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.

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

8. • 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.

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

10. 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.

11. 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.

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

14. • 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.

16. • 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.

17. • 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).

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

20. 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.

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

22. Ischemia-Reperfusion Injury
• The restoration of blood flow to ischemic but
otherwise viable tissues results, paradoxically, in
exacerbated and accelerated injury.

23. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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)

31. • 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).

32. 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
I. Decreased workload (atrophy of disuse).
II. Loss of innervation (denervation atrophy).
III. Diminished blood supply

33. IV. Inadequate nutrition.
V. Loss of endocrine stimulation.
VI. Aging (senile atrophy)
VII.Pressure.
• Although atrophic cells may have diminished
function, they are not dead

34. 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.

35. 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.

36. 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

37. • 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.

38. • 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.

39. • 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.

40. 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.

41. Thank You