Lesson one Cell Injury

1. Lesson oneCell Injury DR .HALA BADAWI LECTURER OF PATHOLOGY

2. Introduction • Pathology is the study of diseases. • It is a bridge between basic science and clinical practice • The study of pathology is divided into general pathology and special, or systemic, pathology. • General pathology is concerned with the basic reactions of cells and tissues to abnormal and injurious stimuli that underlie all diseases. • Special pathology examines the specific responses of specialized organs and tissues to more or less well-defined stimuli.

3. Introduction • The four aspects of a disease process that form the core of pathology are: • Etiology, the cause of disease, • Pathogenesis, mechanisms of its development, • Morphology, the structural alterations induced in the cells and organs of the body, • Clinical significance & complications, the functional consequences of the morphologic changes.

4. Cellular Responses to Stress and Injury • The normal cell is able to handle normal physiologic demands, maintaining a steady state called homeostasis. • More severe physiologic stresses and some pathologic stimuli may produce a number of physiologic and morphologic changes called cellular adaptations, preserving the viability of the cell and modulating its function as it responds to such stimuli.

5. Cellular Responses to Stress and Injury • If the limits of adaptive response to a stimulus are exceeded, or when the cell is exposed to an injurious agent or stress, a sequence of events follows that is termed cell injury. • Cell injury is reversibleup to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell reaches a “point of no return” and suffers irreversible cellinjury and ultimately cell death.

7. Reversible Cell injury Irreversible Cell injury Necrosis Apoptosis Cell swelling Fatty changes

9. Causes of Cell Injury 1-Hypoxia:caused either by: A- Ischemia, which is a loss of blood supply from impeded arterial flw or reduced venous drainage in a tissue. B- Inadequate oxygenation as in a) Cardio-respiratory failure, or b) Loss of the oxygen-carrying capacity of the blood, as in anaemia or carbon monoxide poisoning. 2- Physical Agents. trauma, burns, deep cold, radiation, and electric shock.. 3- Chemical Agents and Drugs 4-Infectious Agents. viruses, bacteria, fungi and tapeworms. 5- Immunologic Reactions 6-Nutritional Imbalances. both under-nutrition and over-nutrition

10. Mechanism of Cell Injury The cellular response to injurious stimuli depends on: • The type of injury, its duration, and its severity: thus low doses of toxins or brief duration of ischemia may lead to reversible injury, whereas large dose of toxins or longer ischemic intervals may result in irreversible injury and cell death. • The type of cell being injured: for example, striated skeletal muscles in the leg can tolerate complete ischemia for 2 to 3 hours without suffering irreversible injury, whereas cardiac muscle suffers death after only 20 to 30 minutes.

11. Mechanism of Cell Injury Four intracellular systems are particularly vulnerable to injury: • Aerobic respiration involving mitochondrial oxidative phosphorylation and production of ATP. • Protein synthesis. • Cell membrane integrity, critical to cellular ionic and osmotic homeostasis. • The integrity of the genetic apparatus.

14. Reversible Cell Injury Cell Swelling Fatty Changes

15. Cellular Swelling • Cellular swelling is the first manifestation of almost all forms of cell injury . • It appears when cells are incapable of maintaining fluid homeostasis as a result of decrease ion pumps. • When it affects many cells in an organ; it causes some pallor, and increase in weight of the organ. • The cytoplasm contains small clear vacuoles

16. Fatty Change (Steatosis) • Fatty changes is abnormal accumulation of lipid (neutral fat) within parenchymal cells. • It is commonly affects the liver, • But it can affect the heart, kidney, skeletal muscle and other organs.

17. Fatty Change (Steatosis) Causes: Fatty changes may be due to; Hypoxic or toxic depression of mitochondrial enzymes Hepatocellular specific causes: because the liver is the main organ responsible for fat metabolism, its cells undergo fatty changes in the following conditions. • Obesity . • Starvation and diabetes mellitus. • Deficiency of lipotropic factors . • Hepatotoxins as alcohol . • Some liver cell disease as viral hepatitis.

18. Fatty Change (Steatosis) Normal liver • Morphology • The affected organ isenlarged, • Soft and heavy. • Cut section is yellow and greasy. fatty liver

19. Fatty Change (Steatosis) • Clinical Significans: • fatty change is a severer form of cell injury, but still can be reversed if the cause is eliminated . • If the injury is sustained and severe, this fatty change progress to cell necrosis.

