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Disease and Defense > Unit 2a > Flashcards

Unit 2a Flashcards

1
Q

Major causes (etiologies) of cell injury (7)

A

1) Physical agents: trauma/heat/electric shock/radiation/aging…
2) Chemical and drugs: drug toxicity, poisoning
3) Infection: pathogenic bacteria, virus, fungi, protozoa
4) Immunologic reactions: anaphylaxis, autoimmunity
5) Genetic derangement: phenylketonuria, cystic fibrosis
6) Nutritional imbalance: atherosclerosis, protein and vitamin deficient
7) Hypoxia

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2
Q

Human diseases occur due to …

A

cell / tissue injury

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3
Q

Major mechanisms of cell injury (6)

A

1) ATP depletion
2) Mitochondrial damage
3) Influx of calcium
4) Accumulation of ROS
5) Increased permeability of cellular membranes
6) Accumulation of damaged DNA and misfolded proteins

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4
Q

ATP depletion –> ________, ________ and _________

A

1) Decrease in Na+ pump activity

→ influx Ca2+, H2O, and Na+ and efflux of K+ → ER swelling, cellular swelling, loss of microvilli, blebs

2) Increase in anaerobic glycolysis

→ decrease glycogen, increase in lactic acid, decrease in pH → clumping of nuclear chromatin

3) Detachment of ribosomes –> decreased protein synthesis

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5
Q

ATP is produced via ___________ or _________

A

oxidative phosphorylation of ADP in mitochondria OR glycolytic pathway in absence of O2

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6
Q

Tissues with greater _________ are better able to withstand ischemic injury

A

glycolytic capacity

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7
Q

Susceptibility of specific cells to ischemic injury:

  • Neurons
  • Cardiac myocytes, hepatocytes, renal epithelium
  • Cells of soft tissue, skin, skeletal muscle
A

Neurons = 3-5 min

Cardiac myocytes, hepatocytes, renal epithelium = 30 min - 2 hr

Cells of soft tissue, skin, skeletal muscle = many hours

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8
Q

Failure of oxidative phosphorylation –> (4)

A

1) ATP depletion
2) Formation of ROS
3) Formation of high-conductance channel (mitochondrial permeability transition pore) and loss of membrane potential
4) Release of proteins that activate apoptosis

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9
Q

Influx of calcium and cell injury

A

Ordinarily - big calcium gradient between extra and intracellular Ca2+

Ischemia and toxins → release of Ca2+ from intracellular stores and increased influx across plasma membrane → membrane damage, nuclear damage, decreased ATP

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10
Q

Two major pathways to accumulate ROS

A

1) during cells redox reactions during normal mitochondrial respiration
2) Phagocytic leukocytes (neutrophils and macrophages)

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11
Q

How are ROS produced during mitochondrial respiration?

A

1) Fenton Reaction
O2 → superoxide (O2-) → H2O2 + Fe++ → OH* + OH-

2)
O2 → superoxide + NO → peroxynitrite ONOO-

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12
Q

Superoxide Dismutase (SOD)

A

removes superoxide

Converts superoxide to H2O2 (however, this reaction can also occur spontaneously)

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13
Q

Catalase and Glutathione Peroxidase

A

decomposes hydrogen peroxide (H2O2) to H2O

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14
Q

Phagocytic leukocytes produce ROS via…

A

oxidative burst –> peroxynitrite, hypochlorite

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15
Q

Consequences of free radicals (3)

A

1) Damage determined by rate of production vs. rate of removal
2) Increased production or ineffective scavenging → oxidative stress
3) Removal via spontaneous decay and specialized enzymatic systems

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16
Q

Pathologic effects of ROS (3)

A

Lipid peroxidation → membrane damage

Protein modification → breakdown, misfolding

DNA damage → mutations

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17
Q

Important sites of membrane damage include _______, _______ and _______

A

mitochondria, plasma membrane, lysosome

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18
Q

Reversible cell injury includes _______ and ________

A

cellular swelling

fatty change

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19
Q

Reversible cell injury

A
  • Recoverable if damaging stimulus removed
  • Injury has not progressed to severe membrane damage and nuclear dissolution
  • CAN result in IRREVERSIBLE injury if changes persist (especially severe mitochondria damage and disturbances in membrane function)
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20
Q

Cellular swelling

A

failure of energy dependent ion pumps in plasma membrane → disrupted ionic and fluid homeostasis

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21
Q

Fatty change

A
  • accumulation of lipid vacuoles WITHIN cytoplasm of cells (typically those participating in fat metabolism - hepatocytes, myocardial cells, etc.)
  • Due to increased entry and synthesis of free fatty acids and decreased fatty acid oxidation
  • NOT SPECIFIC FOR INJURY type (could be alcoholic liver disease, NAFLD, etc.)
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22
Q

Intracellular changes of reversibly damaged cell include…(4)

A

1) plasma membrane alteration
2) mitochondrial changes
3) Dilate of ER with detachment of ribosomes
4) Nuclear alterations (with clumping of chromatin)

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23
Q

Plasma membrane alterations due to cell injury can cause…

A

blebbing (bulging), blunting, distortion of microvilli, loosening of intercellular attachments

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24
Q

Myelin figures

A

phospholipid masses derived from damaged cellular membranes

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25
Q

Mitochondrial changes resulting from cell injury

A

swelling and appearance of phospholipid-rick amorphous densities

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26
Q

Irreversible cell injury includes… (2)

A

Necrosis
Apoptosis

aka cell death

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27
Q

Necrosis signs

Cell size = ?
Nucleus = ?
Plasma membrane = ?
Inflammation?
Pathologic or physiologic?
A

Cell size = enlarged (swelling)

Nucleus = pyknosis → karyorrhexis → karyolysis

Plasma membrane = disrupted (Cellular contents enzymatically digested, may leak out of cell)

Inflammation? YES

Pathologic or physiologic? - ALWAYS pathologic

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28
Q

Apoptosis

Cell size = ?
Nucleus = ?
Plasma membrane = ?
Inflammation?
Pathologic or physiologic?
A

