LECTURE II. Cell Injury &causes (1).pptx

Cell injusry and causes

1. CELL INJURY: BASIC PRINCIPLES IN THE STUDY OF DISEASES BY DR. M. A. SEIDU 6/1/2024 DR. M. A. SEIDU (PhD) 1

2. CELL INJURY I 1. CELLULAR BASIS OF DISEASE 2. HOMEOSTASIS AND STEADY STATE 3. CAUSES OF CELL INJURY 6/1/2024 2 M. A. SEIDU (PhD)

3. LECTURE OBJECTIVES At the end of this lecture a student should: Know and explain the concept Cellular basis of diseases Know and explain the concept of homeostasis . Know and explain the concept of steady state Know and explain cell injury or disease Know and explain the role of various factors that can cause cell injury (disease) 6/1/2024 DR. M. A. SEIDU (PhD) 3

4. 6/1/2024 DR. M. A. SEIDU (PhD) 4 CELLULAR BASIS OF DISEASE

5. CELLULAR BASIS OF DISEASE “All diseases are reducible to disturbances, either active or passive , of large groups of living units ( cells ) whose functional capacity is altered in accordance with the state of their molecular composition and is thus dependent on physical and chemical changes of their contents" Rudolph Virchow (1855) This statement means that all diseases are reducible to changes at the cellular level 6/1/2024 5 DR. M. A. SEIDU (PhD)

6. The  human  consists of eleven organ  systems Integumentary  System , Skeletal  System , Muscular  System , Lymphatic Respiratory Digestive Nervous  System , Endocrine  Cardiovascular Urinary Reproductive 6/1/2024 DR. M. A. SEIDU (PhD) 6

7. 6/1/2024 M. A. SEIDU (PhD) 7 Integumentary System Skeletal System Muscular System

8. 6/1/2024 M. A. SEIDU (PhD) 8 Lymphatic System Respiratory System Digestive System

9. 6/1/2024 M. A. SEIDU (PhD) 9 Nervous System Endocrine System Cardiovascular System

10. 6/1/2024 DR. M. A. SEIDU (PhD) 10 Urinary System Female Reproductive System Male Reproductive System

11. 6/1/2024 M. A. SEIDU (PhD) 11 MACROMOLECULE MOLECULE ATOM ORGANELLE CELL TISSUE ORGAN SYSTEM ORGANISM

12. FUNCTIONAL SYSTEMS ORGANS TISSUES CELLS Cell as the unit of life 6/1/2024 12 M. A. SEIDU (PhD)

13. 6/1/2024 DR. M. A. SEIDU (PhD) 13 HOMEOSTASIS

14. HOMEOSTASIS 1/3 Cells By their differentiation, cells are restricted to a narrow range of function and structure. They are affected by the activity of neighbouring cells. 6/1/2024 14 DR. M. A. SEIDU (PhD)

15. HOMEOSTASIS 2/3 Cells Cells exist in an environment that requires continuous work against chemical gradients requiring energy expenditure to ensure that their internal environment is maintained. They constantly degrade and replace intracellular molecules, which have reached the end of their "shelf lives” 6/1/2024 15 DR. M. A. SEIDU (PhD)

16. HOMEOSTASIS 3/3 The tendency of cells to maintain relatively constant conditions in the internal environment of the cells despite changes around the cells is called HOMEOSTASIS . 6/1/2024 DR. M. A. SEIDU (PhD) 16

17. GOOD HEALTH - Good health depends on the ability of cells to adjust to changes in the conditions around them and at the same time maintain normal function and structure 6/1/2024 17 DR. M. A. SEIDU (PhD)

18. 6/1/2024 DR. M. A. SEIDU (PhD) 18 STEADY STATE

19. STEADY STATE The narrow range of physiologic stimulation around the cells which the cells respond to in order to maintain HOMEOSTASIS is described as the: STEADY STATE 6/1/2024 19 DR. M. A. SEIDU (PhD)

20. EFFECT OF ALTERATIONS IN STEADY STATE The steady state may alter in response to stimuli that are greater in intensity (extent or duration) than those normally experienced by the cell. This can result in cell injury or ill health 6/1/2024 20 DR. M. A. SEIDU (PhD)

21. CELL INJURY Cell injury or disease occurs when cells fail to maintain homeostasis in the face of stimuli that alter the steady state. 6/1/2024 21 DR. M. A. SEIDU (PhD)

