1. Cell injury
Dr. Gehan Mohamed

2. Cell Injury Definition Causes Mechanisms of Cell Injury
Cellular response to injury:
- Cellular adaptation
- Reversible cell injury ( nonlethal hit)
- Irreversible injury and cell death (apoptosis, necrosis and gangrene)

3. Injury alters the preceding normal steady state of the cell.
CONCEPT OF INJURY AND
CELLULAR RESPONSE TO INJURY
Cells are constantly exposed to a variety of stresses. At first cells try to adapt themselves to overcome this stressful condition But When stress is too severe or for prolonged duration, INJURY results.
Injury alters the preceding normal steady state of the cell.

4. The cellular response to injurious stimuli depends on :
1. Type ,duration and severity of injurious agent.
2-the type, status, adaptability, and genetic
makeup of the injured cell.
Cellular function is lost far before cell death occurs

5. Causes of cell injury EXCESS or DEFICIENCY OF OXYGEN PHYSICAL AGENTS
CHEMICAL AGENTS
INFECTION
IMUNOLOGICAL REACTIONS
GENETIC DERANGEMENTS
NUTRITIONAL IMBALANCE
AGING

6. Mechanisms of cell injury
(1)Cell membrane damage leading to Loss of structural integrity and Loss of function.
(2)Mitochondrial damage leading to inadequate aerobic respiration.
(3)Ribosomal damage leading to altered protein synthesis.
(4)Nuclear change leading to abnormal proliferation.
(5)Decrease ATP production so Plasma membrane energy-dependent sodium pump is reduced, resulting in cell swelling.
(6)increase intra cellular calcium.
(7)Production of oxygen derived free radicals.

8. How the cell respond to injurious agent ?

9. Etiologic agents

10. Adaptation

11. Cellular adaptation
A- Disorders leading to diminished growth i.e atrophy
B- Disorders leading to excessive growth i.e
hypertrophy and hyperplasia
C- Disorders of cellular differentiation i.e
metaplasia and dysplasia

12. But when the injurious agent is sever and persist for long duration so the cell can not tolerate it even by adaptation so cell injury result either in the form of :
(1)Degeneration which is change in metabolism inside cytoplasm which may lead to intracellular accumlations without affection of nucleus so degeneration is a reversible process.
(2)Necrosis which is death of the cell so it is irreversible process.

13. Degenerations

14. Degeneration Examples of degenerative diseases:
Osteoarthritis is a degenerative joint disease in which gradual destruction and deterioration of the bones and joint occurs.
Alzheimer's disease is a degenerative neurological disease where there is a progressive deterioration in brain function.

15. Some Degenerative diseases may lead to intracellular Accumulation due to :
increased rate of production of a normal substance, but metabolic rate is inadequate to remove it (e.g. fatty change in liver).
genetic or acquired defects in folding, packaging, transport, or secretion of the accumlated material .

16. 3. An inherited defect in an enzyme may result in failure to degrade a metabolite.
(e.g. Accumulations of carbon or silica particles)

17. Types of intracellular accumlations:
Cloudy swelling and hydropic changes:
Cytoplasmic swelling and vacuolation due to intracellular accumulation of water and electrolytes secondary to failure of energy-dependent sodium pump.

18. Vacuolar (hydropic) change in cells lining the proximal tubules of the kidney
Reversible
changes

19. Fatty Change
(Steatosis)

20. Fatty Change
Fatty change refers to any abnormal accumulation of triglycerides within parenchymal cells.
Site:
liver, most common site which has a central role in fat metabolism.
it may also occur in heart as in anaemia or starvation (anorexia nervosa)
Other sites: skeletal muscle, kidney and other organs.

21. Causes of Fatty Change Toxins (most importantly: Alcohol abuse)
diabetes mellitus
Protein malnutrition (starvation)
Obesity
Anoxia

22. Defects in any of the steps of uptake, catabolism, or secretion can lead to lipid accumulation.

23. The significance of fatty change
Depends on the severity of the accumulation.
Mild it may have no effect .
In the severe form, fatty change may precede cell death, and may be an early lesion in a serious liver disease called nonalcoholic steatohepatitis

25. Is Fatty liver reversible?
Fatty change is reversible
except if some vital intracellular process is irreversibly impaired .

26. Prognosis of Fatty liver
In Mild cases: 3% will develop cirrhosis
Moderate to sever: inflammation, degeneration in hepatocytes, fibrosis (30% develop cirrhosis).

27. Other form of accumulation
Cholesteryl esters
These give atherosclerotic
plaques their characteristic
yellow color and contribute to
the pathogenesis of the lesion
This is called atherosclerosis

28. Pigments

29. Pigments are colored substances that are either:
exogenous, coming from outside the body, or
endogenous, synthesized within the body itself.

30. Exogenous pigment
Pigments and insoluble substances may enter the body from a variety of sources.
They may be toxic and produce inflammatory tissue reactions or they may be relatively inert.
Indian ink pigments produce effective tattoos because they are engulfed by dermal macrophages which become immobilized and permanently deposited.

