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FOM - WLB > Week 6 Nelson - Tissue Injury, Acute & Chronic Inflammation, and Repair > Flashcards

Week 6 Nelson - Tissue Injury, Acute & Chronic Inflammation, and Repair Flashcards

1
Q

What is hypertrophy?

A
  • Due to increased demand/increased stimulation
  • Increase in the size of cells
    • results in increased size of organ or tissue
    • increased production of cellular proteins
  • Physiologic OR pathologic
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2
Q

What is atrophy?

A
  • Decrease in cell size and number
    • results in reduced size of a tissue or organ
    • decreased protein synthesis & increased protein degradation (proteasome/autophagy)
  • Due to decreased nutrients/decreased stimulation
  • Physiologic or Pathologic
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3
Q

What is Hyperplasia?

A
  • Increase in the number of cells
    • results in an increase in size of organ or tissue
  • Due to increased demand/increased stimulation
  • Physiologic or pathologic
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4
Q

What is Metaplasia?

A
  • One differentiated type of cell is replaced by another cell type
    • results from the reprogramming of stem cells present in normal tissue or reprogramming of undifferentiated mesenchymal cells
    • due to chronic irritation
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5
Q

What are the four adaptive responses to physiologic stimuli and injurious stimuli?

A
  1. Hyperplasia
  2. Hypertrophy
  3. Atrophy
  4. Metaplasia
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6
Q

Describe the two pathways of cell death.

A
  • Necrosis
    • denaturation of intracellular proteins and enzymatic digestion of lethally injured cells
    • necrotic cells are unable to maintain membrane integrity and their cell contents leak out
      • cell specific proteins and anzymes can be detected in the blood (diagnostic tests)
      • INFLAMMATION
  • Apoptosis
    • regulated enzymatic “suicide” program
    • cells devoured by phagocytes
      *
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7
Q

What are some of the microscopic changes/findings of individual cell necrosis?

A
  • Increased cytoplasmic eosinophilia in tissue stains (more pink!)
  • Myelin figures (damaged cell membrane)
  • Nucleus fades away (karyolysis)
  • Nucleus shrinks (pyknosis)
  • Nucleus undergoes fragmentation (karyorrhexis)
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8
Q

What are some gross patterns of tissue necrosis?

A
  • Coagulative necrosis
    • architechture of dead tissue is preserved
  • Liquefactive necrosis
    • digestion of dead tissue → liquid viscous mass
  • Gangenous necrosis
    • limb undergoing coagulative ischemic necrosis
  • Caseous necrosis
    • cheese-like necrosis associated with necrotizing granulomas
  • Fat necrosis
    • refers to focal areas of fat destruction
  • Fibrinoid necrosis
    • Pattern of necrosis seen in immune reactions involving vessels
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9
Q

What are the seven causes of cell injury?

A
  1. Oxygen deprivation (hypoxia, ischemia, anemia)
  2. Physical agents (trauma, temp change, pressure change, radiation, electric shock)
  3. Chemical agents and drugs
  4. Infectious agents
  5. Immunologic reactions
  6. Genetic derangements
  7. Nutritional imbalances
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10
Q

What are some of the mechanisms of cell injury?

A
  • Depletion of ATP
  • Mitochondrial damage
  • Influx of calcium and loss of calcium homeostasis
  • Accumulation of oxygen-derived free radicals
  • Defects in membrane permeability
  • Damage to DNA and proteins
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11
Q

What are typical microscopic findings/morphologic features in apoptotic cells?

A
  • Cell shrinkage
  • condensation of nuclear chromatin
  • formation of blebs and fragments (apoptotic bodies)
  • phagocytosis, usually by macrophages

**NO INFLAMMATION!

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12
Q

Which enzyme pathway is typically activated in apoptosis?

A

Caspaces

(cysteine proteases)

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13
Q

Define autophagy.

A
  • Survival mechanism in a state of nutrient deprivation
    • cell can cannibalize itself and recycle the digested contents
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14
Q

Describe the four mechanisms of intracellular accumulations, and list some examples discussed in class.

