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Disease & Defense > PI session 1 > Flashcards

PI session 1 Flashcards

1
Q

What is cell death?

A

Irreversible severe cell injury that exceeds attempts at repair or adaptation induces cell death

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2
Q

What are the two distictive forms of cell death?

A
  • Apoptosis
  • Necrosis
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3
Q

Why does apoptosis occur?

A
  • cell no longer needed by the body
  • OR it is damaged beyond repair
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4
Q

Why is there no inflammatory response associated with apoptosis?

A
  • Dissolution of nucleus without perforation of cell membrane
  • Prevents cell contents from leaking into extracellular matrix
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4
Q

Why is there no inflammatory response associated with apoptosis?

A
  • Dissolution of nucleus without perforation of cell membrane
  • Prevents cell contents from leaking into extracellular matrix
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5
Q

Cells destined to die activate intrinsic enzymes that degrade genomic DNA and nuclear and cytoplasmic proteins. These enzymes are called what?

A

Caspases

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6
Q

What 2 pathways converge on caspase activation?

A
  • Mitochondrial pathway (intrinsic) - mitochondrial membrane becomes more permeable and releases pro-apoptotic molecules
  • Death receptor pathway (extrinsic) - activates inflammatory cascade
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7
Q

What are the anti-apoptotic proteins in the intrinsic pathway?

A

BCL2, BCL-xL, and MCL1

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8
Q

What are the pro-apoptotic proteins in the intrinsic pathway?

A

BAX and BAK

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9
Q

What are the regulated apoptosis initiator proteins?

A

BAD, BIM, BID, Puma, and Noxa

sensors of cellular stress/damage & initiate apoptosis when activated

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10
Q

What occurs in the intrinsic (mitochondrial) pathway of apoptosis?

A
  • Growth factors and other survival signals stimulate BCL2, protecting cells from apoptosis
  • When no signals are sent, or in the case of DNA damage or ER stress, BH3-only proteins (apoptosis initiators) are upregulated
  • BH3-only proteins activate BAX and BAK which insert into mitochondrial membrane forming the permeability transition pore
  • Results in cytochrome C leaking into the cytoplasm and binding to APAF-1 (apoptosis activating factor) and forms an apoptosome which binds CASPASE-9
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11
Q

Explain the extrinsic (death receptor-activated) pathway with regards to Fas.

A
  • When FasL binds to Fas, 3 or more molecules of Fas are brought together along the inner cell membrane, and their collective cytoplasmic death domains form a binding site for an adapter protein called FADD (Fas-associated death domain)
  • FADD then binds to Caspase-8 (or caspase-10), activating the EXECUTIONER caspase sequence of the extrinsic path
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12
Q

What is karyolysis?

A
  • Basophilia of the nucleus fades
  • Loss of DNA due to enzymatic destruction
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13
Q

What is pyknosis?

A
  • Nuclear shrinkage and increased basophilia
  • Chromatin condenses into a ‘dense, shrunken basophilic mass
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14
Q

What is karyorrhexis?

A
  • Pyknotic nucleus undergoes fragmentation
  • Within 1-2 days, the nucleus in the necrotic cell totally disappears
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15
Q

What are the 6 patterns of tissue necrosis?

A
  • Coagulative
  • Liquefactive
  • Gangrenous
  • Caseous
  • Fat
  • Fibrinoid
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16
Q

What occurs in coagulative necrosis?

A
  • Denaturation of structural proteins and enzymes
  • Shadow of dead cells/tissue persists for days
  • Leukocytes eventually remove dead cells
  • Classic example: infarcts (ischemic necrosis) in solid organs

Brain infarcts are an exception–> Liquefactive instead

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17
Q

On histology slides, necrotic cells will lack what organelle?

A

Nucleus

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18
Q

What are the gross appearance characteristics of infarcts?

