Cellular Responses to Stress and Toxic Insults

1. Cellular Responses to Stress and Toxic Insults Lisa Stevens, D.O.

2. Introduction • Pathology • Study (logos) of disease (pathos) • Structural, biochemical, and functional changes • Cells, tissues, and organs that underlie disease

3. Introduction • Four aspects of a disease process • Cause (etiology) • Mechanisms of its development (pathogenesis) • Biochemical and structural alterations (molecular and morphologic changes) • Functional consequences of these changes (clinical manifestations)

4. Etiology • Two major classes • Genetic • Inherited mutations • Disease-associated gene variants • Acquired • Infectious • Nutritional • Chemical • Physical

5. Pathogenesis • Sequence of events in the response of cells or tissues to the etiologic agent • From the initial stimulus to the ultimate expression of the disease • One of the main domains of pathology

6. Molecular and Morphologic Changes • Structural alterations in cells or tissues • Characteristic of a disease • Diagnostic of an etiologic process

7. Functional Derangements and Clinical Manifestations • Functional abnormalities • End results of genetic, biochemical, and structural changes in cells and tissues • Lead to the clinical manifestations (symptoms and signs) Lead to the progression of disease (clinical course and outcome)

8. Functional Derangements and Clinical Manifestations • Disease • Starts with molecular or structural alterations in cells • Concept first put forth by Rudolf Virchow (19th century) • Father of modern pathology • Injury to cells and to extracellular matrix • Tissue and organ injury • Determine the morphologic and clinical patterns of disease

9. Cellular Responses to Stress and Noxious Stimuli • Normal cell • Confined to a narrow range of function and structure • State of metabolism, differentiation, and specialization • Constraints of neighboring cells • Availability of metabolic substrates • Maintains homeostasis (steady state)

11. Cellular Responses to Stress and Noxious Stimuli • Adaptations • Reversible functional and structural responses • Usually due to physiologic stresses and pathologic stimuli • Hypertrophy (increase in the size of cells) • Hyperplasia (increase in the number of cells) • Atrophy (decrease in the size and metabolic activity of cells) • Metaplasia (change in the phenotype of cells)

12. Cellular Responses to Stress and Noxious Stimuli • Cell injury • Exposure to injurious agents or stress • Deprivation of essential nutrients • Compromised by mutations that affect essential cellular constituents • Reversible • Up to a certain point • Irreversible injury and cell death • Stimulus persists

13. Cellular Responses to Stress and Noxious Stimuli • Cell death • End result of progressive cell injury • One of the most crucial events in the evolution of disease • Results from diverse causes • Ischemia (reduced blood flow) • Infection • Toxins

14. Cellular Responses to Stress and Noxious Stimuli • Cell death • Normal and essential process • Embryogenesis • Maintenance of homeostasis • Two principal pathways of cell death • Necrosis and apoptosis

16. Adaptations of Cellular Growth and Differentiation • Hypertrophy • Increase in the size of cells • Results in an increase in the size of the organ • No new cells, just larger cells • Due to synthesis of structural components of the cells • Cellular proteins

17. Adaptations of Cellular Growth and Differentiation • Hypertrophy • Physiologic or pathologic • Cause • Increased functional demand • Stimulation by hormones and growth factors

18. Adaptations of Cellular Growth and Differentiation • Hypertrophy • Example: Striated muscle cells (heart and skeletal muscle) • Limited capacity for division • Respond to increased metabolic demands • Hypertrophy • Most common stimulus • Increased workload • Example: Bodybuilders "pumping iron" • Increase in size of the individual muscle fibers

19. Hypertrophy • Mechanisms • Induced by linked actions • Mechanical sensors • Growth factors • Vasoactive agents • Two main biochemical pathways • Phosphoinositide 3-kinase/Akt pathway • Signaling downstream of G protein-coupled receptors

20. Hypertrophy • Usually refers to increase in size of cells or tissues • HOWEVER, a subcellular organelle may undergo selective hypertrophy • Example: Individuals treated with drugs (barbiturates) • Hypertrophy of the smooth endoplamic reticulum (SER) in hepatocytes • Adaptive response • Increases the amount of enzymes (cytochrome P-450 mixed function oxidases) available to detoxify the drugs • Eventually, patients respond less to the drug • May result in an increased capacity to metabolize other drugs

