patho exam 4 Flashcards
Steps in the Development of Disease
etiology: cause of disease -
hypoxia & ischemia
toxins
infections
abnormal immune rxns
genetic abnormalities
nutritional imbalances
physical agents
pathogenesis: mechanisms of disease
biochemical changes
structural changes
abnormalities in cells & tissues
molecular
functional
morphologic
clinical manifestations
signs & symptoms of disease
Cellular Adaptation
Adapt to change in the internal environment
Adaptation includes changes in cells:
◼ Size
◼ Number
◼ Type
Changes may lead to
◼ Atrophy - decreased cell size
◼ Hypertrophy- increased cell size
◼ Hyperplasia- increased cell number
◼ Metaplasia - change from one adult cell type to another
◼ Dysplasia - cells of varying size, shape, and organization in a specific tissue
normal myocyte and its progression
ischemia leading to cell injury =
- reversibly injured myocyte - then cell death
adaptation: response to increased load:
- adapted myocyte hypertrophy
parts in a tissue
basement membrane
normal columnar epithelium
squamous metaplasia
Cell Injury and Death
Cell injury may be reversible or irreversible
healthy cell + insult/injury <-> cell injury -> death
Causes of cell injury
Hypoxia and ischemia
◼ Toxins
◼ Infectious agents
◼ Immunologic reactions
◼ Genetic abnormalities
◼ Nutritional imbalances
◼ Physical agents
Hypoxia and ischemia
◼ Hypoxia: oxygen deficiency
◼ Ischemia: reduced blood supply (thus O2)
◼ Among the most common causes of cell injury
◼ Deprive tissues of O2
◼ Essential for generating E for cell function and survival
◼ Ischemia also reduces the nutrient supply
- e.g., artery blockage, lung disease, anemia
Toxins
Multiple sources:
◼ Air pollutants, insecticides, carbon monoxide, asbestos, cigarette smoke, ethanol, drugs
Multiple mechanisms:
◼ Direct damage to cell
◼ Enzyme interference
◼ Protein denaturation
◼ Disrupt cellular osmotic/ionic balance
Infectious agents
◼ Viruses: DNA incorporation
◼ Bacteria: direct; exo-/endo-toxins
◼ Fungi
◼ Parasites
Immunologic Reactions
◼ The good: immune responses to injury and infection are absolutely essential
◼ The bad: autoimmune reactions against one’s own tissues, allergic reactions against environmental substances, excessive or chronic immune responses to microbes
◼ Problem: immune responses elicit inflammatory reactions (which are good), but inflammation can damage cells and tissues
Genetic abnormalities
◼ Chromosomal (e.g., Down Syndrome) or single nucleotide mutations (e.g., sickle cell anemia)
◼ Role in CA development
Cell injury consequence of:
◼ decrease (e.g., enzymes in inborn errors of metabolism) or increase in protein function
◼ accumulation of damaged DNA or misfolded proteins can trigger cell death.
Nutritional imbalances
Deficiencies
◼ Vitamins
◼ Minerals
◼ Protein
◼ Carbohydrate
◼ Fat
◼ Starvation: all nutrients deficient
Excesses
◼ Obesity
◼ Saturated fat
physical agents
Trauma/Mechanical forces
◼ Impact with other objects
Temperature extremes
◼ Low-intensity heat
◼ More intense heat
◼ Cold
Radiation
Electrical injuries
◼ Voltage, amperage, AC vs. DC
Physical Agent: Radiation injury
Ionizing radiation: High frequency
◼ Free radical formation
Ultraviolet radiation
◼ Sunburns -> skin CA
Nonionizing radiation: Lower frequency (IR, ultrasound, microwaves, laser energy)
Case: stresses and injury
◼ Homer Simpson has a terrible cold
◼ He starts a fire at his job in a nuclear power plant
◼ In attempting to put out the fire, Homer burns his hands and is exposed to ionizing radiation
◼ The nuclear plant is evacuated and Homer stands in the snow for 2 hours; he gets frostbite
◼ He is sent for treatment, where he develops a Clostridium infection in his burned hands
◼ What are the stressors on his cells and how are they causing cell damage?