Cell size = reduced (shrinkage)

Nucleus = fragmentation into nucleosome size fragments

Plasma membrane = remains intact (may have altered structure - e.g. lipid orientation)

Inflammation? NO

Pathologic or physiologic? - often physiologic BUT can be pathologic (due to DNA/protein damage)

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29
Q

5 patterns of tissue necrosis

A
  1. Coagulative
  2. Liquefactive
  3. Caseous
  4. Fat
  5. Fibrinoid
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30
Q

Pyknosis

A

nuclear shrinkage and increased basophilia (DNA condenses)

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31
Q

Karyorrhexis

A

pyknotic nucleus fragments

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32
Q

Karyolysis

A

dissolution of nucleus (basophilia of chromatin fades secondary to deoxyribonuclease activity - breakdown of denatured chromatin)

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33
Q

Cytoplasmic changes present with necrosis (2)

A

increased eosinophilia (increase binding of eosin to denatured cytoplasmic proteins)

loss of RNA basophilia in cytoplasm

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34
Q

Apoptosis

A
  • Programmed cell death
  • tends to involve individual, scattered cells
  • Pathway of cell death - cells activate enzymes that degrade cells nuclear DNA and nuclear and cytoplasmic proteins which then fragment (“falling off”)
  • Does NOT elicit inflammatory response
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35
Q

Apoptotic bodies

A

membrane bound vesicles containing cytosol and organelles → taken up by macrophages

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36
Q

Physiologic causes of apoptosis

A

Programmed cell destruction during embryogenesis

Involution of hormone-dependent tissues upon hormone deprivation

Cell loss in proliferating cell populations

Elimination of cells that have served their purpose

Elimination of self reactive lymphocytes

Cell death induced by cytotoxic T-lymphocytes

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37
Q

Pathologic causes of apoptosis (4)

A

1) DNA damage (Radiation, cytotoxic drugs, temp extremes, hypoxia) where repair mechanisms inadequate → better to eliminate cell than risk propagating mutated DNA
2) Accumulation of misfolded proteins (ER stress)
3) Cell injury in certain infections (especially viral)
4) Pathologic atrophy in parenchymal organs after duct obstruction (pancreas, parotid, kidney)

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38
Q

Two pathways of apoptosis:

A

1) Mitochondrial (intrinsic pathway) = caspase 9

2) Death receptor (extrinsic pathway) = caspase 8

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39
Q

Anti-apoptotic species (3)

A

BCL2, BCL-XL MCL1

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40
Q

pro-apoptotic species (2)

A

BAX, BAK

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41
Q

Mitochondrial (intrinsic) apoptosis pathway steps (4)

A

1) Cell injury –> BCl-2 family effectors activated (BAX, BAK)
2) Mitochondria releases cytochrome C and other pro-apoptotic proteins
3) –> caspase 9 activated
4) –> executioner caspases activated –> apoptosis

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42
Q

Death receptor (extrinsic) apoptosis pathway steps (4)

A

1) Binding to Fas or TNF receptor on cell membrane surface
2) –> adaptor proteins activated (FADD)
3) –> Caspase 8 activate
4) –> Executioner caspases activated –> apoptosis

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43
Q

Autophagy

A
  • process in which cell eats its own contents
  • Adaptive response/survival mechanism in times of nutrient deprivation
  • Dysregulation implicated in many diseases (cancers, inflammatory bowel disease, neurodegenerative disorders)
  • Role in host defense - some pathogens degraded by autophagy (e.g. mycobacteria, HSV-1, etc)
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44
Q

4 main pathways of intracellular accumulations

A

1) Inadequate removal (fatty change liver - buildup of triglycerides)
2) Accumulation of abnormal endogenous substance (alpha1-antitrypsin)
3) Failure to degrade due to inherited enzyme deficiencies (storage diseases)
4) Deposition and accumulation of abnormal exogenous substances (anthracosis)

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45
Q

Pathologic calcification

A

abnormal deposition of Ca2+ salts (together with smaller amounts of iron, magnesium, and other minerals)

-Dystrophic or metastatic calcification

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46
Q

Dystrophic Calcification

A

Occurs in dead or dying tissues

Absence of systemic derangements in Ca2+ metabolism

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47
Q

Metastatic calcification

A

Normal tissues

Secondary to derangement in Ca2+ metabolism (hypercalcemia, hyperparathyroidism, Paget disease, etc.)

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48
Q

Necrosis

A

cell death due to loss of membrane integrity → leakage of cellular contents → dissolution of cells due to degradation by enzymes

Most commonly seen with ischemia (blood flow to tissues is compromised) = Ischemic/Coagulative necrosis

Large portions of tissue die all at once

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49
Q

4 ways cells/tissues can adapt to injury

A

1) Hypertrophy
2) Hyperplasia
3) Atrophy
4) Metaplasia

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50
Q

Hypertrophy

A

increase in SIZE of cells → increase in size of organ

  • Corresponding increase in # of mitochondria and ER, etc.
  • Physiologic (e.g enlargement of uterus during pregnancy) or Pathologic (e.g. left ventricular hypertrophy due to HTN)
  • Caused by increased functional demand or growth factor/hormonal stimulation
  • Hypertrophy and hyperplasia can occur together
  • Eventually limit is reached, enlargement cannot compensate for increased burden ( → injury)
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51
Q

Hyperplasia

A
  • increased NUMBER of cells in response to stimulus or injury
  • Physiologic (e.g. proliferation of glandular epithelium of female breast during puberty or pregnancy) or Pathologic (e.g. endometrial hyperplasia in abnormal menstrual bleeding)
  • Cellular proliferation stimulated by growth factors or hormones
  • If stimulation is removed, hyperplasia should abate (in contrast with cancer)
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52
Q

