Mechanism of cell injury

Mechanism of cell injury

1. Mechanism of cell injury and cellular adaptation to injury By Dr Ajish M Saji Deparment of Oral Pathology Malabar Dental College Edappal

2. Contents Mechanisms of cell injury Principles Depletion of ATP Mitochondrial damage Influx Of Intracellular Calcium And Loss Of Calcium Homeostasis Accumulation Of Oxygen-derived Free Radicals (Oxidative Stress)

3. Defects in membrane permiability Ischemic and hypoxic injury Ishcemic and reperfusion injury Cellular adaptations to injury Hyperplasia Hypertrophy Atrophy Metaplasia Summary References

4. Mechanisms of cell injury Principles The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. The consequences of cell injury depend on the type, state , and adaptability of the injured cell.

5. Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components. (1) aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP. (2)the integrity of cell membranes, on which the ionic and osmotic homeostasis of the cell and its organelles depends; (3) protein synthesis; (4) the cytoskeleton (5) the integrity of the genetic apparatus of the cell.

6. DEPLETION OF ATP ATP depletion and decreased ATP synthesis are frequently associated with both hypoxic and chemical (toxic) injury.

7. Depletion of ATP to <5% to 10% of normal levels has widespread effects on many critical cellular systems: The activity of the plasma membrane energy-dependent sodium pump ( ouabain -sensitive Na+ , K +- ATPase ) is reduced. Cellular energy metabolism is altered. Failure of the Ca2+ pump leads to influx of Ca2+. Reduction in protein synthesis. Unfolded protein response.

8. MITOCHONDRIAL DAMAGE Failure of oxidative phosphorylation and progressive depletion of ATP. Death by apoptosis

9. INFLUX OF INTRACELLULAR CALCIUM AND LOSS OF CALCIUM HOMEOSTASIS Increased cytosolic Ca2+ activates a number of enzymes; Phospholipases -cause membrane damage Proteases-break down both membrane and cytoskeletal proteins. Endonucleases -are responsible for DNA and chromatin fragmentation Adenosine triphosphatases - thereby hastening ATP depletion.

10. ACCUMULATION OF OXYGEN-DERIVED FREE RADICALS (OXIDATIVE STRESS) Free radicals are chemical species that have a single unpaired electron in an outer orbit. Free radicals may be initiated within cells in several ways; Absorption of radiant energy. Enzymatic metabolism of exogenous chemicals or drugs. The reduction-oxidation reactions that occur during normal metabolic processes.

11. Transition metals such as iron and copper donate or accept free electrons during intracellular reactions and catalyze free radical formation. Nitric oxide (NO).

12. Reactions relevant for cell injury are; Lipid peroxidation of membranes. Double bonds in membrane polyunsaturated lipids are vulnerable to attack by oxygen-derived free radicals. Cross-linking of proteins. Free radicals promote sulfhydryl -mediated protein cross-linking, resulting in enhanced degradation or loss of enzymatic activity. DNA fragmentation. Free-radical reactions with thymine in nuclear and mitochondrial DNA produce single-strand breaks.

13. Mechanisms to remove free radicals and minimize injury. Antioxidants either block the initiation of free radical formation or inactivate free radicals and terminate radical damage. Iron and copper can catalyze the formation of reactive oxygen species.

14. A series of enzymes acts as free radical-scavenging systems Catalase , present in peroxisomes , which decomposes H2O2 (2 H202 -> O2 + 2 H20). Superoxide dismutases are found in many cell types and convert superoxide to H2O2 (2 02 + 2 H -> H202 + O2 ). Glutathione peroxidase also protects against injury by catalyzing free radical breakdown (H 202 + 2 GSH -> GSSG [glutathione homodimer] + 2 H 2O2 or 2 OH +2 GSH —> GSSG + 2 H2O).

15. DEFECTS IN MEMBRANE PERMEABILITY Mitochondrial dysfunction. Loss of membrane phospholipids. Cytoskeletal abnormalities. Reactive oxygen species Lipid breakdown products.

16. Ischemic and Hypoxic Injury Ischemia, or diminished blood flow to a tissue, is the most common cause of cell injury. In hypoxia energy generation by anaerobic glycolysis can continue.

17. loss of ATP leads to the failure of many energy-dependent cellular systems; Ion pumps. depletion of glycogen stores. reduction in protein synthesis.

