1. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Altered Cellular and Tissue Biology Chapter 3

2. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Adaptation  Physiologic vs. Pathogenic  Atrophy - decrease or shrinkage in cell & organ size Example – skeletal muscle deprived of innervation. Example – skeletal muscle deprived of innervation.  Hypertrophy - increase in the size of cells & organ Example – skeletal and cardiac muscle (due to increased workload). Example – skeletal and cardiac muscle (due to increased workload).  Hyperplasia - increase in number of cells Examples – liver if part is removed (enlarges to compensate), breasts due to hormonal signals during pregnancy. Examples – liver if part is removed (enlarges to compensate), breasts due to hormonal signals during pregnancy.

3. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Adaptation

4. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Adaptation  Dysplasia - abnormal changes in size, shape and organization of mature cells. Not a true adaptive change. Not a true adaptive change. Due to persistent severe irritation. Due to persistent severe irritation. Often reversible if stimulus is removed. Often reversible if stimulus is removed. Example – cervical dysplasia due to human papillomavirus. Example – cervical dysplasia due to human papillomavirus.

5. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Adaptation

6. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Adaptation  Metaplasia - reversible replacement of one mature cell type by another cell type (sometimes less differentiated). This can be reversible, or it can progress to dysplasia and neoplasia (cancer). This can be reversible, or it can progress to dysplasia and neoplasia (cancer). Example – in the bronchi pseudostratified ciliated columnar ep. → stratified squamous ep. Example – in the bronchi pseudostratified ciliated columnar ep. → stratified squamous ep.

7. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Activity Match each description with one of the processes above. Circle the letter of those that are pathologic. a) Excessive hormonal stimulation causes cells in the ducts of the breast to change their shape, size and arrangement. b) During childhood, the thymus decreases in size. c) During puberty, the male and female reproductive organs grow and develop into their mature forms.

8. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury  Reversible  Cells can recover if injurious stimuli ceases  Irreversible  Cells die due to injury

9. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury  Reversible  Irreversible

10. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Hypoxic injury – due to lack of sufficient oxygen  Ischemia - reduced blood supply; if gradual, then adaptation can occur. Example – a growing thrombus which gradually blocks a vessel. Example – a growing thrombus which gradually blocks a vessel.  Anoxia – total lack of oxygen. This is not well tolerated by most tissues. Example – an embolus which lodges in a vessel. Example – an embolus which lodges in a vessel.

11. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Cellular responses  Decrease in ATP, causing failure of sodium- potassium pump and sodium-calcium exchange – Na + and Ca ++ accumulate inside cells, K + outside cells  Cellular swelling – due to movement of Na + into cells. This is reversible if oxygen is restored.  Vacuolation – if O 2 is not restored, vacuoles accumulate in cytoplasm and organelles swell.

12. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury

13. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Damage is irreversible when there is:  Lack of ATP production due to mitochondrial damage  Major disturbances and damage in membrane function  Reperfusion injury due to oxidative stress  When O 2 is restored, reactive oxygen intermediates damage organelles.  Can be prevented using antioxidants.

14. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury

15. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Free radicals and reactive oxygen species  Electrically uncharged atom or group of atoms having an unpaired electron that cause damage by: Lipid peroxidation – damages membranes of cell and organelles, increases permeability. Lipid peroxidation – damages membranes of cell and organelles, increases permeability. Alteration of proteins – especially those for ion pumps and transport proteins. Alteration of proteins – especially those for ion pumps and transport proteins. Alteration of DNA – fragmenting of DNA reduces protein synthesis. Alteration of DNA – fragmenting of DNA reduces protein synthesis. Mitochondrial damage – allows liberation of calcium into cytosol. Mitochondrial damage – allows liberation of calcium into cytosol.

16. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Reactive Oxygen Species

17. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Chemical injury  Carbon tetrachloride (CCl 4 ) Liver converts this to a toxic free radical Liver converts this to a toxic free radical Causes lipid peroxidation → damage to membranes, release of lysozyme, and mitochondrial damage Causes lipid peroxidation → damage to membranes, release of lysozyme, and mitochondrial damage These result in fatty liver, cellular autodigestion, and decreased ATP production. These result in fatty liver, cellular autodigestion, and decreased ATP production.

18. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Chemical Injury by CCl 4

19. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Chemical injury  Lead – causes: Neurological problems (interferes with neurotransmitter release) Neurological problems (interferes with neurotransmitter release) Anemia Anemia Renal problems Renal problems

20. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Chemical injury  Carbon monoxide Prevents oxygen from binding to hemoglobin → hypoxic injury Prevents oxygen from binding to hemoglobin → hypoxic injury Cherry red coloring of skin. Cherry red coloring of skin.

21. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Chemical injury  Ethanol Ethanol → acetaldehyde and free radicals in liver Ethanol → acetaldehyde and free radicals in liver Causes inflammation, fatty liver, membrane damage Causes inflammation, fatty liver, membrane damage Depresses CNS by acting on reticular formation which normally inhibits unacceptable behaviors. Depresses CNS by acting on reticular formation which normally inhibits unacceptable behaviors.

22. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Metabolism of Ethanol

23. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Injury Mechanisms  Chemical injury  Mercury Causes birth defects and brain damage in fetuses and small children. Causes birth defects and brain damage in fetuses and small children.

24. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Activity Indicate whether each of these is primarily associated with a lack of oxygen (–) or with free radicals and oxidative stress (+). a) CO poisoning b) Damage by CCl 4 c) Cellular swelling d) Damage to DNA e) Formation of vacuoles f) Decreased ATP production

25. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Unintentional and Intentional Injuries  Review this information in the lecture notes and textbook.

26. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Infectious Injury  Pathogenicity of a microorganism  Disease-producing potential depends on organisms ability for:  Invasion and destruction  Toxin production  Production of hypersensitivity reactions

27. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Immunologic and Inflammatory Injury  Phagocytic cells  Immune and inflammatory substances  Histamine, antibodies, lymphokines, complement, and proteases  Membrane alterations  Cause leakage of K + out of cell and influx of Na + and water.  Antibodies can block membrane receptors and intercellular communication.

28. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Manifestations of Cellular Injury  Cellular accumulations (infiltrations)  Pathologic accumulations can occur due to: 1) excess production of normal substance, 2) the substance not being broken down due to lack of an enzyme, or 3) accumulation of harmful exogenous substances.

29. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Manifestations of Cellular Injury  Cellular accumulations (infiltrations)  Water – enters cells due to lack of ATP and failure of Na + /K + pump, causing cellular swelling. Oncosis (hydropic degeneration) – water accumulates in endoplasmic reticulum forming vacuoles separate from cytoplasm (vacuolation); organs appear pale. Oncosis (hydropic degeneration) – water accumulates in endoplasmic reticulum forming vacuoles separate from cytoplasm (vacuolation); organs appear pale.

30. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Oncosis (oncosis)

31. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Manifestations of Cellular Injury  Cellular accumulations (cont.)  Lipids and carbohydrates – accumulate (usually in spleen, liver and CNS) due to metabolic disorders like Tay-Sachs and Niemann-Pick disease. Fatty change - can be caused by disruptions of normal lipid metabolism; liver appears yellow. Fatty change - can be caused by disruptions of normal lipid metabolism; liver appears yellow.

32. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Manifestations of Cellular Injury  Cellular accumulations (cont.)  Glycogen – occurs in disorders of glucose and glycogen metabolism, including diabetes mellitus.  Proteins – accumulate during pathological change in renal tubules, and B cells (antibodies)

33. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Manifestations of Cellular Injury  Cellular accumulations (cont.)  Pigments – accumulation may be normal or signal pathological changes (melanoma, jaundice) Melanin (suntan, melanomas) Hemoproteins, hemosiderin and bilirubin (from RBC breakdown)

34. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Manifestations of Cellular Injury

35. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Manifestations of Cellular Injury  Cellular accumulations (cont.)  Calcium – occurs in hypoxic cells due to entry of extracellular Ca 2+ into mitochondria  Urate – due to increased levels of uric acid from purine catabolism; causes gout.

36. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Calcium Infiltration

37. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Death  Necrosis – cellular dissolution  Sum of cellular changes after local cell death and the process of cellular autodigestion

38. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Death  Processes  Karyolysis Nuclear dissolution and chromatin lysis Nuclear dissolution and chromatin lysis  Pyknosis Clumping of the nucleus Clumping of the nucleus  Karyorrhexis Fragmentation of the nucleus Fragmentation of the nucleus

39. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cellular Death

40. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Coagulative Necrosis  Coagulative necrosis  Kidneys, heart, and adrenal glands  Protein denaturation - results from hypoxia caused by chemical injury (mercuric chloride intake)

41. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Coagulative Necrosis

42. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Liquefactive Necrosis  Liquefactive necrosis  Neurons and glial cells of the brain  Hydrolytic enzymes – from lysozyme in dying cells  Bacterial infection Staphylococci, streptococci, and Escherichia coli Staphylococci, streptococci, and Escherichia coli

43. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Liquefactive Necrosis

44. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Liquefactive Necrosis http://library.med.utah.edu/WebPath/CINJHTML/CINJ025.html

45. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Caseous Necrosis  Caseous necrosis - “cheese-like”  Tuberculous pulmonary infection  Combination of coagulative and liquefactive necrosis  Cells disintegrate but are not completely digested

46. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Caseous Necrosis

47. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Caseous Necrosis

48. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Fat Necrosis  Fat necrosis  Breast, pancreas, and other abdominal organs (that have lipase enzyme)  Action of lipases - releases free fatty acids that react with Ca 2+, Mg 2+ and Na + → soaps

49. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Fat Necrosis

50. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Gangrenous Necrosis  Gangrenous necrosis  Death of tissue from severe hypoxic injury – often due to atherosclerosis or trauma Dry gangrene → coagulative Dry gangrene → coagulative Wet gangrene → liquefactive necrosis (internal organs) Wet gangrene → liquefactive necrosis (internal organs)  Gas gangrene –bacteria produce hydrolytic enzymes and create gas bubbles in muscles Clostridium – anaerobic bacteria responsible Clostridium – anaerobic bacteria responsible

51. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Gangrenous Necrosis

52. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Activity Which type of necrosis would most likely occur in each of the following situations? a) Damage to a tissue rich in hydrolytic enzymes. b) Damage to a tissue rich in lipid digesting enzymes. c) Tissue destruction by a chemical that denatures protein.

53. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Apoptosis  Apoptosis – death of unnecessary cells due to enzymes produced within cell; genetically programmed  Programmed cellular death – prevents overgrowth of cells; also occurs during fetal development  Physiologic (normal) vs. pathologic – due to enzyme deficiencies, viruses, free radicals, etc.

54. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Apoptosis vs. Necrosis

55. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Apoptosis  Normal, genetically programmed cell death.  Usually involves individual, scattered cells.  Cellular enzymes cleave key cellular proteins; cells shrink and fragment.  Cellular debris remains bound in a membrane forming apoptotic bodies which are removed by neutrophils and macrophages.  This process does not stimulate the inflammatory response.

56. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Necrosis  Due to damage from exogenous injury.  Usually involves many cells in area of injury.  Cell membranes rupture, releasing cell contents into tissue.  Triggers inflammatory response.

57. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Aging and Altered Cellular and Tissue Biology  Aging – time-dependent loss of structure and function that proceeds slowly due to accumulated small injuries. Q: At what point does this become disease? There is some overlap.  Disease – abnormal dysfunction due to injury.

58. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Aging and Altered Cellular and Tissue Biology  Normal life span- across cultures the maximal life span is 80-100 years.  Gender differences – females have a life expectancy about 5 years greater than males.

59. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Theories and Mechanisms of Aging 1. Genetic and Environmental-Lifestyle Factors  Includes three basic mechanisms:  Programmed aging – cells have a finite lifespan with a finite number of possible divisions, after which the DNA loses the capacity for mitosis.  Somatic mutation hypothesis  Catastrophic or error-prone theory

60. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Theories and Mechanisms of Aging  Somatic mutation hypothesis – repetitive injury to the DNA causes progressive mutations that interfere with the ability of the cell to repair itself and maintain DNA and protein synthesis.  Catastrophic or error-prone theory – the enzymes responsible for transcription and translation become increasingly abnormal, leading to increasing errors in protein synthesis.

61. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Theories and Mechanisms of Aging 2. Alterations of cellular control mechanisms  Neuroendocrine theory – the genetic program for aging is encoded in the brain and is controlled and relayed to peripheral tissues through hormonal and neural signals.  Immune theory - with aging, there is decreased immunity to invaders and cancer and increased autoimmunity (immune system attacks self).

62. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Theories and Mechanisms of Aging 3. Degenerative extracellular and vascular changes  Binding of collagen – crosslinking, decreased synthesis and increased breakdown of collagen  Free radical effects (oxidative stress) – damage to DNA → malignancies and cell death  Alterations in peripheral blood vessels – decreased vessel integrity and atherosclerosis

63. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Aging  Cellular aging – characterized by:  Atrophy, decreased function, and loss of cells  Tissue and systemic aging - every physiologic process declines in efficiency with age.  Progressive stiffness and rigidity – arterial, pulmonary, and musculoskeletal systems.  Sarcopenia – loss of muscle mass and strength.

64. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Aging  Frailty  Decreased mobility, balance, muscle strength, motor activity, cognition, nutrition, endurance and bone density result in increased falls and fractures.  Accompanied by declining hormone levels and increased levels of proinflammatory cytokines

65. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Activity  What are some lifestyle changes that might slow down the effects of aging? Why might these be beneficial?

66. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Somatic Death  Death of an entire person  Postmortem changes – after death, diffuse changes that do not involve the inflammatory response.  Algor mortis – postmortem reduction of body temperature. Body temp drops by 1- 1.5 °F per hour.

67. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Somatic Death  Livor mortis – purplish discoloration of tissues due to accumulating blood drawn down by gravity.  Rigor mortis – stiffening of muscles due to depletion of ATP; begins after 6 hours and continues until about 36 hours after death.  Postmortem autolysis – digestion of body tissues due to release of lysozymal enzymes causing liquefactive changes and putrification.

68. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Activity A coroner examines a body at the scene of a murder and takes note of the following: the core body temperature is 95 °F, the surface resting on the ground is purplish, and there is no abnormal stiffening of the muscles. Roughly how long ago did death occur?