A
  • Abnormal metabolism (ex. alcohol → lipid accumulation & fatty liver)
  • Defect in protein folding, transport (ex. accumulation of abnormal proteins)
  • Lack of enzyme (ex. lysosomal storage diseases accumulation of enogenous materials)
  • Ingestion of indigestible materials (accumulation of exogenous materials → cause injury to cell)
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15
Q

What are the two types of pathologic calcifications? What is the difference between the two?

A
  • Dystrophic calcification
    • necrosis associated
    • normal serum calcium level
    • atherosclerosis, fat necrosis, Tb
  • Metastatic calcification
    • due to hypercalcemia (from calcium metabolism disorder)
    • elevated serum calcium
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16
Q

Describe cellular aging.


A
  • Result of progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage due to effects of exposure to exogenous influences
    • DNA damage
    • Decreased cellular replication
    • Defective protein homeostasis
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17
Q

What are the five cardinal signs of inflammation?

A
  1. Redness (rubor)
  2. Swelling (tumor)
  3. Heat (calor)
  4. Pain (dolor)
  5. Loss of function
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18
Q

What are the four stimuli (causes) for acute inflammation?

A
  • Infections
    • bacterial, viral, fungal, parasitic
  • Tissue necrosis
    • ischemia, trauma, chemical/thermal injury
  • Foreign bodies
    • splinters, dirt, sutures
  • Immune reactions (hypersensitivity rxns)
    • autoimmune diseases, allergies,
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19
Q

What are the three major components of the acute inflammatory response?

A
  • Dilation of small vessels that increase blood flow
  • Increased permeability of microvasculature to allow plasma proteins and leukocytes to leave circulation and enter the tissues
  • Emigration of leukocytes from the microcirculation and their accumulation at the sight of injury
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20
Q

What are the three key steps involved in extravasation of neutrophils?

A
  • Marginate, roll, and adhere (via integrins) to endothelium that has been activated
  • Migration across the endothelium and vessel wall into the tissue
  • Migration toward chemoattractants emanating from the source of injury
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21
Q

How do leukocytes recognize microbes?

A

Leukocytes express receptors that recognize external stimuli; once bound to these receptors activating signals are delivered to the leukocyte.

  • Receptors include Toll-like receptors:
    • G-protein coupled receptors
    • receptors for opsonins
    • receptors for cytokines
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22
Q

How do leukocytes remove offending agents?

A
  • Phagocytosis & Engulfment
    • receptor driven process (mannose receptors, scavenger receptors, & opsonins like IgG & complement)
    • phagosome + lysosomal granule → phagolysosome
  • Intracellular killing and degradation
    • free radicals (ROS) & reactive nitrogen species inside phagolysosome
    • oxidative burst
    • bactericidal bleach
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23
Q

Eosinophils contain major basic protein, that is cytotoxic to what pathogenic offenders?

A

Cytotoxic to many parasites!

(not cytotoxic to bacteria)

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24
Q

What are the key cell derived and protein derived mediators of the inflammatory response?

A
  • Vasoactive amines (histamine)
  • Cytokines (TNF, IL-1, Chemokines)
  • Complement proteins
  • Kinins
  • Arachidonic Acid metabolites (prostaglandins, leukotrienes, lipoxins)
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25
Q

What is the primary action of histamine?

A
  • Dilation of arterioles
  • Increased vessel permiability
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26
Q

Where is histamine found/stored?

A

Mast Cells!

(stored as preformed molecules in mast cell granules and released during degranulation as a result of physical injury)

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27
Q

How do anti-histamine drugs function?

A

H1 antagonists that bind and block the receptors for histamine on microvascular endothelial cells.

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28
Q

What are prostaglandins involved in and what cells produce them?

A
  • Prostaglandins are involved in the vascular reactions and systemic reactions of inflamation (fever).
  • Produced by mast cells, macrophages, and endothelial cells.

