cell injury

• Cellular response to injury

  Hypertrophy, hyperplasia, atrophy, metaplasia, intracellular depositions and calcification
• Learning objectives


  • To understand the basic concepts of cellular response to stress
  • To define, the concepts of hyperplasia, hypertrophy, metaplasia and atrophy and understand the mechanisms of these cellular changes and give examples of each
  • To understand the concept of cell death by necrosis and apoptosis
  • To understand the phenomenon of intracellular accumulations and calcifications
• Pathology


  The study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlie disease
• General pathology


  Concerned with the common reactions of cells and tissues to injurious stimuli
• Systemic pathology


  Examines the alterations and underlying mechanisms in organ specific diseases
• Homeostasis


  The normal cell's ability to handle physiologic demands and maintain a steady state
• Adaptations


  Reversible functional and structural responses to changes in physiologic states and some pathologic stimuli, during which new but altered steady states are achieved, allowing the cell to survive and continue to function
• Adaptive responses


  • Increase in the size of cells (hypertrophy)
  • Increase in their number (hyperplasia)
  • Decrease in the size and metabolic activity of cells (atrophy)
  • Change in the phenotype of cells (metaplasia)
• Cell injury


  Reversible up to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell suffers irreversible injury and ultimately undergoes cell death
• Cell death


  The end result of progressive cell injury, one of the most crucial events in the evolution of disease in any tissue or organ, resulting from diverse causes including ischemia, infection, and toxins
• Cell death is also a normal and essential process in embryogenesis, the development of organs, and the maintenance of homeostasis
• Pathways of cell death

  • Necrosis
  • Apoptosis
• Intracellular accumulations


  Metabolic derangements in cells and sublethal, chronic injury may be associated with intracellular accumulations of proteins, lipids, and carbohydrates
• Pathologic calcification


  Calcium is often deposited at sites of cell death
• Causes of cellular injury

  • Oxygen Deprivation (Hypoxia, ischaemia, anaemia, cardiorespiratory failure, CO poisoning etc)
  • Physical Agents (Mechanical trauma, extremes of temperature, sudden changes in atmospheric pressure, radiation, electric shock)
  • Chemical Agents and Drugs (Poisons, arsenic, mercury, cyanide, organophosphate, salt, sugars etc)
  • Infectious Agents (Bacteria, viruses, fungi, rickettsia, parasites etc)
  • Immunologic Reactions (Autoimmune reactions)
  • Genetic Derangements (Accumulation of damaged DNA or misfolded proteins, accumulation of unwanted products from in-borne errors of metabolism)
  • Nutritional Imbalances (Protein-calorie deficiency, calorie excess-obesity, vitamin deficiency)
• Necrosis


  The morphologic appearance is the result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell. Necrotic cells are unable to maintain membrane integrity and their contents often leak out, a process that may elicit inflammation in the surrounding tissue. The enzymes that digest the necrotic cell are derived from the lysosomes of the dying cells themselves and from the lysosomes of leukocytes that are called in as part of the inflammatory reaction
• Nuclear changes in necrosis

  • Karyolysis - enzymatic degradation of DNA by endonucleases
  • Pyknosis - nuclear shrinkage and increased basophilia, chromatin condenses into a solid, shrunken basophilic mass (also seen in apoptosis)
  • Karyorrhexis - the pyknotic nucleus undergoes fragmentation
• Coagulative necrosis


  A form of necrosis in which the architecture of dead tissues is preserved for a span of at least some days. The affected tissues exhibit a firm texture. Ischemia caused by obstruction in a vessel may lead to coagulative necrosis of the supplied tissue in all organs except the brain. A localized area of coagulative necrosis is called an infarct
• Liquefactive necrosis


  Characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass. It is seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of leukocytes and the liberation of enzymes from these cells. The necrotic material is frequently creamy yellow because of the presence of dead leukocytes and is called pus
• Gangrenous necrosis


  Not a specific pattern of cell death, but the term is commonly used in clinical practice usually to refer to lower leg that has lost its blood supply and has undergone necrosis (typically coagulative necrosis) involving multiple tissue planes. When bacterial infection is superimposed there is more liquefactive necrosis because of the actions of degradative enzymes in the bacteria and the attracted leukocytes (giving rise to so-called wet gangrene)
• Caseous necrosis


