Cellular response to stress and toxic insults: adaptation, injury, and death Flashcards Preview

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Flashcards in Cellular response to stress and toxic insults: adaptation, injury, and death Deck (50):
1

What is adaptation?

Adaptations are reversible functional and structural responses to changes in physiologic states and some pathologic stimuli, during which new but altered steady states are achieves, allowing cell to survive and continue to function. When the stress is eliminated the cell can recover to its original state.

2

What is hypertrophy? What types are there? What causes it?

An increase in the size of cells resulting in an increase in the size of the organ. It can be physiologic (enlargement of uterus during pregnancy) or pathologic (enlargement of cardiac muscle due to hypertension) and is caused either by increased functional demand (workload) or by growth factor or hormonal stimulation.

3

Name 3 transcription factors important in hypertrophy!
What are there function?

GATA4
NFAT
MEF2
Increase protein synthesis

4

What are the pathogenesis of hypertrophy?

Hypertrophy is the result of increased production of cellular proteins.
Three basic steps in the molecular pathogenesis of cardiac hypertrophy:

- The integrated actions of mechanical sensors (increased workload), growth factors (TGF-beta, IGF1, fibroblast growth factor) and vasoactive agents (alfa-adrenergic agonists, endothelin-1, and angiotensin II).

- These signals originating in the cell membrane activate a complex web of signal transduction pathways. Two such biochemical pathways involved in muscle hypertrophy are the phosphoinositide 3-kinase (PI3K)/ AKT pathway (important in physiologic, exercise-induced, hypertrophy) and signaling downstream of G-protein-coupled receptors (induced by many growth factors and vasoactive agents, important in pathologic hypertrophy).

- These signaling pathways activate a set of transcription factors such as GATA4, nuclear factors of activated T cells (NFAT), and myocytes enhancer factor 2 (MEF2). These transcription factors work coordinately to increase the synthesis of muscle protein that are responsible for hypertrophy.

5

List biochemical pathways involved in muscle hypertrophy!

The phosphoinositide 3-kinase (PI3K)/ AKT pathway (important in physiologic, exercise-induced, hypertrophy) and signaling downstream of G-protein-coupled receptors (induced by many growth factors and vasoactive agents, important in pathologic hypertrophy).

6

What is hyperplasia?

An increase in the number of cells due to the increased cell mitosis.

7

List the types of hyperplasia1


- Physiologic hyperplasia:
. Compensatory hyperplasia permits tissue and organ regeneration. Example: when part of a liver is resected.
. Hormonal hyperplasia occurs in organs that depend on oestrogen. Example: proliferation of the glandular epithelium of the female breast at puberty.
- Pathologic hyperplasia is caused by excessive or inappropriate actions of hormone or growth factors acting on target cells. Patient with pathological hyperplasia are at a higher risk for developing endometrial cancer.

8

What is atrophy?

Is shrinkage in the size of cells by the loss of cell substance (autophagy). Atrophic cells may have diminished function, they are not dead.

9

what causes atrophy?

Causes: decrease workload, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, and aging.

Cellular atrophy results from a combination of decreased protein synthesis (due to reduced metabolic activity) and increased protein degradation (by ubiquitin ligases). It is accompanied by increased autophagy.

10

What is metaplasia?

Occur when a differentiated cell of a certain type is replaced by another cell type, which may be less differentiated but able to withstand the adverse environment.
The influences that induce metaplastic changes in an epithelium, if persistent, may predispose to malignant transformation in the metaplastic epithelium.

11

What are the mechanisms of metaplasia?

Metaplasia doesn’t result from a change in the phenotype of an already differentiated cell type; instead it is the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells. The differentiation of stem cells is brought about by signals generated by cytokines, growth factors, and extracellular matrix components in the cells’ environment.
Retinoic acid regulates gene transcription directly through nucleus retinoid receptor, which can influence the differentiation of progenitors derived from tissue stem cells.

12

what is dysplasia?

An abnormal change in cellular shape, size, and/or organization.

13

What are the morphology of necrosis?