Atrophy

A
  • decrease/shrinkage in SIZE and FUNCTIONAL capacity of cells
  • Physiologic (e.g. loss of hormone stimulation in menopause) or Pathologic (e.g. skeletal muscle denervation or diminished blood supply)
  • Mechanism: decreased protein synthesis and increased protein degradation (ubiquitin-proteasome pathway)
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53
Q

Metaplasia

A

one adult / differentiated cell type replaced by another adult / differentiated cell type

  • REVERSIBLE change
  • Adaptive measure in response to injury or environmental changes

EX) replacement of squamous epithelium in distal esophagus by columnar intestinal epithelium in chronic reflux esophagitis = Intestinal metaplasia in Barett esophagus

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54
Q

Coagulative necrosis

A
  • tissue architecture preserved for at least several days - dead cells remain as ghost like remnants of their former selves.
  • Eventually dead cells digested by lysosomal enzymes of leukocytes recruited to site
  • Characteristic of INFARCTS (e.g. MI or following ischemia in any solid organ)
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55
Q

Liquefactive necrosis

A

dead cells completely digested and tissue transforms into a liquid viscous mass, which is eventually removed by phagocytes

  • Seen in focal bacterial and fungal infections
  • Microbes → stimulate accumulation of inflammatory cells → leukocyte enzymes digest (liquify) tissue
  • Seen in hypoxic cell death in CNS
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56
Q

Caseous necrosis

A
  • THINK TB
  • central portion of an infected lymph node is necrotic and has a chalky white appearance (like the milk protein casein).
  • Necrotic area appears as a collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border = granulomatous inflammation
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57
Q

Fat necrosis

A

release of activated pancreatic lipases (s/p acute pancreatitis or trauma) → areas of fat destruction

Fats hydrolyzed into free fatty acids → Ca2+ precipitate → “peculiar” chalky gray material

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58
Q

Fibrinoid necrosis

A
  • immune reaction in which complexes of antigens and antibodies are deposited in the walls of arteries
  • Deposited immune complexes combine with fibrin and produce bright pink and amorphous appearance on H&E
  • Seen in certain vasculitis (e.g. polyarteritis nodosa)
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59
Q

Acute inflammation characteristic features (5)

A

1) Fast onset (min, hrs)
2) Cellular infiltrate = mainly neutrophils
3) Usually mild and self-limited tissue injury/fibrosis
4) Prominent local and systemic signs
5) Mostly innate immune response

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60
Q

Chronic inflammation characteristic features (5)

A

1) Slow onset (days)
2) Cellular infiltrate = mostly monocytes/macrophages and lymphocytes
3) Often severe and progressive tissue injury/fibrosis
4) Less prominent local and systemic signs, may be subtle
5) Increasing chronicity → more coordinated response (innate + adaptive immunity)

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61
Q

3 clinical signs of acute inflammation and their causes

A

Increased blood flow → ERYTHEMA (due to congested capillary beds) and local warmth

Increased permeability → SWELLING (exudate of fluid in tissues)

Change in lymph channel/node drainage → LYMPHADENITIS

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62
Q

Stimuli for acute inflammation (4)

A

1) Infections
2) Trauma
3) Foreign Material
4) Immune reactions

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63
Q

Stimuli for chronic inflammation (3)

A

1) Persistent infections
2) Immune mediated disease (autoimmune or allergic)
3) Prolonged exposure to toxins

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64
Q

4 steps of acute inflammation

A

1) Recognition
2) Vascular changes
3) Leukocyte Recruitment
4) Leukocyte Activation

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65
Q

How is acute inflammation recognized by inflammatory (and some non-inflam) cells?

A

Pattern recognition receptors present on cells → pick up microbe-derived substance, toxins, material from necrotic cells (ATP, uric acid, DNA), Fc portions of Abs

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66
Q

pro-inflammatory receptors can be located in ________, _________, and __________

A

Plasma membrane for extracellular triggers

Endosome for ingested triggers

Cytosol for intracellular triggers

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67
Q

Toll-Like Receptors (TLRs)

A

pattern recognition receptors, detect variety of microbes

Present on plasma membrane and endosomes

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68
Q

Inflammasome

A

pattern recognition receptor, complex of proteins that mediates cellular response - especially respond to stuff from dead/damaged cells (but also microbes)

Stuff = uric acid (from DNA breakdown), ATP, decreased intracellular K+ (due to plasma membrane injury), DNA

Receptors in cytoplasm

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69
Q

TLR stimulated –> ?

Inflammasoee stimulated –> ?

A

TLR stimulated → transcription factors → mediators of inflammation and anti-microbial products (e.g. interferons)

Inflammasome stimulated –> caspase-1 activated –> cleaves IL-1 to active form, IL1B –> Inflammation

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70
Q

How is blood flow increased during acute inflammation?

A

Arterioles serving involved cap beds dilate, flooding capillaries

Histamine acts on smooth muscle cells in vascular wall to dilate arterioles

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71
Q

How is blood vessel permeability increased during acute inflammation? (3)

A

1) Endothelial cells contract as a response to mediators → gaps between cells
2) Endothelial injury
3) Transcytosis

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72
Q

Early vs. Later mediators for increased vessel permeability

A

Early: histamine, bradykinin

Later: different mediators (IL1, TNF) - sustained vascular change

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73
Q

5 main phases of Leukocyte recruitment

A

1) Margination
2) Rolling
3) Adhesion
4) Transmigration
5) Chemotaxis

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74
Q

Margination

A

leukocytes accumulate in periphery of blood vessels (b/c they are slow and big) on endothelium

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75
Q

Rolling

A

Stimulated endothelial cells express adhesion molecules with affinity for sugars on leukocytes (transient, not strong binding)

Local tissues detect threat → chemical mediators released → associated small vessels become “sticky”

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76
Q

Mediators induce endothelium to move adhesion molecules to surface:

Histamine –> _______
While IL-1 –>_______

A

Histamine → P selectin

IL-1 → E-Selectin

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77
Q

Adhesion

A

Leukocyte reaches area of high ligand (ICAM-1) concentration on endothelium for CD11/CD18 Integrins on leukocyte