A
  • Firm
  • Located near periphery of organ
  • “Wedge shaped” (like triangle pointing toward center of organ)
  • Pale/white, except for in lungs where it is red
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19
Q

What is liquefactive necrosis?

A
  • Dead cells completely digested into viscous liquid
  • Examples: Abscess d/t bacterial infection; Infarct in brain/CNS
  • If abundant inflammation (neutrophils): pus
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20
Q

What is gangrenous necrosis?

A
  • Not a specific pattern of cell death, but commonly used in clinical practice
  • Coagulative necrosis involving a limb (lower leg)
  • Superimposed bacterial infection attracting leukocytes and degradative enzymes causing liquefactive necrosis
  • Combination causes so-called wet gangrene
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21
Q

What is caseous necrosis?

A
  • Grossly has a soft, pale, crumbly/friable “cheesy” look
  • Buzzword for Tuberculosis
  • Characteristic of a focus of inflammation called a granuloma
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22
Q

What is fat necrosis?

A
  • Focal areas of fat destruction
  • Enzymes leak out of damage cells and liquefy membranes of fat cells in the peritoneum
  • Typical of NECROTIZING PANCREATITIS - (abdominal emergency caused by leaking pancreatic lipases)
  • Fat saponification: chalky white material - broken down lipid combines with calcium to make soap-like substance
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23
Q

What is fibrinoid necrosis?

A
  • Special form of vascular damage - Amorphous pink material (fibrin) associated with blood vessel walls
  • Generally immune-mediated - Immune vasculitis (leukocytoclastic vasculitis, polyarteritis nodosa, etc)
  • Only detected microscopically
24
Q

What is the ECM?

A
  • A secreted network of proteins that surrounds cells and constitutes a significant proportion of any tissue in the body
  • Cell interactions within the ECM are critical for tissue development, healing, and maintenance of normal tissue architecture
25
Q

What are the two basic forms of ECM?

A
  • Interstitial Matrix
  • Basement Membrane
26
Q

What is the interstitial matrix?

A
  • 3-dimensional, amorphous, semi-fluid gel
  • Synthesized by mesenchymal cells (e.g., fibroblasts)
  • Occupies the spaces between stromal cells (in connective tissue)
  • Assists with support/scaffolding and in some tissues acts as a fluid that cushions tissue compression
27
Q

What is the basement membrane?

A
  • Highly organized meshwork
  • Lies between epithelial cells and underlying connective tissue
  • Synthesized by overlying epithelial cells and underlying mesenchymal cells
  • Forms a flat, porous mesh that represents a specialized surface for cell growth
28
Q

What are the functions of the ECM?

A
  • Mechanical support
  • Regulation of cell proliferation
  • Scaffolding for tissue renewal - Disruption of the ECM prevents effective tissue regeneration and repair!
  • Foundation for establishment of tissue microenvironments
29
Q

What are the components of the basement membrane?

A
  • Type IV collagen
  • Laminin
  • Proteoglycan
30
Q

What are the components of the interstitial matrix?

A
  • Fibrillar collagens
  • Elastin
  • Proteoglycan & Hyaluronan
31
Q

Fibrillar collagen does what?

types I, II, III, & V

A

Form linear fibrils that comprise a major proportion of connective tissue as well as in healing wounds and scars

32
Q

Nonfibrillar collagen does what?

type IV

A

Contributes to basement membrane structure, provides an anchor that maintains structure of some tissues, such as stratified squamous epithelium (e.g., skin)

33
Q

What is the function of elastic fibers?

A

Provide tissue recoil and return to baseline structure after physical stress

34
Q

What are water-hydrated gels?

comprised of?

A
  • Provide compressibility to tissues, resilience, and lubrication
  • Reservoir for growth factors secreted into the ECM
  • Proteoglycans (glycosaminoglycans: ie- Keratan sulfate and chondroitin sulfate) are linked to hyaluronan. some are integral cell membrane proteins w/ roles in cell proliferation, migration, and adhesion
  • These proteoglycan – hyaluronan molecules attract sodium and water, producing a viscous, gel-like matrix
  • Present in skin, cartilage, vitreous humor, synovial fluid
35
Q

What is fibronectin?

