and drugs
- Infectious agents
- Immunologic reactions
–Autoimmune disease, immune response to viral agents
- Genetic derangements
- Nutritional imbalances
–Starvation, obesity, atherosclerosis
TWO PRINCIPLE PATHWAYS OF CELL DEATH:
APOPTOSIS AND NECROSIS
•Different injurious stimuli may induce death by one or the other
Necrosis
•Pattern of cell death in which irreversible cell injury leads to
–Denaturation of intracellular enzymes
–Loss of membrane integrity
- Cellular contents leak out, eliciting inflammation in surrounding tissue
- Necrotic cell digested by lysosomal enzymes within the cell and from recruited leukocytes
-When large numbers of cells die a tissue or organ is said to be necrotic (ie. myocardial infarction)
Coagulative necrosis:
- Architecture of dead tissues and cells preserved for at least a few days
- Localized area of coagulative necrosis termed infarct
- Often associated with ischemia secondary to obstructed vessel
Liquefactive necrosis:
- Enzymatic digestion of dead cells results in liquid viscous mass
- Often seen following infectious conditions and in brain infarcts
Gangrenous necrosis:
- Clinical term denoting necrosis of multiple tissue planes
- Superimposed bacterial infection results in more liquefactive necrosis (wet gangrene)
Caseous necrosis:
- Caseous: ‘cheese-like’
- Often seen in context of tuberculosis
- Associated with distinctive pattern of inflammation termed granuloma
Fibrinoid necrosis:
- Usually seen in immune reactions involving blood vessels (vasculitis)
- Antigen-antibody complexes deposit in walls of arteries together with extravasated fibrin
Mechanisms of
cell injury and necrosis
- Cellular response to injurious stimuli depends on nature, duration and severity of injury
- Consequences of injurious stimuli depend on type, state and adaptability of cell
- Cell injury results from different biochemical mechanisms acting on essential cellular components
–Mitochondria, cell membrane, DNA, protein synthesis/packaging machinery most susceptible to damage
Depletion of ATP
•Reduction in ATP levels fundamental cause of necrotic cell death
–High-energy phosphate (in form of ATP) required for virtually all processes within cell
•Major causes of ATP depletion:
–Reduced supply of oxygen, nutrients
–Mitochondrial damage
•Major pathway of ATP generation is oxidative phosphorylation of ADP in mitochondria
–Toxins
Mitochondrial damage
•Consequences of mitochondrial damage
–Formation of mitochondrial permeability transition pores
•Loss of membrane conductance potential results in defective oxidative phosphorylation
–Progressive ATP depletion
–Formation of reactive oxygen species
•Leakage of pro-apoptotic proteins normally sequestered between inner-outer mitochondrial membranes
Apoptosis
•Programmed cell death for cells destined to die
- Tightly regulated suicide program activates intrinsic enzymes to degrade cell DNA and proteins
- Apoptotic cells break up into apoptotic bodies phagocytosed without eliciting inflammatory response
•Programmed cell death for cells physiologically destined to die
–Destruction of cells during embryogenesis
–Involution of hormone-dependent tissues upon hormone withdrawal
–Cell loss in proliferating cell populations
–Inflammatory cells after serving useful purpose
•Programmed cell death in a variety of disease states
–DNA damage
–Accumulation of misfolded proteins
–Viral infections
–Following duct obstruction (such as in salivary glands)
Apoptosis results from activation of enzymes called caspases, activated either by ………………………………………….
mitochondrial or death receptor pathways
- Mitochondrial pathway major mechanism of apoptosis in mammalian cells
- Relative balance of pro-apoptotic and anti-apoptotic proteins of BCL2 family influences outer mitochondrial membrane permeability
Death receptor pathway characterized by activation of plasma membrane death receptors such as TNFR, Fas by cells such as T-cells
Unfolded protein response:
•Cytoprotective response to accumulating misfolded proteins by: increased ER chaperone protein production, enhanced proteosomal destruction of misfolded proteins, and slowed protein translation
ER stress:
- Activation of caspases leading to apoptosis if cell unable to cope with accumulating misfolded proteins
- Common feature of neurodegenerative diseases
Necroptosis:
- Form of cell death that resembles apoptosis mechanistically but necrosis mechanistically
- Triggered by genetically programmed signal transduction events leading to cell death
- Characterized by plasma membrane rupture, cell/organelle swelling, ROS generation
•Does not result in caspase activation
•Occurs in steatohepatitis, acute pancreatitis, reperfusion injury, some viral infections (CMV)
Intracellular accumulations: lipids
•Steatosis (fatty change)
–Abnormal intracellular accumulation of triglycerides
–Often seen in liver (major organ for fat metabolism)
•Alcohol abuse and nonalcoholic fatty liver disease (in context of diabetes/obesity) most common causes in developed nations
•Atherosclerosis
–Intracellular cholesterol accumulation within intimal layer of aorta and large arteries
–Associated with hypercholesterolemia
•Xanthomas
–Intracellular cholesterol accumulations within skin and tendons
–Associated with hypercholesterolemia
- Carbon (coal dust) most common exogenous pigment and ubiquitous in urban areas
- Ingested by pulmonary macrophages following inhalation and transported to regional tracheobronchial lymph nodes
- Results in anthracosis: blackening of lungs and lymph nodes
- Common in smokers and urban dwellers
Tattoo ink is taken up by dermal macrophages where it persists for remainder of life
- Common bruise results in hemorrhage into tissues
- Extravasated RBCs phagocytosed by macrophages over several days, breaking down hemoglobin and recovering iron
- Following iron removal, heme converted to biliverdin (green bile) and ultimately to bilirubin (red bile)
•Iron released from heme incorporated into ferritin
- Heme and iron metabolism account for color changes seen in healing bruises
- Ferritin forms into hemosiderin granules in states of excess iron
Pathologic calcification
•Abnormal tissue deposition of calcium (together with some iron, magnesium, etc.)
–Metastatic calcification
- Calcium deposition in normal tissues
- Associated with hypercalcemia in context of calcium metabolism disturbance
–Hyperparathyroidism
–Skeletal resorption
–Vitamin D-related disorders
–Renal failure
All normal cells have limited capacity for replication and, after fixed number of divisions, become arrested in terminally non-dividing state known as …………
senescence
- Major mechanism of replicative senescence is progressive shortening of telomeres
- Telomere length maintained by enzyme called telomerase expressed in germ cells and in low levels in stem cells, but absent in most somatic tissues
Caloric restriction uniformly increases life span:
- Attenuation of growth factor signaling (following glucose ingestion)
- Less cellular growth and metabolism
- Increase in sirtuins
- Thought to promote expression of several genes whose products increase longevity