(arachidonic acid→ Cyclooxygenase→ prostaglandin)

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29
Q

What are leukotrienes involved in and what cells produce them?

A
  • Involved in vascular and smooth muscle reactions and leukocyte recruitment (chemokine).
  • Produced by leukocytes and mast cells.

(Arachidonic acid→ lipoxygenase→ leukotriene)

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30
Q

What are lipoxins involved in?

A

Suppressing inflammation by inhibitying recruitment of leukocytes.

(Arachidonic acid→ lipoxygenase→ lipoxin)

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31
Q

What do key cytokine mediators TNF and IL-1 do?

A
  • leukocyte recruitment by promoting adhesion of leukocytes to endothelium and their migration through vessels
  • endothelial activation
  • activation of leukocytes & other cells
  • mediators of systemic acute-phase response (fever, sepsis)
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32
Q

What are TNF antagonists used to treat?

A

Chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

(adverse effect: increased risk of mycobacterial infection due to reduced ability of macrophages to kill intracellular microbes)

33
Q

How do chemokines mediate inflammation?

A

Act as chemoattractants.

Chemokines bind to transmembrane G-protein coupled receptors and stimulate leukocyte recruitment.

Control normal migration of the cells through various tissues.

34
Q

How does the complement system function as a mediator of inflammation?

A
  • Stimulate histamine release in inflammation
  • Aid in opsonization and phagocytosis
  • Make cell wall permeable to water and ions causing cell lysis
35
Q

How do kinins function as mediators of inflammation?

A
  • Vasoactive peptides derived from plasma proteins (kininogens)
  • cleaved into bradykinin
    • increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into skin
36
Q

What are the three outcomes of the acute inflammatory response?

A
  1. Complete resolution
  2. Healing by connective tissue replacement (fibrosis/scarring)
  3. Progression of the acute inflammatory response to chronic inflammation
37
Q

What types of conditions or situations give rise to chronic inflammation?

A
  • Persistent infections
    • viral, mycobacterial, fungal
    • may get a granulomatous reaction
  • Immune-mediated inflammatory disease
    • autoimmune diseases
    • allergic diseases
  • Prolonged exposure to toxic agents
    • exogenous or endogenous
    • ex. silicosis, atherosclerosis
  • Chronic inflammation may also play a role in some diseases not conventionally thought of as inflammatory disorders (ex. some neurodegenerative diseases)
38
Q

What are the cell types and key functions of the cells involved in chronic inflammation?

A
  • Macrophages
    • secrete cytokines and growth factors
    • ingest & destroy foreign invadors
    • activate T-cells
    • initiate tissue repair (fibrosis/scar formation)
  • Lymphocytes
    • secrete cytokines
    • promote inflammation
    • activate T-cells & B-cells
  • Eosinophils
    • release granules toxic to parasites
  • Mast Cells
    • release cytokines
    • release histamine and prostaglandins
39
Q

What is a granuloma?

A

A focus of chronic inflammation consisting of microscopic aggregation of macrophages that are transformed into epithelial-like cells (histocytes), with variable numbers of lymphocytes and plasma cells.

(Histocytes may also fuse forming multi-nucleated giant cells.)

40
Q

What are the three types of granulomas?

A
  • Foreign body granulomas
    • see foreign material within histiocytes
  • Caseating granulomas
    • central necrosis (cheese-like)
    • usually associated with myobacterial/fungal infections
  • Non-caseating granulomas
    • granulomas that induce cell mediated immune response without central necrosis
      • ex. Sarcoidosis, Crohn’s disease
41
Q

What are the systemic effects of inflammation?

A
  • Fever
  • Leukocytosis
  • Increased pulse
  • Increased blood pressure
  • Chills
  • Rigors (shivering)
  • Anorexia
  • Somnolence
  • Malaise
  • Sepsis (hypotension)
42
Q

How does Erythrocyte Sedimentation Rate measure inflammation?