–> stable attachment at sites of inflammation

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78
Q

Transmigration

A

begins after adhesion arrests leukocyte on endothelium

Point of no return

Leukocytes (using CD31) squeeze between endothelial cells = diapedesis

Mostly occur in venules

Leukocytes also secrete enzymes (e.g. collagenase) to break up basement membrane of vessels

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79
Q

Chemotaxis

A

Leukocytes move toward site of inflammation following chemical gradients of increasing density

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80
Q

Leukocyte activation

A

leukocytes activated when they encounter certain substances (microbial products, cellular debris, certain cellular mediators)

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81
Q

Once activated, leukocytes…(4)

A

1) readily phagocytize materials
2) are poised to kill/degrade engulfed material
3) readily secrete material to kill/degrade
4) Produce inflammatory mediators (amplifies inflammatory process)

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82
Q

Phagocytosis by leukocytes occur in 3 steps:

A

1) Recognition/attachment of particle to leukocyte
2) Engulfment and formation of vacuole
3) Killing/degradation of vacuolated material

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83
Q

Leukocytes bind material for phagocytosis using _______

A

opsonins

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84
Q

Opsonins

A

host proteins present in blood or produced locally that coat microbes

includes: IgG, complement system (C3b), collectins

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85
Q

______, ______, _______, ________, and ______ are toxic chemicals produced by leukocytes used to kill microbes in phagosomes

A

Superoxide Ion
Hydrogen peroxide
Hypochlorous radical

Other toxic nitrogen compounds
Other lysosomal enzymes

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86
Q

Transudates

A

result of altered intravascular pressure (either hemodynamic or osmotic)

Protein content decreased

Cell content decreased (few cells)

Specific gravity = low

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87
Q

Exudates

A

result of increased vascular permeability usually related to inflammation

Protein content increased
Cell content increased (inflammatory cells and RBCs)
Specific gravity = high

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88
Q

3 possible outcomes of acute inflammation

A

1) Resolution
2) Chronic inflammation
3) Scarring

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89
Q

Systemic Effects of Inflammation mediated by ______, ______ and _____ mediators that distribute systemically to produce ________, __________ and _________ generalized effects

A

TNF, IL-1, and IL-6

Fever

Increased acute phase proteins in blood

Leukocytosis

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90
Q

Fever caused by ______ which bind ________ to produce _______ –> increase in central body temp

A

pyrogens (IL-1, TNF)

bind hypothalamus cells

prostaglandins

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91
Q

Exogenous pyrogens can act directly on _______, but can also cause ________

A

hypothalamic cells

can cause release of IL-1 and TNF (endogenous pyrogens)

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92
Q

Increased acute phase proteins in blood stimulated by ______, which causes _______ to produce more proteins including _______, _______ and ________

A

IL-6
hepatocytes

C-Reactive protein (CRP)
Serum Amyloid A (SAA)
Fibrinogen

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93
Q

CRP and SAA are released upon stimulation from IL-6 and act as ___________

A

opsonins - promote adherence of leukocytes to vessel endothelium

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94
Q

Fibrinogen is released upon stimulation from IL-6 and acts to …

A

bind RBCs → RBCs form stacks and sediments → Erythrocyte Sedimentation Rate (ESR) used as test for inflammation

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95
Q

Leukocytosis is stimulated by ______ and ______

May cause an increase number of immature WBCs = ____________

A

TNF and IL-1

Left Shift of leukocytes

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96
Q

General Rule:

Neutrophilia –>

Lymphocytosis –>

Eosinophilia –>

Leukopneia –>

A

Neutrophilia → Bacterial infections

Lymphocytosis = increased lymphocytes → viral infections

Eosinophilia = increased eosinophils → asthma, parasitic infections

Leukopenia = decreased leukocytes → specific infections (e.g. typhoid)

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97
Q

Whats the difference between a monocyte and a macrophage

A

Monocytes circulate for about 1 day, some → macrophages in peripheral tissues

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98
Q

Macrophage functions (4)

A

1) Ingest microbes and necrotic cellular debris (main phagocytes of adaptive immune system)
2) Initiate tissue repair (often results in fibrosis/scarring)
3) Secrete inflammatory mediators (cytokines, eicosanoids) that promote inflammation
4) Present antigens to adaptive immune system

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99
Q

Two pathways to activate macrophages

A

1) Alternative activation (M2)

2) Classical Activation (M1)

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100
Q

Classical Activation of Macrophages:

Activated by _____ and ______.

Leads to secretion of ________ that promote __________ and __________

A

Endotoxin IFN-y (T cell cytokine) and foreign material

Secrete inflammatory mediators (cytokines and eicosanoids)

chronic inflammation and killing of microbes

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101
Q

Alternative activation of macrophages:

Activated by ______ and ________.
Promotes secretion of factors that promote _______, _________ and _________

A

new vessel growth, fibroblast activation and initiation of tissue repair (often → fibrosis/scarring)

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102
Q

Lymphocytes

A

Involved in many inflammatory responses - especially autoimmune disease and other chronic inflammatory disorders

Activated by adaptive immune response

Share pathways of tissue migration with other inflammatory cells

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103
Q

3 types of CD4+T cells secrete different cytokines that promote inflammation:

TH1 CD4+ –>

TH2 CD3+ –>

TH17 CD4+ –>

A

TH1 CD4+ T lymphocytes → secrete IFN-y → activates classical pathway macrophages

TH2 CD3+ T lymphocytes → secrete IL-4, IL-5, IL-13 → activates alternative pathway of macrophages and activates eosinophils
TH17 CD4+ T lymphocytes → secrete IL-17 → recruit netorophils and monocytes

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104
Q

Eosinophils are found in many inflammatory reactions, especially _______ and _______

Recruited by _________

A

Parasitic infections

Allergic reactions

chemokines (eotaxin)

