TA Reviews

Disease at the Cellular Level

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M2

Pathology

TA Reviews

Diseases at the Cellular Level Lecture Handout

Jill Conway, 8/00

Adaptation = reversible altered steady state of cells in response to stimuli

Forms of:

  • physiologic = hormones, aging, decreased workload in muscle
  • pathologic = bad nutrition, loss of innervation, diminished blood supply

Hypertrophy:  increase in cell or organ size typically in response to increased workload. Probably triggered by mechanical stretch receptors and growth factors or cytokines.

Hyperplasia:  increase in cell number, occurs only in dividing tissue, usually induced via hormones (breast, uterus) or compensation for lost tissue.  Probably induced by growth factors, interleukins (IL-6).

Atrophy:  decrease in cell size through loss of cell substance.  Physiologic--normal for certain structures to regress--thyroglossal duct regresses.  Pathologic = decreased workload, denervation, diminished blood supply.

Metaplasia: reversible replacement of one adult cell type by another, probably through changes in differentiation of stem cells brought about via cytokines.

Non-adaptive change:

Dysplasia:  loss of orientation, hyperchromasia, odd mitotic figures, changes in nuclear size and shape

Calcification:  dystrophic calcification occurs in abnormal, injured or dying tissues as excess calcium deposits following injury as in advanced atherosclerosis.

Metastatic calcification occurs in normal tissues from increases in blood levels of calcium from various causes such as increased PTH.  Will deposit mainly in kidneys, lungs, arteries, pulmonary veins.

Hyaline Change:  alteration in cells that leads to glassy pink homogenous appearance with H&E stains.  May have many different causes.

CAUSES OF CELL INJURY:

Hypoxia = O2 Deficiency

Ischemia = decreased O2 delivery from arterial block or reduced venous drainage

Physical agents:  temp., trauma, radiation, electric shock

Chemicals and drugs:  includes glucose and salt, CO, asbestos, poisons

Microbiologic Agents:  bacteria, parasites, viruses, and fungi

Immunologic Reactions:  such as anaphylaxis or immune complex damage

Genetic defects:  such as hemoglobin S in sickle cell anemia causing cell injury

Nutritional imbalances:  protein-calorie or specific vitamin deficiencies, excess lipid intake increases atherosclerosis. 

Aging:  injury occurs via programmed cell death or toxin buildup, failure of components, lipofuscin excess, etc.

Sublethal Injury:

Some organelle dysfunctions contribute to cell injury and death.  For example, cytoskeleton abnormalities influence cell behavior.  Chediak-Higashi syndrome involves faulty polymerization of microtubules and thus problems with fusion of lysosomes with phagocytosed bacteria.  Microtubule defects can cause sterility or impaired respiratory mucus clearing.  Mallory body = masses of prekeratin intermediate filaments associated with alcoholic liver disease.

Fatty Change = abnormal accumulation of triglycerides in functional cells.  Most often seen on cells that process or depend on fat for energy--i.e., liver and cardiac cells.  Fatty acids from diet and tissues are taken up in the liver, conjugated to apoproteins and exported.  Damage to liver cells decreases apoprotein synthesis and fat export.  Most commonly seen with alcohol abuse in this country, but any liver insult may cause fatty change. 

Intracellular accumulations occur when normally produced substances are produced too quickly, and endogenous substance cannot be metabolized and thus removed, or an exogenous substance is deposited in the tissues and accumulates. 

Glycogen may accumulate in the storage diseases such as McArdles syndrome or in diabetes mellitus where glycogen accumulates in kidney, liver and cardiac tissues. 

Lysosomal storage diseases result from enzyme deficiency in degradative enzymes.  Most common are sphingolipidoses, such as Tay Sachs disease where gangliosides accumulate mainly in neurons.  Mucopolysaccharidoses include Hunter’s and Hurler’s syndrome.

Dead cells and cell parts are phagocytosed by lysosomes that carry multiple digestive enzymes.  Heterophagy denotes uptake of materials from the extracellular matrix in endocytosis.  Cellular components may also be put into autophagic vacuoles which then fuse with lysosomes in autophagy, especially in cells undergoing atrophy.  Undigested debris may persist as residual bodies, lipofuscin pigment, or be expelled from the cell.

General Principles of Cell Injury

Cell response depends on kind, severity, and duration of injury.

Clinical effects of cell injury depend on what kind of cell is affected, its prior state of health, and what sort of adaptive mechanisms are available to it.