A
  • component of interstitial matrix
  • Provides the scaffolding for ECM deposition, angiogenesis, and re-epithelialization in healing wounds
36
Q

What is laminin?

A
  • most abundant glycoprotein in the basement membrane
  • Connects cells to underlying basement membrane; modulates cell proliferation and differentiation
37
Q

What are integrins?

A
  • a type of adhesion receptor, also known as cell adhesion molecules [CAMs]
  • Receptors that allow cells to attach to the adhesive glycoproteins (fibronectin, laminin)
  • Facilitate cell-cell adhesive interactions
  • Involved in signaling cascades that regulate cell locomotion, proliferation, shape, and differentiation
38
Q

What is tissue regeneration and when does it occur?

A
  • Restoration of normal cells
  • Ability to regenerate is determined by
    (1) the ability of the cells to proliferate, and (2)
    the presence of tissue [adult] stem cells
39
Q

What is tissue scarring and when does it occur?

A
  • Deposition of connective tissue
  • Occurs if (1) the injured tissues cannot regenerate, or
    (2) if the supporting structures (ECM) are too severely damaged to support regeneration
40
Q

With mild injury (damage to epithelium but not the underlying tissue), what type of tissue repair occurs?

A

Regeneration

41
Q

With severe injury (damage to connective tissue), what type of tissue repair occurs?

A

Scarring

42
Q

What is Labile tissue?

A
  • continuously dividing; never enter G0 of cell cycle and divide rapidly with short G1)
  • Examples: Hematopoietic cells, skin, and surface epithelia of the GI tract and genitourinary tissues
  • Cells of these tissues are constantly being lost and replaced by (1) maturation from tissue stem cells and (2) proliferation of mature cells
  • Must preserve pool of stem cells for regeneration!
  • Most affected by chemotherapy!
43
Q

What is stable tissue?

A
  • quiescent – G0 of cell cycle – but capable of dividing – enter G1 when stimulated
  • Examples: Endothelial cells (blood vessels), smooth muscle cells, parenchymal cells of most solid tissues (liver, kidney, pancreas), lymphocytes
  • With the exception of the liver, these cells have limited capacity to regenerate after injury
  • Liver has remarkable ability to regenerate after partial hepatectomy – (1) hepatocyte proliferation and (2) regeneration from “progenitor” cells in “canals of Hering” (adult stem cell niche!)
  • Healing ability is dependent on ability of these cells to proliferate
44
Q

What is permenant tissue?

A
  • terminally differentiated; non-proliferative – G0 only)
  • Examples: Neurons, cardiac muscle, skeletal muscle, red blood cells
  • Injury to the brain, spinal cord, or heart is generally irreversible and results in a scar because this tissue cannot regenerate (very limited exceptions)!
  • Repair of these tissues is dominated by scar formation
45
Q

What are the steps in scar formation?

A

Within minutes, hemostasis occurs, followed by:
1. Inflammatory response (aka inflammatory phase of wound healing)
2. Cell proliferation and angiogenesis (aka proliferative phase)
3. Formation of granulation tissue (proliferative phase continued) - Collagen deposition and ECM protein synthesis
4. Remodeling of connective tissue and wound contraction (aka remodeling phase)
5. Acquisition of wound strength (remodeling phase continued)

46
Q

What are the mediators in step 1 (inflammation) of scar formation?

A
  • Break-down products of complement activation; cytokines (from activated platelets) – function as chemotactic agents and recruit (1) neutrophils followed by (2) macrophages
  • Growth factors [GF] (from platelet plug, endothelial cells, other inflammatory cells)
  • PDGF (platelets, macrophages) - induces vascular remodeling, smooth muscle cell migration; stimulates fibroblast growth for collagen synthesis
47
Q

After clot formation (hemostasis), step 1 of scar formation (inflammation) is characterized by what?