18. Ischemia-Reperfusion Injury T he restoration of blood flow to ischemic but otherwise viable tissues results, paradoxically , in exacerbated and accelerated injury.

19. Cellular Adaptations to Injury Cells respond to increased demand and external stimulation by hyperplasia or hypertrophy. They respond to reduced supply of nutrients and growth factors by atrophy. Cells change from one type to another, a process called metaplasia .

20. HYPERPLASIA Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in increased volume of the organ or tissue. Hyperplasia can be physiologic or pathologic.

21. Physiologic Hyperplasia Physiologic hyperplasia can be divided into: (1) hormonal hyperplasia, which increases the functional capacity of a tissue when needed. (2) compensatory hyperplasia, which increases tissue mass after damage or partial resection.

22. Mechanisms of Hyperplasia Increased local production of growth factors. Increased levels of growth factor receptors on the responding cells. Activation of particular intracellular signaling pathways.

23. Pathologic Hyperplasia Excessive hormonal stimulation or growth factors acting on target cells. Endometrial hyperplasia is an example of abnormal hormone-induced hyperplasia. Pathologic hyperplasia, however, constitutes a fertile soil in which cancerous proliferation may eventually arise.

24. HYPERTROPHY Hypertrophy refers to an increase in the size of cells, resulting in an increase in the size of the organ. The increased size of the cells is due to the synthesis of more structural components. Nuclei in hypertrophied cells will have a higher DNA content. Hypertrophy can be physiologic or pathologic.

25. Mechanisms of Hypertrophy. The genes that are induced during hypertrophy include those encoding Transcription factors Growth factors (TGF- β , insulin-like growth factor-1 [IGF-1], fibroblast growth factor); and Vasoactive agents ( α -adrenergic agonists, endothelin-1, and angiotensin II)

26. In the heart, there are two groups of signals: Mechanical triggers, such as stretch, Trophic triggers, such as polypeptide growth factors (IGF-1) and vasoactive agents ( angiotensin II, a-adrenergic agonists).

27. ATROPHY Shrinkage in the size of the cell by loss of cell substance. Atrophy can be physiologic or pathologic. The common causes of atrophy are Decreased workload (atrophy of disuse). Loss of innervation ( denervation atrophy). Diminished blood supply

28. Inadequate nutrition. Loss of endocrine stimulation. Aging (senile atrophy) Pressure. Although atrophic cells may have diminished function, they are not dead

29. METAPLASIA Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal ) is replaced by another adult cell type. The influences that predispose to metaplasia , if persistent, may induce malignant transformation in metaplastic epithelium.

30. Mechanisms of Metaplasia It is the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue. The differentiation of stem cells to a particular lineage is brought about by signals generated by cytokines, growth factors, and extracellular matrix components in the cell's environment.

31. SUMMARY ATP depletion: failure of energy-dependent functions → reversible injury → necrosis Mitochondrial damage: ATP depletion → failure of energy-dependent cellular functions → ultimately, necrosis; under some conditions, leakage of proteins that cause apoptosis Influx of calcium: activation of enzymes that damage cellular components and may also trigger apoptosis

32. Accumulation of reactive oxygen species: covalent modification of cellular proteins, lipids, nucleic acids. Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis. Accumulation of damaged DNA and misfolded proteins: triggers apoptosis.

33. Hypertrophy: increased cell and organ size, often in response to increased workload; induced by mechanical stress and by growth factors; occurs in tissues incapable of cell division Hyperplasia: increased cell numbers in response to hormones and other growth factors; occurs in tissues whose cells are able to divide.

34. Atrophy: decreased cell and organ size, as a result of decreased nutrient supply or disuse; associated with decreased synthesis and increased proteolytic breakdown of cellular organelles. Metaplasia : change in phenotype of differentiated cells, often a response to chronic irritation that makes cells better able to withstand the stress; usually induced by altered differentiation pathway of tissue stem cells; may result in reduced functions or increased propensity for malignant transformation.

35. References 1)Kumar , Abbas , Fasusto ,Robbins And Cotran ,Pathologic Basics Of Diseases ,Elsevier, Seventh Edition,5-18. 2)Harsh Mohan, Essential Pathology For Dental Students, Jaypee , Second Edition ,6-11. J P Cobb , R S Hotchkiss , I E Karl , and T G Buchman ; Mechanism of cell injury and death ; British journal of Anesthesia 1996 ; 77 : 3-10.

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