105
Q

Mast Cells

A
  • Involved in acute and chronic inflammation
  • Widely distributed → wide, quick trigger response to infections
  • Quick release of inflammatory mediators (histamine and arachidonic acid)
  • Coated with IgE → triggers mediator release
  • Involved in allergic reactions
106
Q

Granulomatous inflammation

A

sign of chronic inflammation

Fibrosis often forms around longstanding granulomatous inflammation

Happens with: organisms not eradicated by inflammatory reactions (TB, leprosy, fungi), immune-mediated diseases (Crohn’s), foreign material, Sarcoidosis (chronic granulomatous disease)

107
Q

Sites of mediator production (2)

A
  1. site of inflammation

2. Liver

108
Q

Synthesis of mediators can be:

A
  1. Preformed, ready for secretion (fast acting) - EX histamine
  2. Synthesized (on demand) - rapidly decaying compounds or toxic mediators - EX ROS
109
Q

Vasoactive amines (2)

A

Histamine and serotonin

110
Q

Storrage of vasoactive amines

A

stored in cells and ready for quick release

111
Q

Histamine is released by (3)

A

mast cells, basophils, and platelets

112
Q

Histamine causes (2)

A
  1. arterial dilation

2. endothelial contraction

113
Q

Mast cells release histamine for (5)

A

Physical features (mechanical, temp), immune (binding of IgE), Complement (C3a, C5a), Histamine releasing proteins (from leukocytes), neuropeptides, and cytokines (IL-1, IL-8)

114
Q

Serotonin causes…

A

vasoconstriction to aid in clotting

115
Q

Serotonin is present in

A

platelet granules

116
Q

Release of serotonin is a response to

A

platelet aggregation

117
Q

Arachidonic acids are derived from

A

cell membrane phospholipids

118
Q

Arachidonic acids are released by (4)

A
  1. leukocytes
  2. mast celss
  3. endothelium
  4. platelets
119
Q

Arachidonic acid metabolites are formed by 2 main pathways

A
  1. Cyclooxgenase → prostaglandins and thromboxanes

2. Lipoxygenase → leukotrienes and lipotoxins

120
Q

3 characteristics of prostaglandins and thromboxanes

A

a. Large variety of actions (some opposite) depending on the specific compound and receptor
b. Prostaglandins → symptoms of pain and fever
c. Presence of specific enzymes determines which compounds are made

121
Q

Regeneration

A

cell proliferation of residual (uninjured) cells, and proliferation of stem cells

-can occur in labile tissues

122
Q

Labile Tissues

A

continuously dividing (GI, skin, bone marrow, urothelium, oral cavity)

-Injured cells rapidly replaced by proliferation of residual cells and differentiation of tissue stem cells (provided underlying basement membrane is intact)

123
Q

Stable tissues

A

minimal replicative activity, although capable of proliferating in response to injury or loss of tissue mass (liver, kidney, pancreas, endothelial cells, fibroblasts, smooth muscle cells)

Regeneration can occur, but (with exception of liver) usually limited

124
Q

Scar Formation

A

in cases where injury is severe, chronic, or involves non-dividing cells
Repair occurs by replacement of non-regenerated cells with connective tissue

125
Q

Permanent Tissues

A

terminally differentiated, non proliferative (cardiac muscle cells, neurons)

126
Q

Two types of tissue repair

A

Regeneration

Scar formation

127
Q

Acute vs. Chronic Inflammation onset/duration

A

Acute = seconds to minutes onset / days duration

Chronic = days onset / weeks, months, years duration

128
Q

Vascular response during acute inflammation phase

A

-Dilation / Increased Flow
-Increased Permeability
→ Transudate
→ Exudate

129
Q

Vascular response during chronic inflammation phase

A
  • Variable persistence of dilation and “leakiness”

- Endothelial cell activated (ready to proliferate if necessary)

130
Q

The acute inflammation phase involves ________ cells from _________.

Chronic inflammation phase involves ________ and _______ cells from the _________ and ________

A

Acute = NEUTROPHils from peripheral blood

Chronic = MACROPHAGES and LYMPHOCYTES from peripheral blood and local cells in tissue (sentinel)

131
Q

Is there repair processes in acute inflammation?

In chronic inflammation phase?

A

Acute = NO repair

Chronic = repair is stimulated

132
Q

Repair during chronic phase inflammation include:

Macrophages –> ?
Fibroblasts –> ?
Endothelial cells –> ?

A

Macrophages –> growth factors

Fibroblasts –> fibrosis/scar

Endothelial cells –> neovascularization

133
Q

Growth factor is secreted by _________, and act to ….

A

Macrophages

Proteins that stimulate survival and proliferation of particular cells - may also promote migration, differentiation, and other cellular responses

134
Q

Neovacularization is done by _________ cells

A

endothelial

135
Q

Collagen deposition is done by _______ and ________ cells and requires ________

A

Fibroblasts and Myofibroblasts

ECM intact for tissue regeneration (if ECM damaged, repair only be scar formation)

Myofibroblasts responsible for wound contracture

136
Q

Collagen remodeling and retraction is done by _______ cells

A

fibroblast

137
Q

Re-epithelialization and regeneration is done by _________ and _________ cells

A

epithelial and hepatocytes

138
Q

Granulation tissues

Comprised of ______, _______, __________, and _________

A

named for pink, soft granular appearance grossly (seen beneath scab of skin wound)

Comprised of:

fibroblasts
new capillaries
loose extracellular matrix
inflammatory cells (mostly macrophages)

139
Q

Re-epithelialization

first vs. second intention

A

cells rapidly replaced by proliferation of residual cells provided underlying basement membrane is intact

First intention: epithelial regeneration principal mechanism of repair

Second Intention: more complex repair, involving combination of regeneration and scarring
-Typically larger defect → larger clot/scab, more inflammation, wound contraction, more granulation tissue

140
Q

Liver regeneration

A

unique and robust regenerative capacity

Can regenerate when 40-60% of liver removed, and regenerate after insults (hepatitis, etc.) if enough tissue framework intact

Triggered by cytokines and growth factors in response to loss of liver mass and/or inflammation

May occur by proliferation by surviving hepatocytes and/or re-population from progenitor cells

141
Q

Steps of normal scar formation: (5)

A

1) angiogenesis →
2) migration/proliferation of fibroblasts →
3) deposition of connective tissue (granulation tissue) →
4) maturation and reorganization of fibrous tissue (remodeling) →
5) stable fibrous scar

142
Q

Angiogenesis is mediated by growth factor _________

A

VEGF

143
Q

Deposition of connective tissue is mediated by _____, _______ and ______.