Necrotic cells show increased eosinophilia in haematoxylin and eosin stains, attributable in part of the loss of cytoplasmic RNA and in part to denatured cytoplasmic proteins. Dead cells may be replaced by large, whorled phospholipid masses called myelin figures that are derived from damage cell membrane. These phospholipids are either phagocytosed or degraded into fatty acids; calcification of such fatty acid may result in calcium soaps. The dead cells may become calcified.

14

what are the nuclear changes pattern during necrosis?

Nuclear changes patterns:
- Karyolysis: a change that presumable reflects loss of DNA because of enzymatic degradation by endonucleases.

- Pyknosis - characterized by nuclear shrinkage and increased basophilia. Here the chromatin condenses into a solid, shrunken basophilic mass.

- Karyorrhexis: the pyknotic nucleus undergoes fragmentation and then totally disappear.

15

List the six pattern of necrosis!

Coagulation necrosis
Liquefactive Necrosis
Gangrenous necrosis
Canceous necrosis
Fat necrosis
Fribrinoid necrosis

16

Talk about coagulation necrosis!

Coagulation necrosis is characteristic of infarcts in all solid organs except the brain. When the underlying tissue architecture is preserved for at least several days after death of cells in the tissue. The affected tissue takes on a firm texture. The injury denatures the
structural proteins and enzymes, thereby blocking the proteolysis of the dead cells; eosinophilic, anucleate cells may persists for days or weeks. Leukocytes are then recruited to digest by the action of lysosomal enzymes.

17

Talk about liquefactive necrosis!

Liquefactive necrosis is characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass. Seen in focal bacterial or fungal infections because microbes stimulate the accumulation of leukocytes. Hypoxic death of cell within the central nervous system often manifests as liquefactive necrosis.

18

Talk about gangernous necrosis!

Gangrenous necrosis applied to a limb that has lost its blood supply and has undergone necrosis involving multiple tissue planes.

19

Talk about Fat necrosis!

Fat necrosis refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. The pancreatic enzymes leak out of acinar cells and liquefy the membranes of fat cells in the peritoneum. The released lipases split the triglyceride esters contained within fat cells. The fatty acids combine with calcium to produce grossly visible chalky-white areas.

20

Talk about caseous necrosis

Caseous necrosis is encountered in foci of tuberculous infection. The necrotic area appears as a structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border.

21

Talk about fibrinoid necrosis!

Fibrinoid necrosis is usually seen in immune reactions involving blood vessels. This pattern of necrosis typically occurs when complexes of antigens and antibodies are deposited in the walls of arteries. These complexes and plasma protein produce a bright pink appearance.

22

What are the consequences of mitochondrial damage?

Mitochondrial damage
Mitochondria can be damaged by increases of cytosolic Ca2+, reactive oxygen species, and oxygen deprivation.
Consequences of mitochondrial damage:
- Mitochondrial damage results in formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pore. The opening of this conductance channels lead to loss of mitochondrial membrane potential, resulting in failure of oxidative phosphorylation and progressive depletion of ATP, cell necrosis. One of the components of the mitochondrial permeability transition pore is the protein cyclophilin D (target by the immunosuppressive drug).
- Abnormal oxidative phosphorylation that lead to the formation of reactive oxygen species.
- Mitochondria protein between the outer and inner membranes capable activating apoptotic pathways; these include cytochrome c.

23

What happens when calcium homeostasis is lost?

Calcium protects cells from injury induced by harmful stimuli. Ischemic cause an increase in cytosolic calcium concentration, because of release of calcium from intracellular store and increased influx across membrane.

24

Explain hydropic swelling during cellular damage!

Hydropic swelling is an increase in water content of the cytoplasm in the cell. This can be caused due to the failure of Na+/K+ pump.
During ischemia (lack of adequate blood flow), tissues are deprived of oxygen, ATP can’t be produced by aerobic metabolism and is instead made inefficiently by anaerobic metabolism. This initiates a series of chemical and pH imbalances, which are accompanied by increase generation of injurious free radical.

25

what is oxidative stress?

Oxidative stress is increased production and decreased scavenging of ROS may lead to an excess of free radicals.

26

How is superoxide is built?

Superoxide: is produced by leaks in mitochondrial electron transport or as part of inflammatory response.
- Promiscuity of CoQ and other imperfections in the electron transport chain allow transfer of electron to O2 to yield O2-.
- Phagocytic inflammatory cells, activation of a plasma membrane oxidase produce O2-, which is then converted to H2O2 and to other ROS to destroy pathogens.

