Cellular Adaptation And Injury

Front 1

What is the result of increased production of cellular proteins ?

Back 1

Hypertrophy

Hint 1

Na mumu dey fail this one

Front 2

3 factors hypertrophy is induced by

Back 2

Physiologic demands, hormones and growth factors

Hint 2

No

Front 3

What is hypertrophy?

Back 3

Increased cell size which leads to increased organ size . Physiologic or pathologic

Front 4

Examples of physiologic hypertrophy

Back 4

Uterus during pregnancy, muscles of weight lifters

Front 5

Example of pathologic hypertrophy

Back 5

Enlarged LV wall in hypertensive heart disease

Hint 5

None.

Front 6

Define hyperplasia

Back 6

Increased cell number in an organ or tissue resulting in increased MASS or the organ or tissue. Physiologic or pathologic.

Front 7

Types of physiologic hyperplasia

Back 7

1. Hormonal - proliferation of glandular epithelium of female breast at puberty and pregnancy

2- Compensatory I.e regrowth of liver after hepatectomy

Front 8

Pathologic hyperplasia may be caused by:

Back 8

1. Excess hormones or growth factors e.g. Endometrial hyperplasia, benign prostatic hyperplasia. 2. Viral infections e.g. papilloma virus causing skin warts in which there is hyperplasia of the epithelium.

Front 9

Hyperplasia and hypertrophy may occur together. True or false?

Back 9

True duhh

Front 10

Atrophy is?

Back 10

Atrophy is the reduced size of an organ or tissue resulting from a decrease in cell SIZE AND NUMBER.

Front 11

Physiologic atrophy e.g.

Back 11

Physiologic atrophy e.g. 1. Regression of the thyroglosal duct and notocord during fetal development. 2. Reduction in size of uterus after giving birth

Front 12

6 Pathologic atrophy causes:

Back 12

1.Decreased workload (atrophy of disuse) 2. Loss of innervation 3. Diminished blood supply 4. Inadequate nutrition 5. Loss of endocrine stimulation 6. Pressure atrophy

Front 13

Two Mechanisms of atrophy

Back 13

Two Mechanisms of atrophy 1. Atrophy results from decreased protein synthesis and increased protein degradation. Degradation occurs by the ubiquitinproteosome pathway. 2. Autophagy: cell eats itself to survive.

Front 14

Define metaplasia

Back 14

Metaplasia is an adaptive substitution of cells in which one differentiated cell type is replaced by another adult cell type.

Front 15

3 examples of metaplasia

Back 15

Ciliated columnar to squamous in trachea and bronchi of smokers 2. Squamous to columnar in Barrett eosophagus 3. Myositis ossificans>> formation of bone in muscle

Front 16

Mechanism of metaplasia??

Back 16

Cytokines, growth factors and components of the extracellular matrix around the cells stimulate the precursor cells present to differentiate towards a particular lineage. • Metaplasia, thus, results from reprogramming of the stem cells to produce adult cells which can with stand the stress placed on the tissue.

Front 17

Cell Injury types and causes

Back 17

Reversible 2. Irreversible.

1. Oxygen deprivation 2. Physical agents 3. Chemical agents 4. Infectious agents 5. Immunological reactions 6. Genetic derangements 7. Nutritional imbalances

Front 18

2 REVERSIBLE INJURY CHANGES??

Back 18

-Cell swelling – Fatty change

Front 19

Gross vs microscope view in reversible injury

Back 19

Gross: organ is appear enlarged, some pallor, increased turgor, increased weight and size. • Microscopic: clear vacuoles in the cytoplasm >> > this is hydropic change or vacuolar degeneration.

Front 20

4 Ultrastructural changes in reversible cell injury

Back 20

• Ultrastructural changes: 1. Plasma membrane: Blebbing, blunting, loss of microvilli in plasma membrane. 2. Mitochondrial: swelling and amorphous densitis. 3. Endoplasmic reticulum: dilation, detachment of polysomes 4. Nucleus: disaggregation of granular and fibrillar elements.

Front 21

Cytoplasmic and nuclear changes in irreversible Injury (necrosis)

Back 21

Cytoplasm: – Increased eosinophilia –Glassy homogenous appearance –myelin figures – Calcification, occassionally. • Nuclear changes: – Karyolysis – Pyknosis – karyorrhexis

Front 22

Two principal types of cell death and Other pathways to cell death include.

Back 22

Two principal types of cell death: 1. Necrosis 2. Apoptosis • Other pathways to cell death include: 1. Necroptosis 2. Pyroptosis 3. Feroptosis 4. Autophagy

Front 23

Define necrosis

Back 23

NECROSIS is the sum of morphological changes that follow cell death in a living tissue or organ.

Front 24

Necrosis vs putrefaction

Back 24

Necrosis occurs in living tissue, putrefaction occurs in dead.

Front 25

6 patterns of necrosis

Back 25

1.Coagulative 2. Liquifactive 3. Gangrenous 4. Caseous 5. Fat necrosis 6. Fibrinoid necrosis Coagulative and liquifactive necrosis are the principal patterns of necrosis.