  Encountered most often in foci of tuberculous infection. The term "caseous" (cheeselike) is derived from the friable white appearance of the area of necrosis. Histologically, there is a granuloma
• Fat necrosis


  Refers to focal areas of fat destruction, resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. This occurs in the calamitous abdominal emergency known as acute pancreatitis. The released pancreatic lipases split the triglyceride esters contained within fat cells. The fatty acids, so derived, combine with calcium to produce grossly visible chalky-white areas (fat saponification), which enable the surgeon and the pathologist to identify the lesions
• Fibrinoid necrosis


  A special form of necrosis usually seen in immune reactions involving blood vessels. This pattern of necrosis typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries. Deposits of these "immune complexes," together with fibrin that has leaked out of vessels, result in a bright pink and amorphous appearance in H&E stains, called "fibrinoid" (fibrin-like) by pathologists
• Apoptosis


  A pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplasmic proteins. Apoptotic cells break up into fragments, called apoptotic bodies, which contain portions of the cytoplasm and nucleus. The plasma membrane of the apoptotic cell and bodies remains intact, but its structure is altered in such a way that these become "tasty" targets for phagocytes. The dead cell and its fragments are rapidly devoured, before the contents have leaked out, and therefore cell death by this pathway does not elicit an inflammatory reaction in the host
• Causes of apoptosis


  • Destruction of cells during embryogenesis, including implantation, organogenesis, developmental involution, and metamorphosis
  • Involution of hormone-dependent tissues upon hormone withdrawal, such as endometrial cell breakdown during the menstrual cycle, ovarian follicular atresia in menopause, the regression of the lactating breast after weaning, and prostatic atrophy after castration
  • Elimination of potentially harmful self-reactive lymphocytes, either before or after they have completed their maturation, so as to prevent reactions against one's own tissues
  • Death of host cells that have served their useful purpose, such as neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response
• Apoptosis in pathologic situations

  • DNA damage (Radiation, cytotoxic anticancer drugs, and hypoxia can damage DNA, either directly or via production of free radicals)
  • Accumulation of misfolded proteins (Improperly folded proteins may arise because of mutations in the genes encoding these proteins or because of extrinsic factors, such as damage caused by free radicals)
  • Cell death in certain infections, particularly viral infections, in which loss of infected cells is largely due to apoptosis that may be induced by the virus or by the host immune response
  • Pathologic atrophy in parenchymal organs after duct obstruction, such as occurs in the pancreas, parotid gland, and kidney
• Morphologic features of apoptosis

  • Cell shrinkage
  • Chromatin condensation
  • Formation of cytoplasmic blebs and apoptotic bodies
  • Phagocytosis of apoptotic cells or cell bodies, usually by macrophages
• Caspases


  Enzymes that are activated in apoptosis, cysteine proteases that cleave proteins after aspartic residues
• Mitochondrial pathway


  The major mechanism of apoptosis in all mammalian cells, resulting from increased permeability of the mitochondrial outer membrane with consequent release of death-inducing (pro-apoptotic) molecules
• Death receptor pathway


  The extrinsic pathway that plays a role in the elimination of self reactive T lymphocytes
• Apoptosis process


  Initiation phase - some caspases become catalytically active

  Execution phase - other caspases trigger the degradation of critical cellular components
• Apoptosome


  A wheel-like hexamer formed by cytochrome c binding to APAF-1 (apoptosis-activating factor-1), which is able to bind caspase-9, the critical initiator caspase of the mitochondrial pathway
• Hypertrophy


  An increase in the size of cells, resulting in an increase in the size of the affected organ. The hypertrophied organ has no new cells, just larger cells. The increased size of the cells is due to the synthesis and assembly of additional intracellular structural components
• Hyperplasia


  Cells capable of division may respond to stress by undergoing both hyperplasia (des
• Mechanism of apoptosis


  1. Initiation phase

  2. Execution phase
• Caspases


  Enzymes that become catalytically active during apoptosis
• Mechanism of apoptosis


  1. Cytochrome c released into cytosol

  2. Binds to APAF-1 to form apoptosome

  3. Apoptosome binds and activates caspase-9

  4. Autoamplification process

  5. Formation of apoptotic bodies
• Check up NECROPTOSIS AND AUTOPHAGY Assignment
• Hypertrophy


  Increase in the size of cells, resulting in an increase in the size of the affected organ
• Hypertrophied organ has no new cells, just larger cells