Cell Adaptations, Injury, Death and Pathology Review
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This document discusses various concepts related to pathology including cellular adaptations, injury, and death. It covers topics such as degenerative, inflammatory, and neoplastic diseases; cellular growth adaptations including hyperplasia, hypertrophy, atrophy, and metaplasia; factors that can cause cell injury and death including oxygen deprivation, physical and chemical insults, infection, and nutritional deficiencies; subcellular responses to injury involving organelles and cytoskeleton; common intracellular accumulations of substances; and concepts of programmed cell death versus aging from wear and tear.
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Cell Adaptations, Injury, Death and Pathology Review
- 1. CELL ADAPTATIONS CELL INJURY CELL DEATH
- 2. OBJECTIVES Understand the 3 main anatomic concepts of disease---Degenerative, Inflammatory, Neoplastic Understand the concepts of cellular growth adaptations---Hyperplasia, Hypertrophy, Atrophy, Metaplasia Understand the factors of cell injury and death---O2, Physical, Chemical, Infection, Immunologic, Genetic, Nutritional
- 3. OBJECTIVES Understand the pathologic mechanisms at the SUB-cellular level---ATP, Mitochondria, Ca++, Free Radicals, Membranes Understand and differentiate the concepts of APOPTOSIS and NECROSIS Understand SUB-cellular responses to injury---Lysosomes, Smooth endoplasmic reticulum, Mitochondria, Cytoskeleton
- 4. OBJECTIVES Identify common INTRA-cellular accumulations---Fat, Hyaline, CA+ +, Proteins, Glycogen, Pigments Understand aging and differentiate the concepts of preprogrammed death versus wear and tear.
- 7. PATHOLOGY • ETIOLOGY (“Cause”) • PATHOGENESIS (“Insidious development”) • MORPHOLOGY (ABNORMAL ANATOMY) • CLINICAL EXPRESSION
- 9. PATHOGENESIS “sequence of events from the initial stimulus to the ultimate expression of the disease”
- 11. CLINICAL EXPRESSION • Ironically, even though “clinical expression” is not often present in subclinical diseases, it is the “pathos” of pathology.
- 12. Most long term students of pathology, like myself, will strongly agree that the very best way for most minds to remember, or identify, or understand a disease is to associate it with a morphologic IMAGE. This can be gross, electron microscopic, light microscopic, radiologic, or molecular. LIGHT MICROSCOPIC LEVEL. In MOST cases it is at the
- 13. CLINICAL/FUNCTIONAL Rudolph Virchow 1821-1902 The Father of Modern Pathology
- 15. CELL DEATH • APOPTOSIS (“normal” death) • NECROSIS (“premature” or “untimely” death due to “causes”
- 16. The –plasia brothers • HYPER• HYPO- (A-) • NORMO- • META• DYS• ANA• “Frank” ANA-
- 17. HYPER-PLASIA IN-CREASE IN NUMBER OF CELLS
- 18. HYPO-PLASIA DE-CREASE IN NUMBER OF CELLS
- 19. The –trophy brothers • HYPER• HYPO- (A-) • DYS-
- 20. HYPER-TROPHY IN-CREASE IN SIZE OF CELLS
- 21. HYPO-TROPHY? DE-CREASE IN SIZE OF CELLS? RARELY USED TERM
- 22. A-TROPHY? DE-CREASE IN SIZE OF CELLS? YES IN CELL SIZE DUE TO LOSS OF CELL SUBSTANCE SHRINKAGE
- 23. • • • • • • ATROPHY DECREASED WORKLOAD DENERVATION DECREASED BLOOD FLOW DECREASED NUTRITION AGING (involution) PRESSURE
- 24. METAPLASIA • A SUBSTITUTION of one NORMAL CELL or TISSUE type, for ANOTHER – COLUMNAR SQUAMOUS (Cervix) – SQUAMOUS COLUMNAR (Glandular) (Stomach) – FIBROUS BONE –WHY?
- 25. CELL DEATH • APOPTOSIS vs. NECROSIS • What is DEATH? (What is LIFE?) –DEATH is IRREVERSIBLE
- 26. So the question is…. …NOT what is life or death, but what is REVERSIBLE or IRREVERSIBLE injury
- 27. REVERSIBLE CHANGES • REDUCED oxidative phosphorylation • ATP depletion • Cellular “SWELLING”
- 28. IRREVERSIBLE CHANGES • MITOCHONDRIAL IRREVERSIBILITY • IRREVERSIBLE MEMBRANE DEFECTS • LYSOSOMAL DIGESTION
- 29. REVERSIBLE = INJURY IRREVERSIBLE = DEATH SOME INJURIES CAN LEAD TO DEATH IF PROLONGED and/or SEVERE enough
- 30. INJURY CAUSES (REVERSIBLE) THE USUAL SUSPECTS But…WHO are the THREE WORST?