A

PDGF
FGF-2
TGF-B ** (most important)

Cytokines and GFs released from inflammatory cells (especially M2 activated macrophages)

144
Q

Remodeling of connective tissue is done by _________

A

matrix metalloproteinases (MMPs)

145
Q

Pathologic scar

A

accumulation of excessive amounts of collagen

146
Q

Hypertrophic scar

A

outside boundaries of injury / regress

147
Q

Keloid

A

outside boundaries of injury / persists

148
Q

Local factors that adversely influence repair/regeneration process

A

infection, persistence of insult, trauma (early movement prior to completion of repair), trauma (foreign material), size/location

149
Q

Systemic factors that might adversely influence repair/regeneration process

A

1) Nutritional: impaired collagen synthesis - protein deficiency, vitamin C deficiency
2) Metabolic: delayed repair - diabetes, glucocorticoids (inhibit TGF-B synthesis)

3) Vascular:
Thrombosis, atherosclerosis, venous drainage impairment (varicose veins)

150
Q

COX-1 acts in the GI tract to

A

decrease acid/pepsin secretion

increase mucous/bicarb production

increase smooth muscle contractions

151
Q

COX-1 acts on platelets via ______ to…

A

TXA2 increase aggregation

152
Q

COX-1 and COX-2 act on the kidneys to…

A

increase/maintain renal blood flow, promotion of diuresis

153
Q

COX-1 acts on vascular smooth muscle via ______ to…

A

TXA2

promote vasoconstriction

154
Q

COX-1 acts on bone to…

A

stimulate bone formation and resorption

155
Q

COX 1 is expressed ________ while COX-2 is _________

A

constitutively

induced (by cytokines, growth factors), upregulated (need basis) - in inflamed/activated tissues

156
Q

COX-2 acts in areas of pain/inflammation via _____ to…

A

PGI2 (prostacyclin)

enhance edema and leukocyte infiltration
pain sensitization

(vasodilation, potentiation of bradykinin pain-producing activity)

157
Q

COX-2 effect on body temperature

A

Fever: Increase heat generation, decrease heat loss

158
Q

COX-2 acts on endothelial cells via ______ to promote….

A

PGI2

vasodilation
ANTI-aggregatory platelet effects

159
Q

COX-2 acts on uterine smooth muscle to…

A

enhance labor contractions near parturition

160
Q

COX-2 acts on ductus arteriosus to…

A

maintenan of patent ductus arteriosus via vasodilatory effects

161
Q

Thromboxane (TXA2) is produced by _______ and acts to…

A

COX-1

promote platelet aggregation

162
Q

Prostacyclin (PGI2) is produced by _______ and acts to…

A

COX-2

Vasodilation
Inhibit platelet aggregation
Pain sensitization
Gastric cyto-protection

163
Q

COX-1 + platelets = ?

COX-2 + endothelial cells = ?

A

thromboxane

prostacyclin

164
Q

Mechanism of action:

tNSAIDs

A

inhibition of COX-1 and 2

reversible

165
Q

Mechanism of action:

Celecoxib (celebrex)

A

Inhibition of COX-2

reversible

166
Q

Mechanism of action:

Acetaminophen

A

inhibition of COX-2 in CNS

NO effect on COX in periphery

167
Q

Mechanism of action:

Aspirin

A

inhibition of COX-1 and COX-2 (irreversible)

168
Q

Aspirin can be used for…(4)

A

Analgesic injury
Anti-inflammatory injury
Anti-pyretic
Anti-platelet aggregation**

169
Q

tNSAIDS can be used for…

but NOT for…

A

Analgesic injury
Anti-inflammatory injury
Anti-pyretic

NO anti-platelet aggregation effect

170
Q

Acetaminophen can be used for…

but NOT for…

A

Analgesic injury
Anti-pyretic

NO anti-inflammatory injury effect **
NO anti-platelet aggregation effect

171
Q

Celecoxib can be used for…

but NOT for…

A

Analgesic injury
Anti-inflammatory injury
Anti-pyretic

NO anti-platelet aggregation effect

172
Q

Aspirin side effects include…

but NOT…

A

Stomach (1) - GI upset
Platelet (1) - Bleeding
Kidney (1/2) - decreased renal function
Uterus (2) - decreased labor

NO effect on vessels

173
Q

tNSAIDs side effects include…

but NOT…

A

Stomach (1) - GI upset
Platelet (1) - Bleeding
Kidney (1/2) - decreased renal function
Uterus (2) - decreased labor

NO effect on vessels

174
Q

Acetaminophen side effects include…

but NOT…

A

**NO SIDE EFFECTS on stomach, platelets, kidney, uterus, or vessels

175
Q

Celecoxib side effects include…

but NOT…

A

Kidney (1/2) - decreased renal function
Uterus (2) - decreased labor
**Vessel endothelial cells (2) -increase in clotting

NO effect on:
**Stomach (GI upset)
Platelets (bleeding)

176
Q

tNSAID OD results in…

A

acute renal failure (TX = supportive)

177
Q

Incidence of GI toxicity when using tNSAIDs can be reduced by…

A

concomitant use of proton pump inhibitors (omeprazole)

178
Q

Celecoxib is dangerous because….BUT is often used for patients

A

it has prothrombotic potential –> increased MI risk

with GI problems (has lower risk of GI toxicity)

