MIDTERM

• Cell injury

  reversible up to a point, but if the injurious stimulus is persistent or severe, the cell suffers irreversible injury and ultimately undergoes cell death.
• Causes of cell injury

  • Oxygen Deprivation; Hypoxia is a deficiency of oxygen, which causes cell injury by reducing aerobic oxidative respiration.
  • Physical Agents; Physical agents capable of causing cell injury include mechanical trauma, extremes of temperature.
  • Chemical Agents and Drugs; Simple chemicals such as glucose or salt in hypertonic concentrations may cause cell injury.
  • Infectious Agents
  • Immunologic Reactions
  • Genetic Abnormalities
  • Nutritional Imbalances
• Reversible cell injury is characterized by;

  • generalized swelling of the cell and its organelles, blebbing of the plasma membrane, detachment of ribosomes from the endoplas- mic reticulum (ER), and clumping of nuclear chromatin.
  • Fatty change occurs in organs that are actively involved in lipid metabolism (e.g., liver).
• Nuclear degeneration in the form of the following effects: 

  • Pyknosis: shrinkage of the nucleus due to chromatin condensation
  • Karyorrhexis: fragmentation of the nucleus (mediated by endonucleases)
  • Karyolysis: disintegration or dissolution of the nucleus
• Early Stage of Cell Injury (reversible)

  • Tissue hypoxia leads to decreased ATP production and decrease intracecellular pH.
  • Decreased function of sodium/potassium ATPase which causes diffusion of sodium and water into the cell.
  • Disrupted Calcium ATPase pump activity which causes Calcium accumulation in the cell, leading to swelling of the cell and activation of degredative enzymes.
  • Detachment of ribosomes and polysomes which decreases protein synthesis.
  • Formation of myelin figures.
• Late Stage of Cell Injury (irreversible) and Cell Death

  • Degradation of phospholipids in the plasma membrane which ruptures the cell membrane and releases cytosolic enzymes.
  • Influx of Ca2+ into the cytoplasm increases breakdown of cellular proteins and damage to cytoskeleton (autolysis) by activating lysosomal enzyme.
  • Increased mitochondrial membrane permeability releases cytochrome c from mitochondria which activates apoptosis.
  • Development of inclusions in the mitochondrial matrix.
  • Damaged mitochondria causes dysfunctional electron transport chain and decrease ATP.
• • DNA damage activates p53, which arrests cells in the G1 phase of the cell cycle and activates DNA repair mechanisms.
  • If these mechanisms fail to correct the DNA damage, p53 triggers apoptosis by the mitochondrial pathway.
• Generations of Free Radicals

  • The reduction-oxidation reactions that occur during normal metabolic processes.
  • Absorption of radiant energy (e.g., ultraviolet light, x-rays).
  • ROS are produced in activated leukocytes during inflammation.
  • Enzymatic metabolism of exogenous chemicals.
  • Transition metals
  • Nitric oxide (NO), an important chemical mediator generated by endothelial cells, macrophages, neurons, and other cell types
• Free Radicals cause Lipid peroxidation in membranes, Oxidative modification of proteins, and Lesions in DNA.
• Removal of Free Radicals

  • Antioxidants
  • As we have seen, free iron and copper can catalyze the formation of ROS.
  • Several enzymes break down H2O2 and O2• (eg.Catalase, Superoxidase dismutases (SODs), Glutathione peroxidase)
• Hypertrophy is an increase in the size of cells, due to the synthesis and assembly of additional intracellular structural components

  • Pathologic hypertrophy (increased workload on cardiac muscle)
  • Physiologic hypertrophy (enlarged uterus during pregnancy) 
• Mechanism of Hypertrophy

  • Sensors in the cell detect the increased load
  • PI3K/AKT pathway (physiological) and G protein coupled receptor-initiated pathways (pathological) are activated.
  • Increased production of growth factors (e.g. TGF-β, IGF1, fibroblast growth factor) and vasoactive agents (e.g., α-adrenergic agonists, endothelin-1, and angiotensin II)
  • Activation of transcription factors and increased protein production.
• Hyperplasia is an increase in numbers of cells

  • Hyperplasia can only take place if the tissue contains cells capable of dividing.
  • Physiologic hyperplasia due to action of hormones and growth factors (compensatory hyperplasia of the liver after hepatectomy)
  • Pathologic hyperplasia due to excess actions of hormones and growth factors (Excess estrogen endometrial hyperplasia) 
• Mechanisms of Hyperplasia 

  • Hyperplasia is the result of growth factor-driven proliferation of mature cells.
• Atrophy is a decrease in cell size and number.

  • Physiologic atrophy: common during normal development. Some embryonic structures undergo atrophy during fetal development
  • Pathologic atrophy has several causes, and it can be local or generalized
  • Decreased workload (disuse atrophy) 
  • Loss of innervation (denervation atrophy)
  • Diminished blood supply
  • Inadequate nutrition
  • Loss of endocrine stimulation
  • Pressure
• Mechanisms of Atrophy 

  • Atrophy results from decreased protein synthesis and increased protein degradation in cells
  • Ubiquitin-proteasome pathway
  • Autophagy
• Metaplasia is a reversible change when one cell type is replace with another type.

