CELL INJURY MBBS YEAR 4 PATHOLOGY 1 .pptx

About cell injurious agents

1. CELL INJURY PREPARED BY DR. O. O. KAZEEM IBRAHIM DEPARTMENT OF PATHOLOGY COLLEGE OF HEALTH SCIENCES UNIVERSITY OF ILORIN

2. CELL INJURY I Introduction to pathology Overview of cellular responses to stress and noxious stimuli Causes of cell injury Mechanisms of cell injury

3. Introduction to Pathology Pathology is the study of the structural, biochemical, and functional changes in cells, tissues, and organs that underlie diseases. Pathology uses morphologic, microbiologic, immunologic, and molecular techniques to explain whys and wherefores of the signs and symptoms manifested by patients while providing a rational basis for clinical care and therapy.

4. Introduction to Pathology Pathology serves as the bridge between the basic sciences and clinical medicine. Study of pathology is divided into 2: General pathology: includes cell injury and tissue responses to injurious stimuli, fluid and hemodynamic disorders, immune responses and diseases, genetic basis of diseases, and neoplasia. It also includes environmental pathology. Systemic pathology: Examines the alterations and underlying mechanisms in diseases of particular organ systems; e.g., respiratory pathology, liver pathology, etc.

5. Introduction to Pathology Four aspects of a disease that form the core of pathology are: Causation (etiology) Pathogenesis Morphologic changes Clinical manifestations

6. Introduction to Pathology Etiology This is the initiating cause of a disease. Broadly divided into genetic and environmental Specific etiology to a specific disease is usually applicable to infectious diseases and single gene disorders. Most other diseases are causes by environmental factors mostly in a genetically susceptible individuals. E.g., most cancers, DM, etc - they are referred as multifactorial.

7. Introduction to Pathology Pathogenesis Sequence of molecular, biochemical, and cellular events that lead to development of disease. How the etiology lead to morphologic and clinical manifestation of the disease. PATHOGENESIS IS THE HEART OF PATHOLOGY It answers how. E.g., from single gene abnormality to development of the disease.

8. Introduction of Pathology Morphologic changes Structural alterations in cells or tissues that are characteristic of a disease. They are diagnostic of an etiologic process. They used to be cornerstone of diagnosis. They are now being supplemented by immunohistochemistry and molecular studies.

9. Introduction to Pathology Clinical manifestations The end results of genetic, biochemical, and structural changes in cells and tissues are functional abnormalities that lead to clinical manifestations (signs and symptoms) of disease and its progression.

10. Overview of cellular responses to stress and noxious stimuli These include: Homeostasis: where a normal is confined to a fairly narrow range of function and structure , which are dictated by: i Its state of metabolism, differentiation, and specialization; ii Constraints by neighboring cells; and iii Availability of metabolic substrates. This healthy steady state is called homeostasis

11. Overview of cellular responses to stress and noxious stimuli 2. Adaptations: These are reversible functional and structural responses to changes in physiologic states and some pathologic stimuli (Physiologic vs Pathologic) resulting in new but altered states, allowing the cells to survive and continue to function. Examples include: Hypertrophy, Hyperplasia, Atrophy, and Metaplasia. The cells can return to its original state if the stress is eliminated.

12. Overview of cellular responses to stress and noxious stimuli 3. Cell injury: This results if the limits of adaptive responses are exceeded or the magnitude of the noxious stimulus is much abinitio or in certain types of injurious agents such as heavy metals poisoning. Cell injury may be reversible initially but becomes irreversible if the injury persists or severe, leading to cell death .

13. Overview of cellular responses to stress and noxious stimuli 4. Intracellular accumulations: Metabolic derangements and chronic injury may be associated with intracellular accumulations of substances, e.g., proteins, lipid, carbohydrates, pigments, etc 5. Pathologic calcification: 6. Cellular aging:

14. Causes of cell injury Oxygen deprivation Hypoxia – deficiency of oxygen Causes cell injury by reducing aerobic oxidative respiration – leading to lack of ATP, lactic acidosis, etc It is a common cause of cell injury and cell death. Common cause of diseases in western world, e.g., cerebrovascular accidents, myocardial infarction, etc Causes include ischemia (loss of arterial supply), inadequate oxygenation due to cardiorespiratory failure, reduced oxygen carrying capacity (such as in anemia and CO poisoning)

