1. بسم الله الرحمن الرحيم

2. Pathophysiology
CLS 323
Mrs. Iman Al-Ajeyan

3. Assessments:
First Mid Term Examination : 25
Second Mid Term Examination : 25
Quiz : 5
Presentation :
Final Theoretical Examination : 40
References:
Carol Mattson and Porth, Pathophysiology: Concepts of Altered Health States, J.B. Lippoincott Company, NY, London.
Sylvia A. Price and Lorrain M. Wilson, Pathophysiology: Clinical Concepts of Disease Processes, Mosby; 6 edition (October 15, 2002).

4. Cellular Adaptation Injury and Repair
Lecture 1

5. Pathophysiology
The functional changes associated with or resulting from disease or injury.

6. Cellular Adaptation Injury and Repair
Cellular injury Change in
“Homeostasis”

7. Overview of Cell Injury
“Homeostasis”
•The ability of a system or living organism to adjust its internal environment to maintain a stable equilibrium,
•Under physiological stresses or pathological stimuli (“injury”), cells can undergo adaptation to achieve a new steady state that would be compatible with their viability in the new environment.
•If the injury is too severe (“irreversible injury”), the affected cells die.

8. Cell injury and cell adaptation
-If the changes or stimuli are minor → cell adaptation
-More prolonged or intense stimuli → cell injury or death
To survive, the cells must have the ability to adapt to changes in internal environment.

9. Cellular Adaptation
-When cells are stressed, they respond by changing their
Number
Type
Size
Cellular adaptation occurs by:-
1-Atrophy.
2-Hypertrophy.
3-Hyperplasia.
4-Metaplasia.
5-Dysplasia.

11. Atrophy
* Means decreased size of cell or tissue. * Generally, it is a reversible process except for nervous tissue. * Causes:- 1- Prolonged bed rest. 2- Disuse of limbs. 3- Poor tissue nutrition. 4- Decreased blood supply.

12. Hypertrophy Means increased size of cell or tissue.
Occurs when the tissue can not increase in number.
Cause:
Exposure of the tissue to an increased work load.
Types:
1- Physiological: muscle hypertrophy in athletes.
2- Pathological : cardiac hypertrophy in chronic
hypertension.
3- Compensatory: hypertrophy of one kidney after
removal of the other kidney.

14. Hyperplasia Means increased number of cells in an organ.
Occurs only when the cell is capable of mitosis (not muscle or nerve cell).
Types:-
1- Physiological: uterus and mammary gland.
2- Pathological: gingival hypertrophy occurs with
drug intake e.g, phenytoin.
3- Compensatory: e.g removal part of liver causes
increased number of the remaining hepatocytes.

15. Metaplasia
Means conversing of one cell type to another cell type that may have a better chance for survival.
Causes:
1- Chronic irritation: chronic smoking (ciliated
columnar epithelium converted to stratified
squamous epithelium.
2- Inflammation: Leukoplakia.(white or gray patch that develops on the tongue, the inside of the cheek, or on the floor of the mouth)

16. Dysplasia Means derangement of cell growth or abnormal growth
leading to formation of tissue with various size, shape and appearance.
Causes:
1- Chronic irritation.
2- Inflammation.
It is a strong predisposing factor for cancer e.g bronchogenic carcinoma and cancer cervix.

17. Cell injury
The extent of cell injury is depend on the intensity and duration of the injurious factor.
It may reversible or
irreversible → cell death.

18. • Reversible cell injury denotes pathologic changes that can be reversed when the stimulus is removed and the cellular injury has been mild. Cell injury is reversible only up to certain point.
• Irreversible cell injury denotes pathologic changes that are permanent and cause cell death, they cannot be reversed to normal state

19. Checkpoint Hyperplasia Metaplasia Atrophy Dysplasia
1. derangement of cell growth
2. conversing of one cell type to another
3. increased number of cells in an organ
4. decreased size of cell or tissue.