- 31. INJURY CAUSES (REVERSIBLE) Hypoxia, (decreased O2) PHYSICAL Agents CHEMICAL Agents INFECTIOUS Agents Immunologic Genetic Nutritional
- 32. INJURY MECHANISMS (REVERSIBLE) DECREASED ATP MITOCHONDRIAL DAMAGE INCREASED INTRACELLULAR CALCIUM INCREASED FREE RADICALS INCREASED CELL MEMBRANE PERMEABILITY
- 33. What is Death? What is Life? • DEATH is – IRREVERSIBLE MITOCHONDRIAL DYSFUNCTION – PROFOUND MEMBRANE DISTURBANCES • LIFE is……..???
- 34. CONTINUUM • REVERSIBLE • IRREVERSIBLE • DEATH • EM • LIGHT MICROSCOPY • GROSS APPEARANCES
- 37. NECROSIS BROTHERS: • Liquefactive (Brain) • Gangrenous (Extremities, Bowel, non-specific) – WET – DRY • • • • • Fibrinoid (Rheumatoid, non-specific) Caseous (cheese) (Tuberculosis) Fat (Breast, any fat) Ischemic (non-specific) Avascular (aseptic), radiation, organ specific, papillary • OneLook lists 153 terms preceding the word “necrosis”: http://www.onelook.com/? w=*necrosis&ls=a
- 39. MORE LIQUID MORE WATER MORE PROTONS
- 42. “WET” GANGRENE
- 43. “DRY” GANGRENE
- 44. EXAMPLES of Cell INJURY/NECROSIS • Ischemic (Hypoxic) • Ischemia/Reperfusion • Chemical
- 45. ISCHEMIC INJURY • REVERSIBLE IRREVERSIBLE • DEATH (INFARCT)
- 46. ISCHEMIA/REPERFUSION INJURY NEW Damage “Theory”
- 47. CHEMICAL INJURY • “Toxic” Chemicals, e.g CCl4 • Drugs, e.g tylenol • Dose Relationship • Free radicals, organelle, DNA damage
- 48. APOPTOSIS • NORMAL (preprogrammed) • PATHOLOGIC (associated with Necrosis)
- 49. “NORMAL” APOPTOSIS • Embryogenesis • Hormonal “Involution” • Cell population control, e.g., “crypts” • Post Inflammatory “Clean-up” • Elimination of “HARMFUL” cells • Cytotoxic T-Cells cleaning up
- 50. “PATHOLOGIC” APOPTOSIS • “Toxic” effect on cells, e.g., chemicals, pathogens • Duct obstruction • Tumor cells • Apoptosis/Necrosis spectrum
- 51. APOPTOSIS MORPHOLOGY • DE-crease in cell size, i.e., shrinkage • IN-crease in chromatin concentration, i.e., hyperchromasia, pyknosis karyorhexis karyolysis • IN-crease in membrane “blebs” • Phagocytosis
- 53. PHAGOCYTOSIS
- 54. APOPTOSIS BIOCHEMISTRY • Protein Digestion (Caspases) • DNA breakdown • Phagocytic Recognition
- 55. SUB-Cellular Responses to Injury (APOPTOSIS/NECROSIS) • Lysosomal Auto-Digestion • Smooth Endoplasmic Reticulum (SER) activation • Mitochondrial “SWELLING” • Cytoskeleton Breakdown – Thin Filaments (actin, myosin) – Microtubules – Intermediate Filaments (keratin, desmin, vimentin, neurofilaments, glial filaments)
- 56. INTRAcellular ACCUMULATIONS • Lipids – Neutral Fat – Cholesterol • “Hyaline” = any “proteinaceous” pink “glassy” substance • Glycogen • Pigments (EX-ogenous, END-ogenous) • Calcium
- 57. LIPID LAW • ALL Lipids are YELLOW grossly and WASHED out (CLEAR) microscopically
- 58. FATTY LIVER
- 59. FATTY LIVER
- 61. PIGMENTS EX-ogenous--- (tattoo, Anthracosis) END-ogenous--- they all look the same, (e.g., hemosiderin, melanin, lipofucsin, bile), in that they are all golden yellowish brown on “routine” Hematoxylin & Eosin (H&E) stains
- 63. ANTHRACOSIS
- 65. CALCIFICATION • DYSTROPHIC (LOCAL CAUSES) (often with FIBROSIS) • METASTATIC (SYSTEMIC CAUSES) –HYPERPARATHYROIDISM –“METASTATIC*” Disease *NOT to be confused with “metastatic” calcification
- 66. CELL AGING parallels ORGANISMAL AGING PROGRAMMED THEORY (80%) vs. WEAR AND TEAR THEORY (20%)
Editor's Notes
- General = Pathology I Systemic = Pathology II
- These are the four aspects about every disease you should keep in mind as a knee jerk reflex every time you hear the name of a disease.
- Often risk factors are divided into major and minor, as in atherosclerosis
- The second most profound thing ever said, in the 2nd millenium, after E=mc2, was by Rudolph Virchow. He said, “All diseases are the results of visible cell abnormalities”, i.e., abnormal histology, i.e., histopathology. For this, he earned the undisputed title of “father of pathology.”
- Know the definitions of all these terms, for the rest of your life, even if it is only from the dictionary. Most are cellular/tissue reactions to injury. PLASIA = GROWTH
- Hyperplasia is an increase of the size or weight of an organ or tissue due to increased NUMBERS of cells. Hypoplasia is the opposite.