15. Causes of cell injury Physical agents Mechanical trauma: e.g. automobile accident, blunt and penetrating injuries, etc Extremes of temperature: Frostbites and burns Radiation injuries: All forms of radiation Sudden changes in atmospheric pressure: Up or down Electric shock

16. Causes of cell injury Chemical agents and drugs Heavy metals Industrial and occupational chemicals Insecticides, pesticides, herbicides, fungicides, etc Most drugs Glucose and salt in hypertonic concentrations

17. Causes of cell injury Infectious agents Commonest cause of cell injury and diseases in developing countries. Viruses Bacteria Fungi Parasites

18. Causes of cell injury Others causes of cell injury include: Immunologic reactions: In form of hypersensitivity reactions and autoimmune diseases. Genetic abnormalities: Single gene disorders, chromosomal abnormalities, etc Nutritional imbalances: In form of nutritional deficiencies and excessive nutrition such as obesity.

19. Mechanisms of cell injury General principles of cell injury: Cellular response to injurious stimuli depends on the nature of the injury, the duration of the injury, and severity of the injury. Consequences of cell injury depend on the type of the cell, state of the cell, vulnerability, and adaptability of the injured cell. Any injurious stimulus may simultaneously trigger multiple interconnected mechanisms that damage cells.

20. Mechanisms of cell injury The main targets of injurious stimuli are: Mitochondria Cell membranes Protein synthesis and secretion DNA

21. Mechanisms of cell injury Mitochondria damage They are the power house of cells; supplying energy by producing ATP. They are the determinants of life and death of cells. Irreversibly damage to the mitochondria will result in cell death. They can be damaged by the followings: Increases of cytosolic calcium ions. Reactive oxygen species Oxygen deprivation Toxins Mutations in mitochondria genes

22. Mechanisms of cell injury Consequences of mitochondria damage ATP depletion: frequently seen in hypoxic and chemical injury. ATP is produced by oxidative phosphorylation of ADP with resultant reduction of oxygen by mitochondrial electron transport system; and glycolytic pathway (lesser ATP) in the absence of oxygen. How?? Mitochondrial damage – formation of high-conductance channel in the mitochondrial membrane (mitochondrial permeability transition pore) – loss of mitochondrial membrane potential – leading to failure of oxidative phosphorylation – progressive ATP depletion – cell death. ATP is required for all synthetic and degradative processes within cell

23. Mechanisms of cell injury Consequences of mitochondrial damage 2. Reduction in the activity of Na + ,K + -ATPase: Sodium accumulates intracellularly and potassium depletion – net gain of solute – increase osmolality – water accumulation – cell swelling and endoplastic reticulum dilation. 3. Altered cellular energy metabolism (due to reduced ATP increased AMP) with glycogenolysis and glycolysis: leading to glycogen depletion and lactic acid accumulation – reduction in intracellular pH – decreased activity of many cytosolic enzymes. 4. Reduction in protein synthesis: due to detachment of ribosomes from rough ER and dissociation of polysomes. 5. Incomplete oxidative phosphorylation with formation of reactive oxygen species.

24. Mechanisms of cell injury Membrane damage This may result from: ATP depletion Calcium-mediated activation of phospholipases Direct damage by bacterial toxins, viral proteins, lytic components of complement, physical, and chemical agents. Mechanisms of damage include: Reactive oxygen species Decreased phospholipid synthesis Increased phospholipid breakdown Cytoskeletal abnormalities Membranes include mitochondrial membrane, plasma membrane, lysosomal membrane.

25. Mechanisms of cell injury Damage to DNA Frequent causes include: Exposure to radiation, Drugs (especially anticancer), Reactive oxygen species, Spontaneously (as part of aging). Note the role p53 in DNA repair and possible apoptosis in case of failure of repair.

26. Mechanisms of cell injury Disturbance of Calcium Homeostasis Increased cytosolic Ca 2+ can cause cell injury. To maintain low cytosolic concentration (1.3mmol/L extracellular compared to about 0.1micronmol/L intracellular), calcium ions are usually sequestered in mitochondria and endoplastic reticulum. Ischemia and certain toxins cause increase in cytosolic concentration by release of sequestered calcium ions initially and later due to increased influx across plasma membrane. Excessive intracellular calcium causes injury through: Accumulation in mitochondria results in opening of mitochondria transition pore with failure of ATP generation. Activation of hydrolytic enzymes such as phospholipases, proteases, ATPases, endonucleases