21. Causes of cell injury: 1) Free radical injury.
Free radicals are chemical species with a single unpaired electron in an outer orbital, e.g hydrogen peroixde
Free radicals are chemically unstable and therefore readily react with other molecules, resulting in chemical damage
Free radicals initiate autocatalytic reactions; molecules that react with free radicals are in turn converted to free radicals

22. 1- Endogenous: Free radical are generated as a by- product of normal metabolism. E.g. - Normal redox reactions generate free radicals - Nitric oxide (NO) can act as a free radical 2- Exogenous: e.g, tobacco smoke, organic solvents, pollutants, radiation and pesticides.
Sources of free radical:

23. Normally free radicals are inactivated by free radical scavengers e
Normally free radicals are inactivated by free radical scavengers e.g catalase & glutathione peroxidase.
When excess free radicals are formed → failure of protection mechanism→ cell injury.

24. 1- Lipid peroxidation of membranes 2- Damage of cellular proteins.
Mechanism of action of free radicals:
1- Lipid peroxidation of membranes
2- Damage of cellular proteins.
3- Mutation of cellular DNA.
Free radicals play role in the aging process and number of diseases e.g. cancer , atherosclerosis , Alzheimer’s disease and rheumatoid arthritis.

25. Causes of cell injury( cont.)
2) Hypoxic cell injury:
Hypoxia means lack of oxygen in cells and tissues that generally result from ischemia (blood flow deficiency).
Decreased O2 supply to cells→
Decreased ATP production.
Activation of anaerobic metabolism→ production of lactic acid → decreased pH of ECF.

26. Hypoxic cell injury may be :
Reversible→ if O2 supply is restored.
Irreversible→ cell death.
N.B Death of brain occurs after 4-6 min of hypoxia.

27. Causes of cell injury( cont.)
3) Chemical” agents: including drugs and alcohol
4) Physical” agents: including trauma and heat
5) Infections
6) Immunological reactions
7) Genetic defects
8) Nutritional defects
including vitamin deficiencies, fat leading to atherosclerosis
9)Aging

28. Manifestation of cell injury
1- Cellular Swelling : injury ---> decreased ATP or direct membrane damage - --> Na+ and H20 increase in cytoplasm * Is reversible.
Balance this force the cell must continuously actively pump sodium out via an energy dependent Na-K ATPase pump located in the plasma membrane. Water passively diffuses out of the cell due to the sodium gradient created by this pump (b)

29. Manifestation of cell injury (contin)
2- Cellular accumulation: * In addition to water cells may accumulate fat, protiens , glycogen , Ca ++ , uric acid and pigments as melanin. * They cause enlargement of the organ e.g fat accumulation in an injured liver. * These accumulation indicate greater degree of cellular injury. * They are generally reversible.

30. Checkpoint
*Causes of cell injury

32. Cell death
TYPES OF CELL DEATH –
Necrosis and Apoptosis

33. 1- Apoptosis: . A form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding area. Apoptosis plays a role in developing and maintaining the health of the body by eliminating old cells, unnecessary cells, and unhealthy cells - Is programmed cell death - Mechanism: Activation of “suicide” genes by certain chemical signals → cell lysis and destruction. - Failure of normal apoptosis in damaged and mutated cells → cancer.

34. 2-Necrotic cell death:
Necrosis occurs when a cell is damaged by an external force, such as poison, a bodily injury, an infection or getting cut off from the blood supply. When cells die from necrosis, it's a rather disordered affair. The death causes inflammation that can cause further distress or injury within the body.
Means the unregulated enzyme digestion “autolysis “ of cells and its components.
*Occurs as a result of irreversible cell injury.
Always pathogenic

35. 3 main types: Liquefaction necrosis. Caseous necrosis
*3 main types: Liquefaction necrosis. Caseous necrosis. Coagulative necrosis.

