1. YOUNAS MASIH NEW LIFE COLLEGE OF NURSING KARACHI Patho-pharma Trauma and cell injury unit-iv-b

2. Cell injury When the cell is exposed to an injurious agent or stress, a sequence of events follows that is loosely termed cell injury. Cell injury is reversible up to a certain point If the stimulus persists or is severe enough from the beginning and is dangerous, the cell reaches a point of no return and suffers irreversible cell injury and ultimately cell death.

3. Overview

4. Cell injury Reversible : Cell swelling develops when cells are incapable of fluid an ion homeostasis (↓ed function of ATP dependant pumps). Fatty change the accumulation of lipid vacuoles in the cytoplasm. Irreversible cell injury Denaturation of protein Enzymatic digestion of cell components

5. Cell death it is the ultimate result of cell injury and it can be classified as 1- Necrosis (is always pathologic) occurs after chemical or ischemia 2- Apoptosis(when a cell dies through activation of an internally controlled suicide program. )

6. Mechanism of cell injury Depletion of ATP Mitochondrial Damage Influx of Intracellular Calcium and Loss of Calcium Homeostasis Accumulation of Oxygen-Derived free radical (Oxidative stress) Defects in Membrane Permeability Physical agents Nutritional imbalance

7. Mechanism of cell injury 1. DEPLETION OF ATP:. ATP depletion and decreased ATP synthesis are associated with both hypoxic and chemical (toxic) injury.. ATP is required for many synthetic and degradative processes within the cell.

8. Mechanism of cell injury ATP is produced in two ways. A- The major pathway is oxidative phosphorylation of adenosine diphosphate. B-The second is the glycolytic pathway, which generate ATP in absence of oxygen using glucose derived from body fluids or from glycogen

9. Mechanism of cell injury Effects of depleted ATP a) The activity of the plasma membrane energy- dependent sodium pump is reduced. It causes sodium to accumulate intracellularly and potassium to diffuse out of the cell causing cell swelling, and dilation of the endoplasmic reticulum. b) If oxygen supply to cells is reduced, as in ischemia, oxidative phosphorylation ceases and cells rely on glycolysis for energy production (anaerobic metabolism) resulting in depletion of glycogen stores. Glycolysis results in the accumulation of lactic acid which reduces the intracellular pH, resulting in decreased activity of many cellular enzymes.

10. Mechanism of cell injury c) Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects on numerous cellular components d) Ribosomes detach from the RER and polysomes breakdown into monosomes, leading to reduction in protein synthesis. Ultimately, irreversible damage to mitochondrial and lysosomal membranes occurs, and cell undergoes necrosis

11. Mechanism of cell injury 2- Mitochondrial Damage:. Mitochondria are important targets for all types of injury, including hypoxia and toxins. Mitochondria can be damaged by : A- Increases Ca2+ B- Oxidative stress C- Breakdown of phospholipids, D- Lipid breakdown products.

12. Mechanism of cell injury 3.INFLUX OF INTRACELLULAR CALCIUM & LOSS OF CALCIUM HOMEOSTASIS.. Ischemia causes an increase in cytosolic calcium concentration. Increased Ca2+ in turn activates a number of enzymes, e.g. - ATPases (thereby hastening ATP depletion), -Phospholipases (which cause membrane damage), - Proteases (which break down both membrane and cytoskeletal proteins), and -Endonucleases (which are responsible for DNA and chromatin fragmentation).

13. Mechanism of cell injury 4. ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS) - Small amounts of partially reduced reactive oxygen forms are produced as a byproduct of mitochondrial respiration. - Some of these free radicals can damage lipids, proteins, and nucleic acids. - They are referred to as reactive oxygen species

14. Mechanism of cell injury - Free radicals are chemical species that have single unpaired electron in an outer orbit. - They are initiated within cells in several ways: a) Absorption of radiant energy (e.g., ultraviolet light, x-rays). b) Enzymatic metabolism of exogenous chemicals or drugs. (c ) The reduction-oxidation reactions that occur during normal metabolic processes. During normal respiration, small amounts of toxic intermediates are produced; these include superoxide anion radical (O2- ), hydrogen peroxide (H2O2), and hydroxyl ions (OH).

15. Mechanism of cell injury Defects In Membrane Permeability: - In ischemic cells, membrane damage may be the result of ATP depletion and calcium-modulated activation of phospholipases. - It can also be damaged directly by certain bacterial toxins, viral proteins etc. - Physical mechanism - Extreme temperature - Mechanical forces

16. Mechanism of cell injury Extreme temperature Extreme heat and cold causes cell injury (43 -46 C) It causes Vascular injury Increasing Cell metabolism Inactivation of the enzymes Disruption of the cell membrane

17. Mechanism of cell injury Exposure to low temperature Increases blood viscosity and promotes blood vessels constriction Decreases blood flow that may lead towards hypoxic injury Injury from freezing Ice crystal formation Blood flow is decreased This leads to capillary stasis and thrombosis Edema is caused by the increased capillary permeability

18. Mechanism of cell injury Nutritional imbalances Excess and deficiencies Problems like “beriberi”, pellagra” and scurvy are caused by nutritional imbalances

19. APOPTOSIS AND ITS SIGNIFICANCE Number of cells inn the body are maintained by the cell death and cell proliferation Significance In normal physiological process: Destruction of the cells during embryonic development Death of the immune cells Cell death in proliferating cells

20. APOPTOSIS AND ITS SIGNIFICANCE Examples Separation of webbed fingers and toes in developing embryo Apoptosis controls the number of auto reactive T cells in the thymus Pathological process Suppression of this process is an indicator of the neoplastic growth It is associated with the cell death by viral infections, thermal and radiationinjury

21. http://www.phschool.com/science/biology_place/bi ocoach/biomembrane1/solutions.html http://www.phschool.com/science/biology_place/bi ocoach/biomembrane1/solutions.html http://www.nursingcenter.com/lnc/ce_articleprint? an=00152258-201301000-00010 http://www.nursingcenter.com/lnc/ce_articleprint? an=00152258-201301000-00010 http://www.nursingcenter.com/lnc/cearticle?tid=11 57503 http://www.nursingcenter.com/lnc/cearticle?tid=11 57503 http://www.yournursingtutor.com/hypertoni c-iv-solutions/