Front 26

Six mechanisms of cell injury :

Back 26

1. ATP depletion 2. Mitochondrial damage 3. Increased cytosolic calcium 4. Increased reactive oxygen species 5. Plasma and lysosomal membrane damage 6. Protein misfolding and DNA damage

Front 27

3 primary outcomes of ATP depletion

Back 27

1. Decreased Na+ pump >> increased influx of Ca2+, water and Na+ >>> ER swelling, cellular swelling, loss of microvilli and blebs. 2. Increased anaerobic glycolysis >> decreased glycogen, increased lactic acid and decreased pH >>> clumping of nuclear chromatin. 3. Detachment of ribosomes >> decreased protein synthesis >>> lipid deposition.

Front 28

Two outcomes result from mitochondrial damage

Back 28

1. Formation of mitochondrial permeability transition pore >> loss of membrane potential >>> inability to generate ATP >>> Necrosis. 2. Leakage of cytochrome C and other proapoptotic proteins >> Apoptosis

Front 29

Increased cytotoxic calcium mechanisms:

Back 29

Has three major consequences: 1. Plasma membrane damage: result from activation of phospholipase and protease. 2. Nuclear membrane damage: resulting from activation of endonuclease. 3. Decreased ATP: because of increased mitochondrial permeability transition. ATPase is also activated.

Front 30

Free radicals are

Back 30

Free radicals are chemical species that have a single unpaired electrons in an outer orbit. • This makes them unstable and very quickly react with any adjacent molecules and compounds like proteins, carbohydrates and fats, nucleic acids, etc. • Free radical induced injury occurs in conditions such as chemical and radiation injury, reperfusion injury, cellular aging, etc.

Front 31

Free radical may be generated by:

Free radical may be generated by:

Back 31

1. REDOX reactions during normal metabolism. 2. Absorption of radiant energy (UV light, Xray). 3. During inflammation by activated leukocytes. 4. Enzymatic metabolism of exogenous chemicals or drugs. 5. Transition metals eg iron and copper. 6. Nitric oxide.

Front 32

Removal of free radicals occur by:

Back 32

1. Antioxidants eg vit E, vit A, ascobic acid, glutathione. 2. Metal binding plasma proteins eg transferrin, ferritin, lactoferrin, cerruloplasmin. 3. Enzymes such as: catalase, superoxide dismutase, glutathione peroxidase.

Front 33

Free radicals cause damage to cells by 3 methods:

Back 33

1. Lipid peroxidation in membranes. – Membrane lipids are converted to peroxides, also unstable leading to extensive membrane damage. 2. Oxidative modification of proteins. – Oxidation of amino-acid side chains – Protein-protein cross-linkage formation – Oxidation of protein back bone 3. Lesions in DNA: – Single and double stranded breaks. – Cross-linking of DNA strands – Formation of adducts

Front 34

Four mechanisms of membrane damage:

Back 34

1. Reactive oxygen species (ROS). 2. Reduced phospholipids synthesis because of ATP depletion. 3. Increased phospholipids breakdown caused by increased cytosolic calcium 4. Cytoskeletal abnormalities caused also by increased cytosolic calcium.

Front 35

Three consequences of membrane damage:

Back 35

1. Mitochondrial membrane damage – ATP depletion – Release of pro-apoptotic proteins. 2. Plasma membrane damage – Loss of osmotic balance – Influx of fluids and ions – Loss of cellular contents 3. Lysosomal membrane damage: – Leakage of enzymes into cytoplasm – RNase, Dnase, proteases, phosphatases, etc

Front 36

Apoptosis vs Necroptosis

Back 36

Apoptosis is genetically programmed cell death. Necroptosis is a distinct process which resembles necrosis morphologically, but it is a genetically controlled form of cell death. Apoptosis may be physiologic or pathologic.

Front 37

Physiologic apoptosis examples

Back 37

Programmed destruction of cells during embryogenesis 2. Involution of hormone dependent tissues upon hormone withdrawal eg endometrium in menstrual cycle. 3. Cell loss in proliferating cell populations immature lymphocytes in bone marrow. 4. Elimination of potentially harmful self reactive lymphocytes. 5. Removal of neutrophils and lymphocytes, at the end of immune response or inflammation.

Front 38

Pathologic apoptosis examples

Back 38

1. DNA damage 2. Accumulation of mis-folded proteins: – ER stress (induced by excess proteins in ER), – Responsible for neurodegerative diseases 3. Viral infections: – induced by cytotoxic T cells 4. Pathologic atrophy in parenchymal organs after duct obstruction

Front 39

What are the phases and pathways of apoptosis?

Back 39

Process of apoptosis dived into 2 phases: 1. Initiation phase 2. Execution phase • Initiation occurs by 2 pathways: 1. Intrinsic [mitochondrial pathway] pathway 2. Extrinsic [death receptor initiated] pathway

Front 40

Examples of

Anti-apoptotic: • Pro-apoptotic: • Regulated apoptosis initiators:

Back 40

Anti-apoptotic: BCL-2, BCL-XL , MCL-1 • Pro-apoptotic: BAX and BAK • Regulated apoptosis initiators: BIM, BID, BAD, Puma, Noxa. These are modulated by sensors of cellular stress and damage; when upregulated and activated, they can initiate apoptosis.