Mechanisms of Cell Injury: General Principles
◼ Cell response depends on type of injury, its duration, and severity
◼ Consequences depend on the type of cell and its metabolic state, adaptability, and genetic makeup
◼ Usually results from functional and biochemical abnormalities in one or more essential cellular components
Mechanisms of cell injury
- Mitochondrial dysfunction and damage
- Oxidative stress
- Membrane damage
- Disturbance in calcium homeostasis
- ER stress
- DNA damage
Mechanisms of cell injury
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- Mitochondrial Dysfunction and Damage
Mechanism of injury: Failure of oxidative phosphorylation, leading to decreased ATP generation and depletion of ATP in cells
◼ “Power failure” in cell
◼ Oxidative metabolism falters; cell reverts to
anaerobic metabolism (less efficient; less E)
◼ pH falls due to lactic acid accumulation
◼ Effects: clumping of nuclear chromatin; destruction of cell membranes, intracellular components
◼ Loss of E: failure of Na+/K+-ATPase membrane pumps
◼ Cells swell
Hypoxic cell injury
O2 deprivation
◼ Reduced aerobic metabolism ◼ Reduced ATP production
Reversible or irreversible, depending on:
◼ Degree of deprivation
◼ Metabolic needs of cells (high tissue O2 demands: Heart, brain, kidneys)
Hypoxic cell injury (cont.)
causes
◼ Low [O2] in air: “pure” hypoxia
◼ Respiratory disease
◼ Ischemia (decreased blood flow = circulatory disorders)
◼ Anemia
◼ Edema
1/24/2024
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- Oxidative Stress
◼ Oxidative stress = cellular damage induced by the accumulation of reactive oxygen species (ROS), a form of free radical
◼ Free radicals: Chemical species with free (unpaired) electron in outer orbit
(smoke, radiation)
◼ Protection: antioxidants
◼ Highly unstable; very reactive
◼ Normal cellular reactions produce free radicals
(cellular respiration, Mfs)
◼ Extrinsic factors can produce free radicals
principle of free radicals involved in cell injury
- Membrane Damage
◼ Most forms of cell injury that end in cell death: characterized by increased membrane permeability → membrane damage
◼ Cell membranes may be damaged by: ROS, phospholipid biosynthesis, degradation, cytoskeletal abnormalities that disrupt the anchors for plasma membranes
◼ Most important sites of membrane damage: Mitochondrial membrane damage
Plasma membrane damage
Injury to lysosomal membranes
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- Disturbance in calcium homeostasis
Importance of intracellular [Ca2+]
◼ Cellular messenger
◼ Stored in ER and mitochondria
Normally, intracellular [Ca2+] low vs. extracellular levels
◼ Maintained by Ca2+/Mg2+-ATPase exchange system
Toxins and ischemia can increase intracellular [Ca2+]
◼ Cell damage from activated enzymes: phospho- lipases, proteases, ATPases, endonucleases
- Endoplasmic Reticulum Stress
Protein synthesis in ER: chaperones enhance proper folding of newly synthesized proteins
◼ Process is imperfect; some misfolded polypeptides made
◼ Targeted for proteolysis by ubiquitination
Accumulated misfolded proteins in ER induce
protective cellular (adaptive) response = unfolded protein response
◼ Activates signaling pathways that increase the production of chaperones and retard protein translation, reducing levels of misfolded proteins
◼ If quantity of misfolded protein exceeds capacity of adaptive response, additional signals activate proapoptotic sensors →apoptosis (intrinsic, more later)
Unfolded Protein Response and ER Stress
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- DNA Damage
DNA damage may result from:
◼ Exposure of cells to radiation or chemotherapeutic agents ◼ Intracellular generation of ROS
◼ Acquisition of mutations
If severe damage: may trigger apoptotic death
Damage to DNA sensed by intracellular sentinel proteins, which transmit signals that lead to the
accumulation of p53 protein
◼ p53 first arrests the cell cycle (at the G1 phase) to allow the
DNA to be repaired before it is replicated
◼ If the damage is too great to be repaired successfully, p53
triggers apoptosis, mainly by the mitochondrial pathway