20. Irreversible Cell Injury Necrosis Apoptosis

21. I- Necrosis Definition Necrosis is local death of tissue within a living body Types: • Coagulative Necrosis • Liquifactive Necrosis • Caseation Necrosis • Fat Necrosis

22. Coagulative Necrosis • When denaturation is the primary pattern, It implies preservation of the basic outline of the coagulated cell for some days. • The affected tissues exhibit firm texture. The process of coagulative necrosis is characteristic of hypoxic (ischemic) death of cells in all tissues except the brain. • Examples, Myocardial, kidney and splenic infarction. ( kidney infarction) Coagulative necrosis ( splenic infarction)

23. Liquifactive Necrosis • When enzyme digestion is dominant, liquifaction of necotic tissue occurs. • Examples: • - Focal bacterial infections (abscess) . • - Hypoxic death of cells within the central nervous system (Brain infarction). • Gangrenous necrosis is not a distinctive pattern of cell death, the term is still commonly used in surgical clinical practice. • It is usually applied to massive ischemic coagulation necrosis ( cutting blood supply of a limb), when superimposed by bacterial infection with liquifactive component. Liquifactive necrosis (brain infarction)

24. Caseous Necrosis • Caseous necrosis, is encountered most often in foci of tuberculous infection. • The term caseous is derived from the cheesy white gross appearance of the area of necrosis. • On microscopic examination, the necrotic focus appears as amorphous strucureless granular debris . • Unlike coagulative necrosis, the tissue architecture is completely obliterated. Caseation necrosis

25. Fat Necrosis • Fat nesrosis is well-accepted term but does not in reality denote necrosis. • It describes focal areas of fat destruction. • I-Enzymatic fat necrosis: • Occurring in acute pancreatitis as a result of release of activated pancreatic lipases into the pancreas and the peritoneal cavity. • The activated enzymes liquefy fat cell. • The released fatty acids combine with calcium to produce chalky white areas. • II-Traumatic fat necrosis: • Commonly seen in female breast due to trauma. • Rupture of fat cells result in their autodigestion and release of fatty acids which combine with calcium forming hard mass. Enzymatic fat necrosis of pancrease

26. Fate of necrosis • Eventually, in the living patient, most necrotic cells and their debris disappear by a combined process of enzymatic digestion and fragmentation, followed by phagocytosis of the particulate debris by leukocytes. • If necrotic cells and cellular debris are not promptly destroyed and reabsorbed, they tend to attract calcium salts and become calcified (dystrophic calcification)

27. II-Apoptosis • Apoptosisis a programmed cell death that is induced by a tightly regulated intracellular mechanism in which cells designed to die. • The cell’s plasma membrane remains intact, but its structure is altered in such a way that the apoptotic cell becomes an avid target for phagocytosis. • The dead cell is rapidly cleared, before its contents have leaked out, and therefore cell death by this pathway does not elicit an inflammatory reaction in the host. • Thus, apoptosis is fundamentally different from necrosis, which is characterized by loss of membrane integrity, enzymatic digestion of cells, and frequently associated with inflammation.

28. II-Apoptosis Examples of Apoptosis(physiological & pathological) • The programmed destruction of cells during embryogenesis • Hormone-dependent involution in the adult, such as endometrial cell breakdown during the menstrual cycle, the regression of the lactating breast after weaning, and prostatic atrophy after castration.

29. Physiological & pathological Not associated with inflammation Pathological Associated with inflammation

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

32. Hyperplasia • Definition; Hyperplasia is an increase in the number of cells in an organ or tissue, usually resulting in increased volume of the organ or tissue. • Although hyperplasia and hypertrophy are two distinct processes, frequently both occur together, for example, hormone-induced growth of the uterus (pregnancy). • Hyperplasia takes place in the cells capable of division by contrast, hypertrophy involves cell enlargement without cell division. • Hyperplasia can be physiologic or pathologic.

33. Hyperplasia • Physiologic Hyperplasia:can be divided into: • (1) Hormonal hyperplasia, Examples, hyperplasia of the female breast at puberty and during pregnancy and hyperplasia of the pregnant uterus. • (2) Compensatory hyperplasia, Examples, after partial hepatectomy, proliferation of residual liver cells leading to restoration of liver weight in 2 weeks. • Similar mechanisms happened, after unilateral nephrectomy, when the remaining kidney undergoes compensatory hyperplasia. • Bone marrow hyperplasia following haemorrhage is another example of compensatory hyperplasia

34. Hyperplasia • Pathologic Hyperplasia • Mostly caused by excessive hormonal stimulation or growth factors acting on target cells. • Examples: • Endometrial hyperplasia is an example of abnormal hormone-induced hyperplasia, due to increases in estrogen, • Benign prostatic hyperplasia, due to abnormal response to androgens. • Hyperplasia of lymphoidtissue in response to antigenic stimulation. • NB; although these forms of hyperplasia are abnormal, the process remains controlled, because the hyperplasia regresses if the hormonal stimulation is eliminated.

35. Hypertrophy • Definition: hypertrophy is an increase in the size of cells, resulting in an increase in the size of the organ. • Thus, the hypertrophied organ has no new cells, just larger cells. • The increased size of the cells is not due to cellular swelling but to the synthesis of more structural components in nondividing cells. • Hypertrophy can be physiologic or pathologic and is caused by increased functional demand or by specific hormonal stimulation.

36. Hypertrophy PathologicHypertrophy: Examples: -Hypertrophy of left ventricle in hypertension, or valve lesions - Urinary bladder hypertrophy in bladder neck stricutre PhysiologicHypertrophy: Examples; • 1) the bulging muscles of bodybuilders. • 2) enlargement of the uterus during pregnancy (both hypertrophy and hyperplasia).