22. DISEASE Poor response of cells to abnormal stimuli that increases or decreases conditions around the cell in relation to steady state results in ill health or disease 6/1/2024 22 DR. M. A. SEIDU (PhD)

23. ALTERATION IN STEADY STATE The effects of alteration in steady state may be reflected by: Molecular or genetic, Biochemical, Physiologic or Structural changes In various combinations 6/1/2024 DR. M. A. SEIDU (PhD) 23

24. Factors influence cell response to abnormal stimuli The primary factors depends on the nature of stimulus the intensity of the stimulus. the duration of the stimulus . 6/1/2024 24 DR. M. A. SEIDU (PhD)

25. The nature of stimulus Extra and intracellular environment: High and low concentration of metabolites. (e.g. Cardiac muscles and intra or extra-cellular glucose) Pattern and level of metabolic activity : Cells that are metabolically more active readily succumb to hypoxic injury. Cerebral neuron + myocardial cell vrs fibroblast 6/1/2024 25 DR. M. A. SEIDU (PhD)

26. The nature of stimulus Level of cell differentiation : Relatively undifferentiated nerve cells of the developing infant brain are more resistant to hypoxic injury than the fully differentiated neurones in the adult. This is due to the level of their dependence on oxidative metabolism. 6/1/2024 26 DR. M. A. SEIDU (PhD)

27. The nature of stimulus Genomic expression: This determines the adaptability of cells: The availability or non-availability of some cellular proteins influences how and to what extent a cell will respond to noxious stimuli (see examples) 6/1/2024 27 DR. M. A. SEIDU (PhD)

28. Examples of genomic expressions that affect response to stimuli Lack of DNA repair enzymes - inability to repair sun-damaged DNA of squamous epithelial cells resulting in a high incidence of skin cancer in affected individuals. Xeroderma pigmentosa 2. G-6-PD deficiency - inability to protect against oxidant injury following exposure to certain chemicals. 3. Sickle cell disease - structurally abnormal haemoglobins cause sickling and haemolysis of red cells under low oxygen tension 6/1/2024 28 DR. M. A. SEIDU (PhD)

29. 6/1/2024 DR. M. A. SEIDU (PhD) 29 CAUSES OF CELL INJURY (DISEASE)

30. MAJOR CAUSES OF CELL INJURY (DISEASES) Hypoxia /anoxia. Chemicals and drugs Physical agents Microbiological agents Immunologic reasons Genetic defects Nutritional imbalance Aging 6/1/2024 30 DR. M. A. SEIDU (PhD)

31. Hypoxia or anoxia Reduced or total absence of oxygen leads to low energy output. Due to: Inoperative oxidative phosphorylation/Electron transport chain The electron transport chain in the cell is the site of oxidative phosphorylation . The NADH, FADH etc generated in the citric acid cycle are oxidized, releasing energy to power the ATP synthase . 6/1/2024 31 DR. M. A. SEIDU (PhD)

32. 6/1/2024 DR. M. A. SEIDU (PhD) 32

33. The electron transport chain 6/1/2024 DR. M. A. SEIDU (PhD) 33 ATP ATP ATP

34. Causes of Hypoxia or anoxia Reduced or total absence of oxygen (leads to low energy output) This can occur in 3 ways: i . Loss of blood supply due to impeded arterial flow caused by vascular Disease or thrombi (ischemia) ii. Cardio-respiratory failure. No oxygen, no nutrient circulation iii. Loss of oxygen carrying capacity due to anemia or carbon monoxide poisoning (stable carbon mono- oxyhaemoglobin that blocks oxygen transport) 6/1/2024 DR. M. A. SEIDU (PhD)

35. Chemicals and drugs: Many chemicals are capable of causing cell injury. Some can cause death to cells in minutes even in small amounts. killing the whole organism – poisons ”. Examples: Cyanide: Prevent oxygen utilization (affects cytochrome oxidase) Fluoroacetate: Blockage of Krebs's cycle (aconitase) 6/1/2024 35 DR. M. A. SEIDU (PhD)

36. 6/1/2024 DR. M. A. SEIDU (PhD) 36 CYANIDE BLOCKS CYTOCHROME OXIDASE ACTIVITY

37. The electron transport chain AND THE ROLE OF CYTOCHROMES 6/1/2024 DR. M. A. SEIDU (PhD) 37

38. Chemicals and drugs: Examples: Mercuric chloride: binds to sulphydryl groups of the cell membrane and other proteins to prevent utilization of some proteins . Racin : Blockage of protein synthesis at the ribosomal level (inhibit IF3) 6/1/2024 38 DR. M. A. SEIDU (PhD)