21. Hyperplasia • Increase in the number of cells in an organ or tissue • Results in increased mass of the organ or tissue • May occur in the setting of hypertrophy • Physiologic and pathologic

22. Hyperplasia • Increase in the number of cells in an organ or tissue • Physiologic hyperplasia • Hormonal hyperplasia • Increases the functional capacity of a tissue when needed • Compensatory hyperplasia • Increases tissue mass after damage or partial resection

23. Hyperplasia • Physiologic hyperplasia • Hormonal hyperplasia • Proliferation of the glandular epithelium of the female breast • Puberty • Pregnancy • Compensatory hyperplasia • Myth of Prometheus • Ancient Greeks recognized the capacity of the liver to regenerate • Liver transplantation (donor)

25. Hyperplasia • Pathologic Hyperplasia • Caused by excesses of hormones or growth factors acting on target cells • Endometrial hyperplasia • Abnormal hormone-induced hyperplasia • Common cause of abnormal menstrual bleeding

26. Hyperplasia • Pathologic Hyperplasia • Benign prostatic hyperplasia • Induced by responses to androgens • Constitutes a fertile soil in which cancerous proliferation may eventually arise

27. Atrophy • Reduced size of an organ or tissue • Results from a decrease in cell size and number • Physiologic atrophy • Common during normal development • Embryonic structures • Notochord • Thyroglossal duct • Uterus • Decreased size shortly after parturition

28. Atrophy • Pathologic atrophy • Depends on the underlying cause • Local or generalized • Common causes of atrophy • Decreased workload (atrophy of disuse) • Muscle atrophy secondary to immobilization/bedrest • Loss of innervation (denervation atrophy) • Diminished blood supply

29. Atrophy • Common causes of atrophy • Inadequate nutrition • Profound protein-calorie malnutrition (marasmus) • Use of skeletal muscle as a source of energy after other reserves (adipose stores) have been depleted • Loss of endocrine stimulation • Hormone-responsive tissues (breast and reproductive organs) • Pressure • Tissue compression for any length of time

30. Atrophy • Mechanisms • Results from decreased protein synthesis • Reduced metabolic activity • Results from increased protein degradation in cells • Ubiquitin-proteasome pathway • Responsible for the accelerated proteolysis • Catabolic conditions (cancer cachexia)

31. Atrophy • Accompanied by increased autophagy • Increases in the number of autophagic vacuoles • Autophagy ("self eating") • Process in which the starved cell eats its own components to survive

32. Atrophy • Autophagic vacuoles • Membrane-bound vacuoles that contain fragments of cell components • Vacuoles ultimately fuse with lysosomes • Contents are digested by lysosomal enzymes • Some cell debris (in the autophagic vacuoles) resist digestion • Persist as membrane-bound residual bodies • Lipofuscin granules (brown atrophy)

34. Metaplasia • Reversible change • One differentiated cell type replaced by another cell type • Adaptive substitution of cells (sensitive to stress) • Cell types better able to withstand adverse environments

35. Metaplasia • Most common epithelial metaplasia • Columnar to squamous • Occurs in the respiratory tract • Chronic irritation • Cigarette smoker • Normal PCCE replaced by stratified squamous epithelial cells • Lack of mucociliary elevator • If persistent, may initiate malignant transformation in metaplastic epithelium

36. Metaplasia • Metaplasia from squamous to columnar type • Barrett esophagus • Esophageal squamous epithelium is replaced by intestinal-like columnar cells • Influence of refluxed gastric acid • Connective tissue metaplasia • Formation of cartilage, bone, or adipose tissue (mesenchymal tissues) in tissues that do not contain these elements • Bone formation in muscle (myositisossificans) • Can occur following an intramuscular hemorrhage

37. Metaplasia • Mechanisms • Does not result from a change in the phenotype of an already differentiated cell type • Result of reprogramming • Stem cells (known to exist in normal tissues) • Undifferentiated mesenchymal cells present in connective tissue • Precursor cells differentiate along a new pathway