  • It is an adaptive response
• Types of Metaplasia

  • Columnar to squamous 
  • In the respiratory tract in response to chronic cigarette smoke exposure 
  • Squamous to columnar
  • Barrett esophagus - esophageal squamous epithelium gets replaced by intestinal-like columnar cells under the influence of refluxed gastric acid
  • Connective tissue metaplasia 
  • Formation of cartilage, bone, or adipose cells (mesenchymal tissues) in tissues that normally do not contain these elements
  • Bone formation in muscle
• Mechanisms of Metaplasia 

  • Metaplasia does not result from a change in the phenotype of an already differentiated cell type; 
  • It results from either the reprogramming of local tissue stem cells, or colonization by differentiated cell populations from adjacent sites
• Necrosis is the consequence of severe injury

  • Necrosis is characterized by denaturation of cellular proteins, leakage of cellular contents through damaged membranes, local inflammation, and enzymatic digestion of the lethally injured cell. 
  • two phenomena consistently characterize irreversibility—the inability to reverse mitochondrial dysfunction even after resolution of the original injury, and profound disturbances in membrane function. 
• Coagulative necrosis is the most common form of necrosis. It occurs as a result of prolonged hypoxia due to vascular occlusion, does NOT occur in the brain.

  • Anaerobic metabolism → ↑ lactic acid production → ↓ pH → denaturation of proteins (including proteolytic enzymes) → cell death
  • Impaired Na+/K+-ATPase → ↑ intracellular Na+ → ↑ intracellular H2O → cell swelling
  • Perserved; cellular architecture
• Gangrenous necrosis is caused by bacterial infection and is associated with gas gangrene.

  • Dry gangrene: caused by ischemia and shows coagulative necrosis.
  • Wet gangrene: caused by superinfection of dry gangrene and shows coagulative and liquefactive necrosis.
• Liquefactive necrosis is found in abscesses and cysts. Liquefaction is the conversion of solid material into liquid. As liquefactive necrosis progresses, the center of the lesion becomes soft and watery, occurs in the brain. (damage caused by alkaline solution)

  • Release of enzymes from lysosomes
  • Tissue softening→ fluid necrosis→ cavitation, pseudocyst formation
  • Early: macrophages and cellular debris
  • Late: cavitations or cystic spaces
• Caseous Necrosis is a type of necrosis characterized by granular debris that results from macrophages walling off a pathogen.

  • Macrophages, epitheloid cells, and multinucleated giant cells surround a site of infection → granular debris

  Tuberculosis

  Systemic fungi infection (e.g., histoplasmosis)

  Nocardiosis
• Fatty necrosis is seen in organs rich in fat such as liver, pancreas, kidney, and breast. Fatty necrosis a type of necrosis in which adipose cells die off prematurely, either caused by an enzymatic reaction, or traumatic injury.

  • Breakdown of triglycerides by lipase → binding of fatty acids to calcium → saponification → chalky-white appearance
  • Fat saponification and calcium → dark blue appearance on H&E stain
• Fibrinoid necrosis is characterized by deposition of fibrin like materials in blood vessels. The term “fibrinoid” refers to the presence of eosinophilic deposits resembling fibrin in the vessel walls.

  • Vessel wall damage caused by immune complex deposition (e.g., due to type III hypersensitivity reaction) → fragmentation of collagenous and elastic fibers → leakage of fibrin and other plasma proteins

  Rheumatoid arthritis, Peptic ulcer disease, Immune vasculitis, Vascular reactions
• Apoptosis is programmed cell death.

  • Characteristics
  • ATP-dependent physiological process 
  • Usually affects individual cells and not groups of cells (in contrast to necrosis) 
  • Cell membrane usually stays intact: no inflammatory response or no cellular swelling (in contrast to necrosis)
• Mechanism of Apoptosis

  1. The Mitochondrial (Intrinsic) Pathway of Apoptosis

  • Stimulus activates p53 gene which decreases anti-apoptic genes (BCL2, BCL-X, and MCL) but activates pro-apoptic genes (BAK and BAX).
  • Pro-apoptic genes create an outer mitochondrial membrane which allows cytochrome c to leave the mitochondria.
  • Cytochrome c binds to APAF-1 to form an apoptosome.
  • The apoptosome binds to caspase-9 , which activates caspase-3,6.
  • Execution phase is then mediated (DNA break down)
• Mechanis of Apoptosis

  The Extrinsic (Death Receptor–Initiated) Pathway of Apoptosis.

  • Death receptors (FAS-R, TNFR) bind to ligands (FAS-L, TNF-a) to form a binding site for the adaptor protein (FADD).
  • FADD binds to inactiavte caspase-8/10, which activates caspase-3,6.
  • Execution phase is mediated.
  • Cytoxic T-cells use perforin to release Granzyme B into the cell, which activates caspase-10
• Adaptor Protein FADD can be inhibited by FLIP in extrinstic pathway.
• Autophagy is a process in which a cell eats its own contents.

  • Nucleation and formation of an isolation membrane, also called a phagophore.
  • Formation of a vesicle, called the autophagosome, from the isolation membrane.
  • Maturation of the autophagosome by fusion with lysosomes, to deliver digestive enzymes that degrade the contents of the autophagosome
• Intracellular accumulation

  • Endogenous
  • Increased production of substances naturally occurring in the body (e.g., lipids, carbohydrates, proteins)
  • Decreased metabolization of substances naturally occurring in the body (e.g., lipids, carbohydrates, proteins)
  • Production of abnormal substances (e.g., misfolded proteins, inclusion bodies)
  • Exogenous: storage of substances not naturally occurring in the body (e.g, tattoo ink, carbon from coal dust or smoke)
• Metastatic calcification

  • calcification of otherwise noncalcified tissue
• Dystrophic calcification 

  • Localized calcification (intracellular and extracellular) of otherwise noncalcified tissue