Reversible cell injury
Two patterns visible under microscope: ◼ Cellular swelling
◼ Impaired Na+/K+-ATPase pump, usually from hypoxia
◼ Fatty change: indicative of severe injury
◼ Many small vacuoles of fat in cytoplasm
◼ May be due to high fat load or reduced ability to metabolize fat
◼ Liver, heart, kidneys particularly susceptible
Cell death
Balance exists between death and proliferation
Cell death in two ways:
◼ Apoptosis: controlled cell destruction (“cell suicide”)
◼ Removes cells that are being replaced or have “worn out” ◼ Removes unwanted tissue
◼ Normal process in the body
◼ Necrosis: Unregulated death caused by injuries to
cells; death of organ or tissue that is part of a living
person
◼ Cells swell and rupture ◼ Inflammation results
necrosis
cell size
- enlarged (swelling)
nucleus
- pyknosis to karyorrhexis to karyolysis
plasma membrane
- disrupted
cellular contents
- enzymatic digestion; may leak out of the cell
adjacent inflammation
- frequent
physiologic or pathologic role
- invariably pathologic (culmination of irreversible cell injury)
apoptosis
cell size
- reduced (shrinkage)
nucleus
- fragmentation into nucleosome-sized fragments
plasma membrane
- intact; altered structure, esp. orientation of lipids
cellular contents
- intact; maybe released in apoptotic bodies
adjacent inflammation
- no
physiologic or pathologic role
- often physiological means of eliminating unwanted cells; may be pathologic after some forms of cell injury, esp. DNA & protein damage
Apoptosis
◼ Programmed cell death via controlled cell destruction
◼ Physiologic:
◼ Development, maturation, repair
◼ Pathophysiologic:
◼ Lack of apoptosis in proliferation of CA cells ◼ Hepatocyte death in hepatitis B and C
◼ Control Mechanism: unclear
Apoptosis, the process
◼ Controlled autodigestion via endogenous enzymes
◼ Cell shrinkage:
◼ Disruption of cytoskeleton
◼ Condensation of cytoplasmic organelles
◼ Disruption and clumping of
nuclear DNA
◼ Eventually nucleus breaks into
spheres
◼ Wrinkling of cell membrane
◼ Finally: division of cell into membrane-covered fragment
Necrosis
Necrosis: death of organ or tissue that is part of a living person
Unregulated:
◼ Enzymatic digestion of cell components
◼ Loss of membrane integrity
◼ Uncontrolled release of products into intracellular space
◼ Initiation of inflammatory response
Necrosis, different types
Liquefaction/liquefactive necrosis: e.g., center
of abscess
◼ Characterized by tissue softening
◼ Death of some cells but their catalytic enzymes
still functional
Coagulation necrosis: e.g., hypoxic
injury/infarct
◼ Transformation into gray, firm mass
◼ Acidosis, with resultant denaturation of proteins
Caseous necrosis: e.g., Tb granulomas
◼ Persistence of dead cells as soft, cheeselike debris
Necrosis, different types 2
Fat necrosis: Focal areas of fat destruction (due
to abdominal trauma or acute pancreatitis) ◼ Enzymes leak out of damaged pancreas, digest
peritoneal fat cells and their contents (e.g., stored
triglycerides)
◼ Released fatty acids combine w/ Ca2+: produce
grossly identifiable chalky white lesions
Fibrinoid necrosis: Special form of necrosis,
visible by light microscopy
◼ Seen in immune reactions, in which Ag/Ab
deposited bv walls, and in severe hypertension
Gangrene
Describes large area of necrotic tissue
2 classifications:
◼ Dry gangrene: lack of arterial blood supply but
venous flow can carry fluid out of tissue ◼ Tissue tends to coagulate
◼ Moist (wet) gangrene: lack of venous flow lets fluid accumulate in tissue
◼ Tissue tends to liquefy; infection likely ◼ Special type:
◼ Gas gangrene: Clostridium infection produces toxins and H2S bubbles
Autophagy
Autophagy (“self-eating”): lysosomal digestion
of the cell’s own components
◼ Survival mechanism during nutrient deprivation ◼ Enables starved cell to live by eating its own
contents and recycling these contents to provide nutrients and E
Intracellular organelles and cytosol sequestered
within an ER-derived double membrane
(phagophore); matures into autophagic vacuole ◼ Fuses w/ lysosomes: forms autophagolysosome
◼ Digests cellular components w/in