27

How hydrogen peroxide is built?

Hydrogen peroxide: when H2O2 in excess, it is converted to highly reactive OH•. Neutrophils transfer H2O2 to a radicle to kill microorganisms and, if released extracellularly, can kill the cell.
Cells remove H2O2 by reducing it to water.

28

How hydroxyl radical are built?

Hydroxyl radical (OH•): formed by (1) radiolysis of water, (2) reaction of H2O2 with Fe2+ or CU1+ (3) conversion of O2- with H2O2. H2O2 stimulates iron uptake and increases production of hydroxyl radicals.
- Lipid peroxidation: Hydroxyl radical removes hydrogen atom from unsaturated fatty acids in membrane phospholipids to form free radical. Lipid radical can act with oxygen to form lipid peroxide that can remove H+ from other lipids.
- Protein interactions: hydrogen radical can attack protein (especially amino acid that contain sulphur) resulting in oxidative damage, protein undergo fragmentation, cross-linking, aggregation and degradation.
- Sugar: hydrogen radical can attack sugar to form reactive intermediate that modify proteins.
- DNA damage: Hydrogen radical can cause diverse alternation in DNA including strand breaks, modified bases and cross-links between strands.

29

what are the defence mechanism against ROS?

Detoxifying enzymes
- SOD (Superoxide dismutase) and Catalase defend cells against O2-, converting it to H2O2 and O2.
- GPX (glutathione peroxidase) catalyses the reduction of H2O2 and lipid peroxides in mitochondria and cytosol.

Scavengers of ROS
- Vitamin E (alfa-tocopherol) is a terminal electron acceptor that aborts free radical chain reactions. It is fat soluble and can protect the membrane against lipid peroxidation.
- Vitamin C (ascorbate) is water soluble and react with O2, OH• and some products of lipid peroxidation. It regenerates the reduced form of vitamin E.
- Retinoids (precursors of vitamins A) are lipid soluble and act as chain-breaking antioxidants.
- NO•

Albumin, glutathione, ascorbate (vitamin C), -tocopherol (vitamin E) and an extracellular form of SOD act as extracellular antioxidants.
Oxidative stress in the extracellular matrix can cause damage to collagen, elastin, fibronectin, laminin and basement membrane. This may lead to damage in skin, bone and cartilage.

30

what are the mechanisms of membrane damage?

Mechanism of membrane damage
- Reactive oxygen species that can injure the cell membrane by lipid peroxidation.
- Decreased phospholipid synthesis as a result of a defective mitochondrial function or hypoxia.
- Increased phospholipid breakdown – lipid breakdown products, including unesterified have a detergent effect on membrane.

-- Cytoskeletal abnormalities which cause the cell membrane to stretch and rupture.

31

what is the function of P53?

p53 helps to prevent and repair DNA damage. It can orchestrate cellular metabolic activity in response to levels of oxidative stress. If DNA damages is irreparable, p53 activate cell death programs.
Under normal condition, p53 promote expression of many antioxidant genes, thus promoting cell survival. During severe oxidant stress, p53 activate target genes that impair oxidant defences, allow cellular damage to accumulate and eventuate in cell death. p53 directs metabolic pathways that reinforce its transcriptional activity.

32

what are the mechanism of ischemic cell injury?

- Decrease of ATP production with result in efflux of K+, influx of Na+, water and influx of Ca2+. Loss of glycogen and decreased protein synthesis. The cell and its organelles starts also to swell. IF oxygen is restored, all these disturbances are reversible.
- If ischemia persists, irreversible injury and necrosis ensue. Irreversible injury is associated morphologically with severe swelling of mitochondria, extensive damage to plasma membrane and swelling of lysosomes. Cell death can occur by apoptosis (pro-apoptotic molecules from leaky mitochondria) or necrosis.

33

What are the protective response to deal with hypoxic stress?


- Hypoxia-inducible factor-1 promote new blood vessel formation, stimulate cell survival pathways, and enhances anaerobic glycolysis.


Ischemia-reperfusion injury is tissue damage caused when blood supply returns to tissue after a period of ischemia or hypoxia.

34

what can cause hypoxic stress?