37. Atrophy • Definition: shrinkage in the size of the cell by loss of cell substance (decrease size & number of cells). • Physiologic atrophy: • Atrophy of thymus after puberty. • The uterus decreases in size after delivery. • Atrophy of mammary gland and uterus after menopause. • Aging (senescence), all tissue and organs (including the brain) undergo progressive atrophy (generalized, senile atrophy).

38. Atrophy Pathologic atrophy Generalized Pathologic Atrophy • In cases of chronic malnutrition and advanced stages of malignancy. • In profound protein-calorie malnutrition (marasmus) ,the use of skeletal muscle as a source of energy after depletion of adipose stores, result in genealized atrophy. • In cases of cachexia, result from marked muscle wasting. Cachexia is seen in patients with chronic inflammatory diseases and cancer.

39. Atrophy Pathologic atrophy Localized Pathologic Atrophy: • Decreased workload (disuse atrophy). skeletal muscle atrophy following prolonged immobilization . • Loss of innervation (denervation atrophy). Damage to the nerves leads to rapid atrophy of the muscle fibers supplied by those nerves as in poliomyelitis. • Diminished blood supply. Results from; -Arterial occlusive disease as atherosclerosis. -Pressure atrophy: Tissue compression for time can cause atrophy. An enlarging benign tumor can cause atrophy in the surrounding compressed tissues. • Loss of endocrine stimulation. The loss of estrogen stimulation after surgical removal of ovaries results in atrophy of the endometrium, and breast.

40. Senile atrophy of the brain Normal brain

41. Metaplasia • Definition: Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. • It may represent an adaptive substitution of cells that are sensitive to stress by cell types better able to resist the adverse environment. • Types: • Epithelial metaplasia • Connective tissue metaplasia

42. Metaplasia I- Epithelial Metaplasia • Metaplasia from columnar to squamous: 1- The lungs, in cigarette smokers. The ciliated columnar epithelial cells of the bronchi are replaced by stratified squamous epithelial cells (may change to cancer). 2- Stones in the gall bladder may cause replacement of the normal secretory columnar epithelium by nonfunctioning stratified squamous epithelium. • Metaplasia from transitional to squamousin urinary bladder in case of schistosomal cystitis. • Metaplasia from squamous to columnar typemay occur, as in Barrett esophagus, under the influence of refluxed gastric acid. II-Connective tissue metaplasia:For example, bone formation in muscle, designated myositis ossificans, occasionally occurs after bone fracture and trauma.

43. Epithelial Metaplasia

44. Pathologic Calcification • Pathologic calcification is the abnormal tissue deposition of calcium salts. It is a common process occurring in a variety of pathologic conditions. There are two forms of pathologic calcification. • I – Dystrophic calcification ( most common type) • Dystrophic calcification is encountered in dying or necrotic tissue, in spite of normal blood calcium level. It is due to breakdown of organic phosphate and change of PH in dead tissue, which favour calcium deposition and formation of calcium phosphate crystals. • Examples: caseous tuberculous lesion, dead parasites and ova, fat necrosis, atherosclerosis, venous thrombi, tumours, haematoma and lithopedion.

45. Pathologic Calcification • II-Metastatic Calcification • Metastatic calcification may occur in normal tissues in presence of hypercalcemia. • Causes of hypercalcemia: • (1) Increased secretion of parathyroid hormone (PTH) with subsequent bone resorption, as in hyperparathyroidism. • (2) Destruction of bone tissue, occurring with primary and metastatic bone tumors. • (3) Hyper-vitaminosis D. • (4) Renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism. • Less common causes include milk-alkali syndrome, which is due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate.

46. Pathologic Calcification • Sites: Metastatic calcification may occur widely throughout the body but principally affects tissue with relative alkalinity including the gastric mucosa, kidneys, lungs, and systemic arteries. • In all sites, the calcium salts morphologically occur as chalky amorphous white deposits. •  Idiopathic Calcinosis: This is a rare condition of calcification of unknown aetiology that may affect skin or other soft tissues in a localized or generalized distribution.

47. Cellular Aging Cellular aging is the result of • Progressive decline in the proliferative capacity and life span of cells • And the effects of continuous exposure to exogenous influences that result in the progressive accumulation of cellular and molecular damage.

48. Cellular Aging • Replicative Senescence. After a fixed number of divisions, all cells become arrested in a terminally non-dividing state, known as cellular senescence. • The dividing cells can count their divisions, through telomere shortening, which ultimately results in cell cycle arrest. • Telomeresare short repeated sequences of DNA present at the linear ends of chromosomes that are important for ensuring the complete replication of chromosome. • When somatic cells replicate, the telomeres become progressively shortened. • As the telomeres become short, the cell cycle arrested.

49. Cellular Aging • The lengths of the telomeres are normally maintained by an enzyme called telomerase. • Telomerase activity is expressed in germ cells and is present at low levels in stem cells, but it is usually absent in most somatic tissues. • Therefore, as cells age, their telomeres become shorter, and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones. • Conversely, in immortal cancer cells, telomerase is reactivated, and telomeres are not shortened.