- Hypertrophy is increase in the size (weight) of an organ or tissue due to increase of the size of the cells. Hypotrophy (more commonly called atrophy) is the opposite. There are many common violations to this concept.
- The precise differentiation between cell life and cell death is about as controversial as human life or human death.
- These are three indisputable reversible changes
- These are three indisputable IR-reversible changes. 1) If the mitochondria die, the cell dies 2) If the membrane can’t keep the sodium out, the cell dies 3) If the lysosomes start to autodigest the cell, the cell is dead
- The usual suspects are always suspected in carcinogenesis, teratogenesis, inflammations, or, really, any disease in general. So just as you always tend to think of diseases as inflammatory, neoplastic, degenerative, you should always think of causes as physical, chemical, and infectious.
- Death is easier to define than life. These two definitions of cell death are indisputable. The best definition of life is not death, in all honesty.
- The closer we look at something, the easier it is to tell if it is dead, alive, or dying.
- In light microscopy inability to recognize nuclei because they broke up (karyorhexis, karyolysis) is a common criterion of cell death.
- On routine gross or microscopic examination “necrosis” is used as synonymous with cell or tissue death. These are not really good terms but have been used as common adjectives over the ages. If you want to convince somebody you are a Nobel prize winning Prussian pathologist, you can pronounce the word as neg-ROW-zeese
- When the brain tissue dies it tends to soften, then liquefy, so there can be more water (i.e., protons) to cause increased MRI signals.
- T2 weighted MRI images emphasize water density but some anatomic resolution is lost.
- “Caseous” means “cheese-like” this is a GROSS observation, not a microscopic one. Cheese has less texture than meat, and is flaky. Many people from Wisconsin have been called caseous, i.e., cheeseheads.
- Fibrinoid necrosis looks like fibrin microscopically. In fact, often, it IS fibrin. Fibrinoid necrosis is most often applied to blood vessel walls.
- Wet gangrene may come BEFORE or AFTER dry gangrene. Why? Gangrene is also a type of necrosis, and the term “gangrenous necrosis” is common, most gangrenous necroses are due to lack of blood flow, or “ischemic” necrosis.
- Dry gangrene is deader, i.e., longer standing, than the death of wet gangrene.
- In reperfusion injury, damage occurs AFTER the oxygen, or blood, is restored! Chemical injury can be DIRECT, or INDIRECT, if the chemical is converted into a toxic metabolite.
- An infarct is defined as “dead tissue” due to lack of blood flow, and therefore lack of oxygen, nutrients, etc.
- The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane (Wikipedia definition). Reperfusion injury is of great concern in coronary bypass operations.
- As in pharmacology, EVERY chemical can be toxic, even pure water, so its always a question of dosage.
- Apoptosis come from the Greek word which means “falling off”.
- Cells which have shorter life spans are subject to apoptosis.
- There is often a grey area between apoptosis and necrosis, especially in the area of “pathologic”, rather than normal, apoptosis.
- Nuclei get smaller, “darker”, then fragment, then dissolve. What is the correct name for EACH of these 4 processes? The cellular changes in apoptosis may look exactly the cellular changes in necrosis.
- Shrinkage (pyknosis), increased nuclear staining (hyperchromasia), nuclear fragmentation (karyorrhexis, karryolysis), are classic features of apoptosis.
- The two main cell which clean up dead cell fragments are macrophages (also called “histiocytes”) and neutrophils.
- Caspases, or cysteine-aspartic proteases, are a family of cysteine proteases, which play essential roles in apoptosis (programmed cell death), necrosis and inflammation. http://en.wikipedia.org/wiki/Caspases
- The term “hyaline” is the most commonly confused concept in pathology. ANY eosinophilic staining, amorphic substance, can be correctly called hyaline, especially necrosis, amyloid, various proteinaceous secretions, fibrin are the most common.
- Name the three most common causes of fatty liver: Ans: diabetes, obesity, alcoholism (toxic)
- Sometimes the terms MICROvesicular versus MACROvesicular steatosis is used dependong whether the fat droplets are smaller or bigger than a cell. Sometime the term “fatty change” is also used.
- The slit-like spaces are cholesterol clefts, a classic feature of atherosclerosis.
- If you see a golden brown, slightly refractile pigment on routing light H&E microscopy, it is either hemosiderin, melanin, or bile derived. A few other degenerative pigments, such as lipofucsin, are also possible. Special stains can prove it is one or the other, if it is not abundantly clear from its cellular or pathologic setting and/or location
- This tiny amount of microscopic tattoo pigment can make white skin look quite black! Is this EXogenous or ENDogenous?
- Why does anthracosis look worse along the pleural surface than on cut sections? Why are MANY extrathoracic lymph nodes also anthracotic? What in the body is black and NOT due to EXOGENOUS pigments?
- Why would somebody order a prussian blue stain, or a S-100 immunoperoxidase stain or a HMB-45 stain?
- Calcium stains deep blue (very basophilic) and crunchy in all settings.
- Cellular death is analogous to human death. We don’t die because we exercise, we die because we run out of steam.