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40. 6/1/2024 DR. M. A. SEIDU (PhD) 40 RICIN PREVENTS PROTEIN SYNTHESIS

41. Physical agents (temperatures) Extremes of heat or cold, Cell injury can result if tissue is maintained at temp. level: Greater than 5 o C above normal temp. (hyperthermia) Or 15 o C below (hypothermia) normal body temperature. 6/1/2024 41 DR. M. A. SEIDU (PhD)

42. Physical agents (temperatures). Extremes of heat or cold, In Hyperthermia Proteins may coagulate. In hypothermia, cellular activities may seize Thermal burns – First degree - erythema without significant alteration to the epidermis); Second degree - destruction of epidermis, minor damage to dermis); Third degree- damage to both epidermis and dermis 6/1/2024 42 DR. M. A. SEIDU (PhD)

43. Physical agents (mechanical) Mechanical causes Friction: Abrasions (tearing of epidermal cells) Blunt force: contusions/bruises : (impact is transmitted through the skin resulting in disruption of blood vessels and bleeding) Unplanned cuts : lacerations (excessive stretching resulting in tearing of tissue) Planned cuts: I ncisions (pressure and friction produced by sharp instruments) Pointed objects : S tab 6/1/2024 43 DR. M. A. SEIDU (PhD)

44. Physical agents (light) Photopathy - Pathologic effect caused by light. Examples. Photalgia - P ain in eye caused by light. Photonosus - Any disease due to excess light. Photo- ophthalmia – severe inflammation of the eye caused by intense light. Ophthalmia nivialis - Snow blindness resulting from intense light reflected from snow 6/1/2024 44 DR. M. A. SEIDU (PhD)

45. Physical agents (Pressure) High pressure may cause injury. Example: Injury to the cartilaginous walls of the eustachian tube and ear-drum in aviators, due to difference between atmospheric and intra-tympanic pressures 6/1/2024 45 DR. M. A. SEIDU (PhD)

46. Physical agents (Sound & Radiation) Sound - may damage hearing causing hearing impairment due to injury to eustachian tube and ear-drum. Radiation - x-rays, gamma rays, alpha and beta particles, ultra-violet rays, Microwaves etc. Result in damage to DNA and mutations, burns, free radical injury. 6/1/2024 46 DR. M. A. SEIDU (PhD)

47. Microbiological agents: Bacteria – produce toxins ( exo - and endo ) and other virulence factors Viruses, Clamydiae , Rickettsiae - direct cell lysis , giant cell formation, inclusions, DNA alteration. Yeasts and fungi - chronic inflammation with fibrosis, hypersensitivity reactions. Parasites - cell lysis, tissue destruction by enzymes, competition for nutrients obstructions etc 6/1/2024 47 DR. M. A. SEIDU (PhD)

48. Immunologic reasons Hypersensitivity reactions - complement, T lymphocytes, Macrophages, chemical mediators of inflammation Autoimmune diseases – reactions of the immune system to self antigens Immunodeficiency – inherited and acquired 6/1/2024 48 DR. M. A. SEIDU (PhD)

49. Genetic defects: Additional chromosomes ( trisomies ) eg . 21 (down’s syndrome ): delayed speech, intel. dis’ty 18 ( Edward syndrome) :slow growth, dev’tal delay 13 ( Patau syndrome ): etra fingers, deformed feet Substitution & deletions of nucleotides. Eg substitution valine for glutamic acid at the 6 th position of the Beta chain of Hb leads to sickle cell disease Most neoplastic changes are associated with genetic alteration Variations in genotype can influence the susceptibility of cells to injury by environmental agents 6/1/2024 49 DR. M. A. SEIDU (PhD)

50. Nutritional imbalance: Deficiency or Excess of Metabolites: Deficiency of vitamins, glucose or amino acid can lead to cell injury. Excess of certain vitamins, glucose, fatty food etc. will cause cell injury 6/1/2024 50 DR. M. A. SEIDU (PhD)

51. Aging: Long time exposure to radioactivity leads to DNA damage. Progressive accumulation of random damage and repair in complex organisms leads to structural and functional abnormalities Waste: bone and nerve cells -progeria (premature accelerated ageing) Generation of free radicals gradually wears down tissues 6/1/2024 51 DR. M. A. SEIDU (PhD)

52. 6/1/2024 DR. M. A. SEIDU (PhD) 52 THE END OF LECTURE