- Oxidative stress – caused by reoxygenation by increased generation of reactive oxygen and nitrogen species.
- Intracellular calcium overload
- Inflammation and activation of complement system which cause tissue injury.

35

what is ischemia-reperfusion injury?

Ischemia-reperfusion injury is tissue damage caused when blood supply returns to tissue after a period of ischemia or hypoxia.

36

Explain the mechanism behind endoplasmic reticulum stress!

Accumulation of misfolded proteins in a cell can stress compensatory pathways in the ER and lead to cell death by apoptosis (proapoptotic sensors of the BH3-only family).
Deprivation of glucose and oxygen, as in ischemia and hypoxia, may increase the burden of misfolded proteins.

37

Give example of anit-apoptic Bcl2 family protien!

Bcl2 and Bclxl

38

Give example of pro-apoptotic Bcl2 family protein!

Bax, Bak

39

Give an example of pro-apoptotic BH3-only protein

Bad, Bim, Puma, Noxa

40

Explain the morphological of necrosis!

Morphologically, it resembles necrosis, both characterized by loss of ATP, swelling of the cell and organelles, generation of ROS.

41

Explain the mechanism of necroptosis!

Mechanistically, it is trigged by genetically programmed signal transduction events that culminate in cell death.
Necroptosis involves to unique kinases called receptor associated kinase 1 and 3 (RIP1 and RIP3). Caspases are not activated and in necrosis the terminal events include permeabilization of lysosomal membrane, generation of ROS, damage to the mitochondria, and reduction of ATP levels.

42

what is pytoptosis?

Pyroptosis is programmed cell death that accompanied by the release of fever inducing cytokine IL-1. It results in the death of some microbes that gain access to the cytosol and promote the release of inflammasome-generated IL-1.

43

what are the types of autophagy?

- Chaperone-mediated autophagy
- Microautophagy
- Macroautophagy

44

what are the step of autophagy?

Steps:
- Formation of an isolation membrane and its nucleation.
- Elongation of the vesicle
- Maturation of autophagosome, its fusion with lysosome.

45

what are the pathways for abnormal intracellular accumulation?

Pathways of abnormal intracellular accumulations:
- Defect in mechanisms of packaging and transport, as in fatty change (steatosis) in the liver.
- Accumulation of an abnormal endogenous substance as a result of genetic or acquired defects in its folding, packaging, transport, or secretion, and certain mutated forms of 1-antitrypsin.
- Failure to degrade a metabolite due to inherited enzyme deficiencies.

- Accumulation of an abnormal exogenous substance.

46

What are the causes of lipid accumulation? which organs is mostly at risk?

Abnormal accumulations of triglycerides within parenchymal cells. Fatty change is often seen in the liver because it is the major organ involved in fat metabolism.
Causes include toxins (alcohol), protein malnutrition, diabetes, mellitus, anoxia and obesity.

47

What is hemosiderin? What are the causes?

Hemosiderin, a haemoglobin-derived, golden yellow-to-brown, granular or crystalline pigment. Ferritin forms hemosiderin granules, when there is a local or systemic excess of iron. Main cause of hemosiderosis are (1) increased absorption of dietary iron, (2) hemolytic anemias, in which premature lysis of red cells leads to release of abnormal quantities of iron, and (3) repeated blood transfusions, because transfused red cells constitute an exogenous load of iron.

48

What is destructive calcification?

Dystrophic calcification
Dystrophic calcification is encountered in areas of necrosis. It develops in aging or damaged heart valves. Sometime a tuberculous lymph node is converted to stone. It causes organ dysfunction.

49

What is matastatic calcification?

Occur in normal tissue whenever there is hypercalcemia. Principal causes of hypercalcemia: (1) increased secretion of parathyroid hormone with subsequent bone resorption; (2) resorption of bone tissue (3) vitamin D-related disorder (4) renal failure, which causes retention of phosphate, leading to secondary hyperparathyroidism.

50

How does sirtuins increases longevity?

- Sirtuins promote the expression of several genes whose products increase longevity. These proteins inhibit metabolic activity, reduce apoptosis, stimulate protein folding, and inhibit the harmful effects of oxygen free radicals. Sirtuins increase insulin sensitivity and glucose metabolism.