179
Q

Acetaminophen OD

A

liver failure

TX - N-acetylcysteine

Limit dose to 4 g/day due to concerns of hepatotoxicity

180
Q

Aspirin OD

A

hyperthermia, acidosis
TX - NaHCO3

Reyes Syndrome: seizures, acute encephalopathy, liver damage, rash, fatty liver, AMS

DO NOT use in children under 12 years old (use acetaminophen instead)

181
Q

Hydrocortisone (cortisol)

Anti-inflammatory
Topical
Salt-retaining
Potency
Routes
A 
Anti-inflammatory - 1
Topical - 1
Salt-retaining - 1
Potency - 20 mg
Routes - oral, injectable, TOPICAL
182
Q

Cortisone and prednisone are NOT _______ because…

A

topical

Prednisone and cortisone are 11-keto forms so they are topically inactive

Cortisol MUST have a hydroxyl at 11 position

183
Q

Dexamethasone, methylprednisolone, and triamcinolone all have…

A

zero salt retaining

184
Q

Dexamethasone and triamcinolone have…

A

oral, injectable, AND TOPICAL application

185
Q

Leukotrines

A

mediate specific functions of inflammation

186
Q

LTB4

A

Chemotactic agent for neutrophils

187
Q

LTC, LTD4, LTE4

A

Cause vascular permeability

188
Q

Effects of platelet-activating factor

A

platelet aggregation, vasodilation, vascular permeability, bronchoconstriction, stimulation of platelets and cells to form other mediators

189
Q

Cytokines

A

Polypeptides that function as mediators in innate and adaptive immune system

190
Q

Two important acute inflammatory cytokines

A

TNF and IL-1

191
Q

TNF and IL-1 are produced by (3)

A

macrophages, mast cells, endothelial cells

192
Q

Production of TNF and IL-1 is stimulated by

A

microbial products, immune complexes, and T cell mediators

193
Q

Acute inflammatory cytokines cause

A

endothelial activation (leukocyte binding and recruitment)

Induces systemic effects of inflammation: fever, acute phase protein synthesis

194
Q

Chemokines are separated into 2 groups:

A
  1. CXC: chemotactic for neutrophils (e.g. IL-8)

2. CC: chemotactic for several cells (e.g. eotaxin for eosinophils)

195
Q

2 chronic inflammatory cytokines and function

A

IFN-y: stimulates classical macrophage activation

IL-12: Stimulate growth and function of T cells

196
Q

ROS are released from

A

activated neutrophils and macrophages

197
Q

Production of ROS from NADPH oxidase pathways

A

O2 + e- → O2-* (superoxide)

198
Q

Superoxide ->

A

H202

199
Q

H2O2 -> (2)

A
  1. H2O2 → hydroxyl radical (OH*)

2. H2O2 → hypochlorous radical (HOCL*) - via myeloperoxidase in neutrophils

200
Q

O2, OH, and HOCL* are highly toxic ____ that damage ____ and _____

A

oxidizers
microbes
host tissue

201
Q

Endogenous _____ such as _____ mitigate effect of ROS on host

A

antioxidants

superoxide dismutase

202
Q

NO

A

free radical that can kill microbes

203
Q

NO is a mediator of ____, antagonizes _____, and reduces _____

A
  1. vasodialation
  2. antagonizes platelet activation
  3. Leukocyte recruitment
204
Q

Nitric oxide is produced from

A

L-arginine

205
Q

Type II NOS

A

Inducible NOS-> induce macrophages and endothelial cells

206
Q

Type II NOS is induced by

A

IL-1, TNF, IFN-gamma, and bacterial endotoxins

207
Q

Type III NOS

A

Endothelial NOS

Constitutively expressed in endothelial cells

208
Q

EX of lysosomal enzyme

A

Azurophil granules

209
Q

Azurophil granules

A

(neutrophils and monocytes) similar to lysosomes

Contain enzymes that can kill microbes and digest ingested materials

Significant source for substances that damage normal host tissues

210
Q

Granules in neutrophils

A

NOT all the same

different constituents with different functions (intra vs. extracellular)

211
Q

Acid proteases

A

active within phagolysosomes (low pH)

212
Q

Neutral proteases

A

active outside the cell (neutral pH)

EX: collagenase

213
Q

Protease inhibitors widely present in blood and body tissues (2)

A
  1. Alpha-1-antitrypsin: neutrophil elastase inhibitor → emphysema
  2. Alpha-2-Macroglobulin: inhibits a large variety of proteinases (e.g. collagenase)
214
Q

Neuropeptides

A
  • can initiate inflammation

- particularly active in vascular tone and permeability (lung and GI)

215
Q

EX of neuropeptide

A

Substance P

216
Q

Substance P

A
  • 11 AA peptide
    Secreted by nerves and inflammatory cells (macrophages, eosinophils, lymphocytes, dendritic cells)
  • Binds neurokinin-1 receptor
  • Generates proinflammatory effects in immune and epithelial cells
217
Q

Compliment

A
  • Composed of large number of plasma proteins involved with inflammation and immunity
  • Opsonize pathogens, induce series of inflammatory responses that help fight infections
218
Q

Final activated complement forms

A

Membrane attack complex

219
Q

Compliment increases ____ and ____

A

vascular permeability and leukocyte chemotaxis

220
Q

C1-C9 circulate inactive in ____, activated by ___

A

plasma, proteolysis

221
Q

___ cleaves C3 into ___ and ___

A

C3 convertase

C3a and C3b

222
Q

___ bind C3 convertase, forming ___ convertase, which initiates formation of ___

A

C3b
C5 convertase
C5b-9 (the MAC)

223
Q

Charlie, you are ______. I want to let you know ______. I ___ you.