31. Exogenous pigment The most common is carbon
When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes.

32. Exogenous pigment
Aggregates of the carbon pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).

33. Exogenous pigment Carbon in Lung
Heavy accumulations may induce in a serious lung disease called coal workers' pneumoconiosis)

34. Endogenous pigments
Endogenous pigments include certain derivatives of hemoglobin, melanin, and lipofuscin.

35. Hemosiderin ( iron)
is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron.

36. Hemosiderin ( iron)
Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal.
Where?
in the mononuclear phagocytes of the bone marrow, spleen, and liver.
Why?
there is extensive red cell breakdown.

37. Hemosiderin
The iron ions of hemoglobin accumulate as golden-yellow hemosiderin.
The iron can be identified in tissue by the Prussian blue histochemical reaction

38. Hemosiderosis (systemic overload of iron)
It is found at first in the mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs.
With progressive accumulation, parenchymal cells throughout the body (principally the liver, pancreas, heart, and endocrine organs) will be affected

39. Hemosiderosis increased absorption of dietary iron
Hemosiderosis occurs in the setting of:
increased absorption of dietary iron
impaired utilization of iron
hemolytic anemias
transfusions (the transfused red cells constitute an exogenous load of iron). .

40. Effect of hemosiderosis
However, more extensive accumulations of iron are seen in hereditary hemochromatosis with tissue injury including liver fibrosis, heart failure, and diabetes mellitus

41. Lipofuscin
"wear-and-tear pigment" is an insoluble brownish-yellow granular intracellular material that seen in a variety of tissues (the heart, liver, and brain) as a function of age or atrophy.
Consists of complexes of lipid and protein that derive from the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes.
It is not injurious to the cell but is important as a marker of past free-radical injury.
The brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.

42. PATHOLOGIC CALCIFICATION

43. Pathologic calcification
it implies the abnormal deposition of calcium salts with smaller amounts of iron, magnesium, and other minerals.
It has 2 types:

44. Types of Pathologic calcification
Dystrophic calcification:
When the deposition occurs in dead or dying tissues
it occurs with normal serum levels of calcium
Metastatic calcification:
The deposition of calcium salts in normal tissues
It almost always reflects hypercalcemia.

45. Dystrophic calcification is encountered in areas of necrosis of any type or in advanced atherosclerosis of aorta.
Dystrophic calcification of the aortic valves is an important cause of aortic stenosis in the elderly .

46. Metastatic calcification
Metastatic calcification can occur in normal tissues whenever there is hypercalcemia.

47. Cell Death
Two main categories:
Apoptosis
and
Necrosis

48. Apoptosis Morphologic characters: - Intact cell membrane.
A controlled, “programmed” cell death.
Morphologic characters:
- shrunken cell.
- Intact cell membrane.
- No associated inflammatory process.
- Phagocytosis and replacement by healthy cells.
Pathogenesis:
Activation of “suicide genes” in response to certain injurious agents?

49. Types of apoptosis: Physiologic: (elimination of worn-out cells)
*Embryogenesis.
*Endometrium.
*Intestinal crypt cells.
Pathologic:
*Irradiation-induced injured cells.
*Drug-induced injured cells.
*Viral-infected cells.
*Tumor regression and progression.

50. Necrosis
Definition
Morphological changes follow cell death in living tissue/organ.
Two underlying processes; protein denaturation and enzymatic digestion of cytoplasmic organelles and organoids.
Morphologic characteristics
- Gross
- Microscopic
*Cell membrane changes.
*Nuclear changes.

52. Apoptosis versus Necrosis
Feature
Enlarged, swollen
Reduced, Shrunken
Cell size
Pyknosis  karyorrhexis karyolysis
Fragmentation into nucleosome sized fragments
Nucleus
Disrupted
Intact, altered structure
Plasma membrane
Enzymatic digestion; may leak out of cells
Intact; may be released into apoptotic body
Cellular contents
Frequent
Absent
Adjacent inflammation

53. 1- Coagulative Necrosis (Infarction):
Types of necrosis
1- Coagulative Necrosis (Infarction):
Patho-physiology: protein denaturation with preservation of cell and tissue framework. Characteristic of hypoxia induced death. Necrotic tissue undergoes either heterolysis (digestion by lysosomal enzymes of invading leukocytes) or autolysis ( digestion by own lysosomal enzymes).
Examples: heart, kidney, spleen,

55. 2- Caseation Ncrosis Characters: semi-solid soft tissue
Cause: immune-mediated
Mechanism: cytokines; TNF-alpha
Examples: Tuberculosis in : lung, LNs, Kidney, Brain, …..

56. Caseating necrosis of T.B

57. 3- liquefactive Necrosis
Mechanism: autolysis or heterolysis predominate over protein denaturation. The necrotic area is soft and filled with fluid.,
Examples: abscess, brain infarcts, amebic abscess

58. 4- Fat Necrosis
Types :
A- Traumatic fat necrosis: e.g. trauma to adipose tissue as breast and subcutaneous tissue
B-Enzynmatic fat necrosis: e.g. hemorrhagic pancreatitis. Release of lipase enzyme from ruptured pancreatic duct splits omental fat into glycerol and fatty acids. The latter form complexes with calcium  white chalky areas (fat saponification)

59. Fate of Necrosis 1- Healing by fibrosis  scar 2- Cyst formation
3- Dystrophic calcification
4- Gangrene due to putrefaction of necrotic tissue by saprophytic organism.