Major sensitive cell components:  maintenance of integrity of cell membrane, aerobic respiration, protein synthesis, genetic integrity

Cellular mechanisms are all interdependent, so no matter what kind of injury first occurs, many cell systems are affected.

Morphologic changes become apparent visually after they occur, with cell swelling being evident within minutes but deeper structural changes--genetic dysfunction, chromatin clumping, taking longer to observe.

Major Processes of Cell Injury

  1. Decreased ATP because of decreased cellular respiration is often caused by either ishemia or toxins.  The reduction in ATP starts a cascade of other effects which do further damage including failure to maintain normal Na and Ca gradients. 
  2. Toxic oxygen radicals form normally during respiration, but unless they can be scavenged effectively, they may cause cellular damage.
  3. Calcium regulation within the cell plays an important role in cell homeostasis.  Normal intracellular calcium in the cytosol is less than 0.1 micromol and 1.3 mmol outside the cell or in the mitochondria and ER.  Gradients are maintained by ATPase pumps.  Influx of calcium into cytosol activates phospholipases, proteases, ATPases and endonucleases which then act to further cellular damage.
  4. Mitochondrial damage:  damage to mitochondrial membrane results in formation of MPT, mitochondrial permeability transition, a nonselective inner membrane channel that disrupts normal proton gradient.  MPT may become permanent which indicates impending cell death.  Cytochrome c may also by released into the cytosol playing a role in triggering apoptosis.

Major Types of Cell Injury

Chemical Injury:  some chemicals cause direct cell injury through a variety of mechanisms, e.g., cyanide works to disrupt cytochrome oxidase.  Carbon tetrachloride poisoning occurs only after the P-450 oxidative enzymes convert it to the reactive CCl3 activated species that causes lipid peroxidation.

Hypoxic/Ischemic Injury:

  1. First consequence is loss of oxidative phosphorylation and reduction in ATP production.  This causes effects on the following:
    • failure of ATP dependent Na/K pumps and Ca pump that normally maintains high cell K and low cell Na and Ca.  So now K decreases and Na and Ca increase within the cell.  Na brings water and cell swelling.  Ca causes many effects including activation of phospholipases that disrupt the membrane.
    • decrease in ATP increases glycolysis and thus decreases pH from lactic acid buildup within the cell and decreases glycogen stores
  2. Disruption of organelle membranes and loss of ATP needed for synthesis of proteins results in ribosomes detaching from RER and ER swells.  This decreases protein synthesis, which leads to membrane disruption, decreased mitochondrial function, and disruption of the cytoskeleton.
  3. Ongoing hypoxia will eventually result in formation of blebs and myelin figures (plasma and organelle membranes in lamellar stacks), swollen mitochrondria, dilated ER.

There is not some magical point at which cell function is lost and cell is doomed for destruction.  The changes above are reversible, but at some point, return of oxygen will not lead to cell recovery.  ATP mechanism (if it recommences) and cell membrane seem most important--especially membrane integrity. 

Membrane function depends mostly on mitochondrial function, phospholipid loss of membrane components, mostly from endogenous phospholipase activation, and decreased synthesis of new phospholipids.  Cytoskeleton attaches to plasma membrane and strengthens it.  Proteases may damage this connection and the plasma membrane is thus more susceptible to rupture.  Reactive oxygen species injure cell membranes and lipid byproducts may have a detergent effect on membranes.

Irreversible injury is associated with massive calcium influx which is further worsened when perfusion is re-established.

Morphologically, vacuolated mitochondria with large calcium deposits and nuclear changes (chromatin clumping, etc.) illustrate irreversible damage.  Lysosomal membrane injury causes release of enzyme contents that eventually lead to irreversible nuclear damage.  Myelin figures are phagocytosed by other cells or calcified into calcium soaps.  Enzymes will be leaked to extracellular space--i.e. CK-MB.

Reperfusion injury:

Much of the damage from ischemia or hypoxia occurs on the re-establishment of circulation:  reperfusion can help restore health to reversibly damaged cells, but can also lead to cell death through apoptosis and necrosis.

Causes: 

  1. circulation brings PMNs (neutrophils especially) that release toxic oxygen radicals that do damage to membranes.  Damaged cells may express cytokines that attract PMNs to them and cause inflammation with additional injury.
  2. reperfusion brings a massive influx of Ca++ which leads to activation of phospholipases, endonucleases, proteases (cytoskeleton), and DNAases

Oxygen radicals may get produced via outside energy (radiation), metabolism of chemicals (CCL4), normal metabolic reduction of O2 to water, lysosomal enzymes, and from iron or copper metals or nitric oxide.