  • _____
A

so beautiful
how much you mean to me
LOVE
-Josh

224
Q

C3 convertase formation via 3 pathways

A
  1. Classical: fixation of C1 to antigen-antibody complexes
  2. Alternative: microbe wall components combines with plasma proteins (factors B, D)
  3. Lectin: plasma lectin binds microbial mannose and stimulates classical pathway
225
Q

C3a, C5a:

A

increase vascular permeability, stimulate mast cells to release histamine

226
Q

C5a:

A

activates lipogenous pathway for AA metabolism

227
Q

C5a, C4a, C3a:

A

activate leukocytes, increasing their endothelial adhesion

i. Also chemotactic agents for neuts, eos, basophils, and monocytes

228
Q

C3b:

A

acts as opsonin for enhanced phagocytosis

229
Q

Inhibitors are located where?

A

Free in plasma

230
Q

2 inhibitors of complement

A
  1. C1 inhibitor

2. Decay-accelerating factor (DAF) + factor H

231
Q

DAF + factor H

A

limit C3/5 convertase formation

232
Q

Coagulation system overlaps with

A

inflammation mediators

233
Q

Important clotting factor

A

Factor XII (Hageman factor)

234
Q

Factor XII activates

A

Kinin system → bradykinins → increased vascular permeability, vascular dilation, and pain

Intermediate product Kallkrein = chemotactic and activates Factor XII

235
Q

Factor XII stimulates

A

clotting cascade + inflammatory factors

i. Factor Xa → vascular permeability
ii. Thrombin:
1. Binds protease activated receptors on endothelial cells (activating them)
2. Cleaves fibrinogen → fibrinopeptides → increased vascular permeability and chemotactic
3. Cleaves complement factor 5 forming factor 5a

236
Q

Whenever clotting system active, so is ___

A

fibrinolytic system

Multiple of these factors are active inflammatory mediators resulting in vascular permeability, dilation and C3a formation

237
Q

Molecules and mechanisms that limit and/or terminate inflammatory reactions (5)

A
  1. Lipoxins: antagonize leukotrienes
  2. Complement regulatory proteins (C1 inhibitor)
  3. IL-10 (secreted by macrophages) down regulates activated macrophages
  4. TGF-beta (promotes fibrosis) is anti-inflammatory
  5. Intracellular compounds also antagonize pro-inflammatory cell states
238
Q

Exogenous GC →

A

act at sites of inflammation in periphery AND to H-P-A axis and alter release of releasing factors and growth hormone

239
Q

GC → hypothalamus, anterior pituitary, adrenal gland suppression →

A

less CRF/ACTH/cortisol release (but increase exogenous ACTH, so not typically a problem)

**Problem comes during times of stress when excess cortisol needed - more than you are giving

240
Q

Metabolic effects of cortisol on carbohydrates

A

increase gluconeogenesis → increase blood glucose (increase insulin)

EXCESS → diabetes-like state

241
Q

Metabolic effects of cortisol on protein

A

decrease protein synthesis → increase AA to glucose

EXCESS → muscle wasting, skin-connective tissue atrophy

242
Q

Metabolic effects of cortisol on fat

A

increase lipolysis (peripherally) → increase free fatty acids

EXCESS → increased lipogenesis (centrally via insulin) -> centripetal obesity

243
Q

Acute side effects of glucocorticoids

A

glucose intolerance in diabetics, mood changes (up and down), insomnia, GI upset

244
Q

Side effects of high dose sustained therapy (2-4 weeks)

A
  1. Iatrogenic Cushing’s syndrome → hyperglycemia, protein wasting (muscle), lipid deposition (weight gain - buffalo hump, trunk obesity) → diabetes-like state
  2. HPA axis suppression → insufficient response to stress
    i. More suppression with Dexamethasone and Betamethasone    ii. Decrease ACTH, GH, TSH, LH, sex steroids
  3. Mood disturbance
  4. Impaired wound healing
  5. Increased susceptibility to infection
  6. Osteoporosis
245
Q

Mineralocorticoid effects on aldosterone

A

Increase Na+ reabsorption at kidney → increase blood volume and BP AND increase K+ and H+ secretion

EXCESS → sodium-fluid retention, hypertension, hypokalemia, metabolic alkalosis

246
Q

Mineralcorticoid = salt ____

A

retaining

247
Q

Acute side effects of mineralcorticoids

A

salt and water retention -> edema, increased BP, hypokalemia

248
Q

Pharmacology of glucocorticoids

A

anti-inflammation and immunosuppressive effects

249
Q

GC effects on vascular events

A

reduced vasodilation, decreased fluid exudation

250
Q

GC on cellular events

A

overall decrease in accumulation- activation of inflammatory and immune cells

251
Q

GC effects on inflammatory and immune mediators

A

decrease in synthesis

252
Q

Cortisol (hydrocortisone)

A

i. GC:MC actions 1:1
ii. Oral and parenteral administration
iii. Useful in adrenal crisis

253
Q

Prednisone

A

i. Most commonly used for steroid burst (asthma,inflammatory reaction)
ii. GC:MC actions 5:1
iii. Activated to prednisolone in liver - NO topical activity

254
Q

Methylprednisolone

A

i. IV or oral for steroid burst

ii. Minimal MC action

255
Q

Dexamethasone

A

i. Most potent anti-inflammatory agent
ii. Use: cerebral edema, chemotherapy induced vomiting
iii. Minimal MC action
iv. Greatest suppression of ACTH secretion at pituitary

256
Q

Triamcinolone

A

i. Potent systemic agent with excellent topical activity

ii. No MC action

257
Q

Alternate day therapy glucocorticoids

A

minimize adrenal suppression

i. Anti-inflammatory actions outlast HPA suppression
1. Anti-inflammatory effects longer lasting (48hrs) -HPA suppression shorter acting (24 hrs)
2. Minimizes GC block of ACTH release which can significantly reduce adrenal atrophy

258
Q

Tapered withdrawal

A

i. Required for chronic therapy with GCs

ii. Minimizes disease rebound and potential for symptoms of adrenal insufficiency (adrenal crisis)

259
Q

Triamcilone

A

GC with excellent topical activity, potent (system effects as well)

Disease and Defense (11 decks)

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