36. 1-Liquefaction necrosis:
*Enzymes released by necrotic cells →softening and liquefaction of diseased tissue.
*Occurs in tissues rich in hydrolytic enzymes e.g brain.

37. 2- Caseous necrosis:
*Dead tissue takes on a crumbly (cheese like) appearance. Dead cells disintSegrate , but their debris not fully digested by hydrolytic enzymes.
*Occur in condition when there is prolonged inflammation and immune activity e.g tuberculosis.

38. 3- Coagulative necrosis:
*Dead tissue appears firm, gray and slightly swollen.
*Occurs when cell death results from ischemia and hypoxia.
Ischemia → acidosis → denaturation of cellular proteins and hydrolytic enzymes.
*Occurs in myocardial infarction.

39. Gangrene:
Gangrene refers to the death of body tissue due to a lack of blood flow. Gangrene most commonly affects the extremities, including your toes, fingers and limbs, but it can also occur in your muscles and internal organs.
Gangrene can occur as a result of an injury, infection or a long-term condition affecting blood circulation.
* Is a clinical term used when a large area of tissues undergo necrosis.

40. *Gangrene is classified into :
Dry gangrene : the skin surrounding the affected area shrinks, wrinkles and becomes black.
Wet gangrene : presents with an area that is cold ,wet from tissue secretions and swollen.
N.B gas gangrene may occur if the necrotic area becomes infected with bacteria that produce gases.

41. Tissue Repair Types: 1- Repair by regeneration
2- Repair by CT replacement

42. Tissue Repair (contin)
1- Repair by regeneration
Regeneration of injured tissue (replacement by normal cells of the same kind)
*Full return of functions occur.
*Occurs only in:
Labile cells: are cells that multiply constantly throughout life, e.g skin, oral cavity, bone marrow.
Stable cells: stop dividing, but can regenerate under certain conditions, e.g hepatocytes

43. 2- Repair by CT replacement
*Means replacement of functional tissues by non-functioning CT→ full functions does not return *Occurs in fixed cells e.g, nerve cells, cardiac muscle

45. Steps of tissue repair Occurs in Two Ways Primary intention (union)
small incision
fills and heals rapidly
Secondary intention (union)
large gap or hole to be filled
much slower, leaves larger scar

47. Stages of tissue repair
1)Inflammatory stage:
Starts by formation of fibrin clot to stop bleeding from the injury
The inflammatory stage is the period immediately following the injury. This period generally lasts from 3 to 5 days. Pain, swelling and redness characterize inflammation.
Infiltration of phagocytic cells (neutrophils and macrophages) occurs; macrophages secrete growth factors → growth of epithelial cells and formation of new blood vessels.

48. 2) Proliferative stage:
-This stage begins about the 5th day after injury and continues for 4 to 6 weeks. This stage is characterized by increased fibroblast activity, resulting in increased connective tissue strength and formation of adhesion
-These activated fibroblasts produce collagen that repair the bulk of the wound.
-Proliferated epithelial cells + angiogenesis +collagen fibers → soft pink tissue referred as granulation tissue
-Over time (1-2 weeks) contraction of wound occurs and the edges become closer to each other

50. 3) Maturation and remodelling:
- Beginning about the third or fourth week after an injury
-There is continued synthesis of collagen. This maximize the strength of repair.
- Capillaries begins to disappear, leaving a vascular white scar.
N.B. for large healed wounds , its maturation and remodelling may continue for years, and the strength of the final healed scar will never have the full strength of the original tissues

51. Factors that impair wound healing:
1-Malnutrition 2-Poor blood flow and hypoxia 3-Impaired immune response 4-Infection of the wound 5-Foreign particles in the wound 6-Old age (decreased immunity, poor circulation and poor nutrition).

52. Keloid scars
Large raised scars that result from over synthesis of collagen and decreased collagen breakdown.
Are often unsightly and may extend beyond the original boundaries of the wound.
There is a familial tendency for keloid scar formation; occurs more in blacks
than whites.

53. Thank you