Oxygen radicals (free unpaired electron in outer orbit) do three main things: 

  1. lipid peroxidation -- takes an unsaturated fatty acid in membrane phospholipids and crease a damaged lipid and peroxide, which is autocatalytic and does more damage
  2. promotes sulfhydryl mediated protein cross linking that creates disulfide bonds which inactivate enzymes
  3. interact with DNA causing mutations, especially with thymine causing single strand breaks

Note that these radicals are removed by other mechanisms including antioxidants, catalase (peroxisomes), superoxide dismutase (cytosol), glutathione peroxidase.

Cell death:

Necrosis:  = changes following cell death in living tissue (not fixed specimens)

Four types:  coagulation = most common, occurs in response to hypoxia in all tissues except CNS, preserves cell outline, denaturation of proteins

Liquefactive:  bacterial infection, CNS ischemia, lose all architecture due to enzyme digestion

Fat:  pancreatic lipases escape and digest adipose tissue into free fatty acids with accumulation of calcium that shows up as chalky white areas

Caseous:  form of coagulative necrosis associated with some granulomatous infections such as TB, white cheesy debris surrounded by a granuloma

Apoptosis: programmed cell death that occurs normally in many contexts:  aging, development, homeostasis, method to delete damaged cells, defense mechanism in the immune system.  Specific examples include T cell deletions in thymus, embyrogenesis (loss of tissue between fingers), hormone dependent involution (return of uterine lining to normal following pregnancy), cell death in tumors, neutrophilic death in acute inflammation. Note that this requires active cell metabolism, does not invoke inflammation, may occur in single cells.

Mechanisms:

Signaling pathways may induce or prevent apoptosis via transmembrane signals through specific receptors.  Growth factors, hormones, and TNF all play a role.  TNFR (tumor necrosis factor receptor superfamily) on the surface of the plasma membrane may be activated by TNF or other proteins to initiate programmed cell death.

Control of apoptosis occurs via interrupting the process or allowing it to continue with commitment of the cell to death.  Adapter proteins may be utilized to activate mechanisms that cause death.  (Example:  Fas-Fas ligand mediated apoptosis via Fas receptor and Fas ligand from immune system cells that allows cell killing without immune system activation).  Cytochrome c release from mitochondria seems to commit a cell to apoptosis and may be involved in regulation.  The Bcl-2 family of genes can act to promote or prevent apoptosis by influencing mitochondrial permeability.

Execution of apoptosis also involves the caspase family (cysteine protease that can cleave aspartic acid residues).  Caspases are zymogens which can be activated via hydrolysis through substrate interaction or autocatalytically.  Once the cell is committed to cell death, caspases rapidly degrade proteins in the nucleus and cytoplasm.  Caspase 9 is involved in the reactions stimulated by cytochrome c release causing cell death, and caspase 8 gets triggered by the Fas-Fas ligand binding.  Dead cells are removed by phagocytes because their fragments have signaling molecules targeting them for uptake.

Triggers for apoptosis also include cytotoxic t-lymphocytes recognizing foreign antigens on cell surfaces which causes them to be targeted.  Granules with toxic enzymes are then released into the cell.  DNA damage also triggers apoptosis unless the damage can be repaired.  p53 triggers cell cycle stalling in G1 when there is genetic damage.  If it is not repaired, p53 can initiate apoptosis.

Morphological changes:  cells are smaller with dense cytoplasm.  The chromatin is condensed in fragments near the nuclear periphery.  Apoptotic bodies form which are membrane bound with some cytoplasm and organelles and sometimes nuclear fragments.  These are taken up by normal cells nearby and degraded in lysosomes.

Dysregulated apoptosis plays a role in a variety of diseases.  When inhibited, cells may survive longer as in cancer and autoimmune disorders.  When accelerated, cells may die sooner as in AIDS depletion of lymphocytes and degenerative neurological disorders.

Aging:  There seems to be some indication that aging may be timed by cellular divisions and regulated within particular ranges.  Somatic cells in culture do not divide endlessly, but rather stop in a nondividing state called cellular senescence.  This may be regulated by telomere shortening through successive replications.  In addition, there may be “clock” genes that alter growth rate and influence development and life span.  Aging also occurs from metabolic damage--increase in lipofuscin, oxygen radical damage that accumulates, and accumulations of abnormal DNA.

 

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