39. Practice Question • A 43-year-old man has complained of mild burning substernal pain following meals for the past 3 years. Upper GI endoscopy is performed and biopsies are taken of an erythematous area of the lower esophageal mucosa 3 cm above the gastroesophageal junction. There is no mass lesion, no ulceration, and no hemorrhage noted. The biopsies show the presence of columnar epithelium with goblet cells. Which of the following mucosal alterations is most likely represented by these findings? • A. Dysplasia • B. Metaplasia • C. Hypertrophy • D. Hyperplasia • E. Ischemia

40. Practice Question • A 19-year-old woman gives birth to her first child. She begins breast feeding the infant. She continues breast feeding for almost a year with no difficulties and no complications. Which of the following cellular processes that began in the breast during pregnancy allowed her to nurse the infant for this period of time? • A. Lobular hyperplasia • B. Stromal hypertrophy • C. Epithelial dysplasia • D. Steatocyte atrophy • E. Ductal epithelial metaplasia

41. Practice Question • A study is performed involving the microscopic analysis of tissues obtained from surgical procedures. Some of these tissues have the microscopic appearance of an increased cell size of multiple cells within the tissue, due to an increase in the amount of cytoplasm, with nuclei remaining uniform in size. Which of the following conditions is most likely to have resulted in this finding? • A. Uterine myometrium in pregnancy • B. Female breast at puberty • C. Liver following partial resection • D. Ovary following menopause • E. Cervix with chronic inflammation

42. Practice Question • A 38-year-old man incurs a traumatic blow to his upper left arm. He continues to have pain and tenderness even after 3 months have passed. A plain film radiograph reveals a 4 cm circumscribed mass in the soft tissue adjacent to the humerus. The mass contains areas of brightness on the x-ray. Over the next year this process gradually resolves. Which of the following terms best describes this process? • A. Dysplasia • B. Hyperplasia • C. Hypertrophy • D. Metaplasia • E. Neoplasia

43. Practice Question • A 21-year-old woman has a routine Pap smear performed for a health screening examination. The pathology report indicates that some cells are found cytologically to have larger, more irregular nuclei. A follow-up cervical biopsy microscopically demonstrates disordered maturation of the squamous epithelium, with hyperchromatic and pleomorphic nuclei extending nearly the full thickness of the epithelial surface. No inflammatory cells are present. Which of the following descriptive terms is best applied to these Pap smear and biopsy findings? • A. Dysplasia • B. Metaplasia • C. Anaplasia • D. Hyperplasia • E. Aplasia

44. Practice Question • A 3-year-old child has been diagnosed with ornithinetranscarbamylase deficiency and has developed hepatic failure. The left lobe of an adult donor liver is used as an orthotopic transplant. A year later, the size of each liver in donor and recipient is greater than at the time of transplantation. Which of the following cellular alterations is most likely to explain this phenomenon? • A. Metaplasia • B. Dysplasia • C. Hyperplasia • D. Anaplasia • E. Neoplasia

45. Cellular adaptationsLecture #2 Lisa Stevens, D.O.

46. Causes of Cell Injury Oxygen deprivation Physical agents Chemical agents and drugs Infectious agents Immunologic reactions Genetic derangements Nutritional imbalances

47. Injurious Stimuli • Oxygen Deprivation • Hypoxia • Deficiency of oxygen • Reduces aerobic oxidative respiration • Causes • Reduced blood flow (ischemia) • Inadequate oxygenation of the blood • Cardiorespiratory failure

48. Injurious Stimuli • Oxygen Deprivation • Hypoxia • Causes, continued • Decreased oxygen-carrying capacity of the blood • Anemia • Carbon monoxide poisoning • Severe blood loss • Depending on the severity • Cells may adapt, undergo injury, or die

49. Injurious Stimuli • Physical Agents • Mechanical trauma • Extremes of temperature (burns and deep cold) • Sudden changes in atmospheric pressure • Radiation • Electric shock

50. Injurious Stimuli • Chemical Agents and Drugs • Chemicals (too many to list) • Glucose or salt in hypertonic concentrations • Oxygen at high concentrations • Trace amounts of poisons • Environmental and air pollutants • Insecticides, herbicides • Industrial and occupational hazards • Recreational drugs (alcohol) • Therapeutic drugs