A
  • Increased vessel permeability and neutrophil migration into tissue
  • Inflammatory cells eliminate the injurious agents (such as microbes)
  • Macrophages clear debris, necrotic cells
48
Q

What occurs in step 2 of scar formation (proliferative phase)?

A

Several cell types proliferate and migrate to close the now clean wound
* Epithelial cells – respond to locally released GF and migrate to the wound to cover it (skin: keratinocytes)
* Endothelial cells and pericytes – undergo angiogenesis (proliferation to form new blood vessels)
* Fibroblasts – proliferate and migrate to the wound; lay down collagen fibers that form the scar; deposit ECM proteins

49
Q

What is angiogenesis?

A

the process of new blood vessel development from existing vessels

50
Q

What growth factors are involved in angiogenesis?

A

VEGF (Vascular Endothelial GF)
* Stimulates migration and proliferation of endothelial cells
* Promotes vasodilation (stimulates production of nitric oxide [NO])

FGF-2 (Fibroblast GF-2)
* Stimulates endothelial cell proliferation
* Promote migration of macrophages and fibroblasts to wound
* Stimulate epithelial cell migration to cover wound

Angiopoietins 1 and 1 (Ang 1 and Ang 2)
* GFs that promote angiogenesis and structural maturation of new vessels

51
Q

What occurs in step 3 of scar formation (formation of granulation tissue)?

A

Fibroblasts continue to proliferate, deposit loose connective tissue (mediator: TGF-beta), and synthesize ECM proteins forming granulation tissue

52
Q

How is granulation tissue characterized?

A
  • Proliferation of fibroblasts
  • New, thin-walled, delicate vessels (angiogenesis)
  • Loose ECM, often with admixed inflammatory cells (mostly macrophages)
  • Progressively fills the wound; the amount formed depends on size of tissue defect, and intensity of inflammation
53
Q

What occurs in step 3 of scar formation (deposition of connective tissue, ECM)?

A
  • Granulation tissue is progressively replaced by the deposition of collagen
  • Collagen is critical for the development of wound strength
  • Mediated by locally produced cytokines and GF: PDGF, FGF-2, TGF-beta
54
Q

Explain the role of TGF-beta in step 3 of scar formation.

A
  • Potent fibrinogenic agent: most important cytokine for the synthesis and deposition of connective tissue proteins
  • Produced by most of the cells in granulation tissue, including macrophages
  • Also acts as an anti-inflammatory cytokine by inhibiting lymphocytes and the activity of other leukocytes
55
Q

What is the end result of step 3 of scar formation?

A

Highly vascularized granulation tissue eventually transforms into a pale, largely avascular scar
* Amount of connective tissue increases; deposition of ECM increases
* In contrast, there is progressive vascular regression
* Some fibroblasts acquire features of smooth muscle cells called myofibroblasts - cause scar contraction

56
Q

What occurs in step 4 (remodeling of connective tissue) of scar formation?

A

Matrix metalloproteinases (MMPs)
* Dependent on metal ions (e.g., zinc) for their activity
* Essential for remodeling
* Produced by various cell types (fibroblasts, macrophages, neutrophils, some epithelial cells)
* Mediate degradation of collagens and other ECM components
* Activity is tightly regulated
* Produced as inactive precursors that must be activated by proteases that are expected to be present only at site of injury
* Can be rapidly inhibited by specific tissue inhibitors of metalloproteinases (TIMPs), produced by most mesenchymal cells

57
Q

What occurs in step 5 of scar formation?

A
  • Excess of collagen synthesis over collagen degradation (due to cross-linking of collagen fibers and increased fiber size)
  • Type III collagen is replaced by type I collagen (mediated by fibroblasts)
  • Results in increased tensile strength of tissue

Disease & Defense (37 decks)

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