Front 41

Bim, Bid or Bad activate Bax and Bak when the cells are :_______

Back 41

Bim, Bid or Bad activate Bax and Bak when the cells are : – Deprived of survival signals – DNA damaged – Misfolded proteins induce ER stress

Front 42

________ form oligomers which insert into the mitochondrial membrane and create channels which allow proteins [cytochrome c] from the inner mitochondrial membrane to leak out. • They also block the function of anti-apoptotic proteins [Bcl2 and Bclx].

Back 42

Bax and Bak form oligomers which insert into the mitochondrial membrane and create channels which allow proteins [cytochrome c] from the inner mitochondrial membrane to leak out. • They also block the function of anti-apoptotic proteins [Bcl2 and Bclx].

Front 43

Actions of executioner phases?

Back 43

1. Cleave cytoskeletal and nuclear matrix proteins. 2. Disrupt the cytoskeleton 3. Nuclear breakdown 4. Cleave proteins involved in transcription, DNA replication, and DNA repair.

Front 44

_________ stain is used to identify apoptotic cells • The process of apoptotic cell phagocytosis is called ________.

Back 44

Annexin V stain is used to identify apoptotic cells • The process of apoptotic cell phagocytosis is called efferocytosis.

Front 45

Disorders associated with excessive apoptosis • Leads to excessive cell death. • Examples include: _______

Back 45

Disorders associated with excessive apoptosis • Leads to excessive cell death. • Examples include: 1. Neurodegerative diseases. 2. Ischaemic injury : MI, stroke. 3. Death of virus infected cells.

Front 46

____<< is the abnormal tissue deposition of calcium salts and small amounts of iron, magnesium and other salts. Two forms of pathological calcification recognised:

Back 46

Pathologic calcification is the abnormal tissue deposition of calcium salts and small amounts of iron, magnesium and other salts. Two forms of pathological calcification recognised: 1. Dystrophic calcification 2. Metastatic calcification

Front 47

Dystrophic calcification occurs in ____ • Appear grossly as gritty deposits. • Microscopic view: ???______ appearance. • Asbestos bodies appearing beaded in the lungs. bone may form. • Psammoma bodies in some papillary cancers.

Back 47

Dystrophic calcification occurs in area of necrosis. • Appear grossly as gritty deposits. • Microscopic: appear as basophilic , amorphous granular, sometimes clumped appearance. • Heterotopic bone may form. • Psammoma bodies in some papillary cancers. • Asbestos bodies appearing beaded in the lungs.

Front 48

What is the pathogenesis of dystrophic calcification?

Back 48

Deposition ultimately involve the precipitation of a crystalline calcium phosphate similar to bone hydroxyapatite.

Front 49

What are the phases of dystrophic calcification?

Back 49

• 2 phases >>> initiation and propagation. 1. Initiation: extracellular or intracellular. • Extracellular : occurs on membrane bound vesicles containing charged phospholipids; phosphates formed binds to calcium.

Intracellular: ca2+ is deposited in the mitochondria of dead or dying cells. 2. Propagation of crystal formation: depends on the concentration of calcium and phosphates, the presence of inhibitors and the structural components of the extracellular matrix.

Front 50

_________ is abnormal deposition of calcium in normal tissues when there is hypercalcemia.

Back 50

Metastatic calcification is abnormal deposition of calcium in normal tissues when there is hypercalcemia.

Front 51

What are the causes of metastatic calcification?

Back 51

Four principal causes: 1. Increased secretion of parathyroid hormone. 2. Bone destruction, eg, multiple myeloma, bone metastasis, immobilisation, Pagets dx 3. Vitamin D-related disorders, eg vitD intoxication, sarcoidosis, Williams synd(IHcI) 4. Renal failure, >>> retention of phosphate>>> secondary hyperparathyroidism.

Front 52

Cellular aging is ____

Back 52

Cellular aging is the result of steady decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences.

Front 53

• The functional and structural changes in aging are influenced by??

Back 53

The functional and structural changes in aging are influenced by genetic factors, diet, social conditions, and the presence of age related diseases such as diabetes mellitus, atherosclerosis and osteoarthritis.

Front 54

______ is believed to increase longevity both by reducing the signaling intensity of the IGF-1 pathway and by increasing sirtuins.

Back 54

Caloric restriction is believed to increase longevity both by reducing the signaling intensity of the IGF-1 pathway and by increasing sirtuins.

Front 55

Attenuation of IGF-1 signaling leads to _______. • ______ promote genomic integrity by activating DNA repair enzymes

Back 55

Attenuation of IGF-1 signaling leads to lower rates of cell growth and metabolism and possibly reduced cellular damage. • Sirtuins promote genomic integrity by activating DNA repair enzymes

Front 56

What are the causes of cellular aging ?

Back 56

DNA Damage • Cellular Senescence – Telomere attrition – Activation of tumor suppressor genes • Defective Protein Homeostasis • Dysregulated Nutrient Sensing – Insulin and insulin-like growth factor 1 (IGF- 1) signaling pathway; – Sirtuins