A
  • fibrinogen and immunoglobulins bind to RBCs making them sticky and causing them to stack
  • stacked RBCs will sediment out faster in a tube of blood compared to non-stacked RBCs
  • non-specifically measure rate (mm/hour)
43
Q

How does C-reactive protein (CRP) measure inflammation?

A
  • sensitve, but non-specific indicator of acute injury, bacterial infection, or inflammation
  • inflammatory marker for:
    • sepsis
    • acute appendicitis
    • pelvic inflammatory disease
    • acute MI
    • cardiovascular disease
44
Q

How is WBC count and differential help in determining underlying pathology?

A
  • Neutrophils
    • acute bacterial infections
    • acute inflammation associated with tissue necrosis (ex. acute MI)
  • Eosinophilia
    • allergic disorders
    • parasitic infections
  • Lymphocytosis
    • viral infections
    • Bordetella pertussin infection
    • disorders associated with chronic immunologic stimulation
45
Q

What principal mediators are involved with vasodilation?

A

Histamine & Prostaglandins

46
Q

What principal mediators are involved in increasing vascular permeability?

A
  • Histamine
  • Serotonin
  • Complement proteins
  • Leukotrienes
47
Q

What principal mediators are involved in chemotaxis/leukocyte recruitment and activation?

A
  • TNF
  • IL-1
  • Chemokines
  • Complement proteins
  • Leukotriene
48
Q

What principal mediators are involved in fever?

A
  • IL-1
  • TNF
  • Prostaglandins
49
Q

What principal mediators are involved in pain?

A

Prostaglandins & Bradykinin

50
Q

What principal mediators are involved in tissue damage?

A
  • Lysosomal enzymes of leukocytes
  • Reactive oxygen species
51
Q

Define repair.

A

Healing:

restoration of tissue architecture and function after an injury.

52
Q

What are the two types of reactions in the repair of damaged tissue?

A
  1. Regeneration - proliferation of residual/uninjured cells and maturation of tissue stem cells.
  2. Deposition of connective tissue to form a scar.
53
Q

Define regeneration.

A

Proliferation of cells and tissues following injury

-replaces the damaged components and returns the tissue to the normal state.

54
Q

When does connective tissue deposition occur?

A

If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue.

-a process that may result in scar formation

55
Q

What are the three types of tissues in the body?

A
  • Labile tissues
    • continuously dividing
    • cells are constantly being lost and replaced by maturation from tissue stem cells and by proliferation of mature cells
  • Stable tissues
    • quiescent cells
    • minimal proliferative activity in their normal state, however, they do have the ability to divide in response to injury or loss of tissue mass
  • Permanent tissues
    • cells are terminally differentiated and are nonproliferative in postnatal life
56
Q

Why does repair by connective tissue deposition not always return the tissue to its original functional state?

A
  • If the tissue injury is severe or chronic and results in damage to parenchymal cells and epithelial as well as to the connective tissue framework, or if non-dividing cells are injured.
  • scar formation “patches” rather than restores the tissue (fibrosis)
  • replaces damaged tissue with collagen
57
Q

What are three sequential steps that occur in repair by connective tissue deposition?

A
  1. Angiogenesis (via VEGF)
  2. Formation of granulation tissue
  3. Remodeling of connective tissue
58
Q

Which cell plays a central role in orchestrating the repair process?

A
  • Macrophages (M2)
    • clear offending agents and dead tissue
    • provide growth factors
    • secrete cytokines → fibroblast proliferation
  • Fibroblasts
    *
59
Q

What is the key cytokine inolved in fibrosis?

A

Transforming growth factor beta (TGF-beta)

60
Q

What is the key growth factor involved in angiogenesis?

A

Vascular endothelial growth factor (VEGF)

61
Q

What are the clinical factors that can reduce the quality or adequacy of the repair process?

A
  1. Infection
  2. Diabetes
  3. Nutritional status
  4. Glucocorticoids (steroids)
  5. Mechanical factors (cause wounds to pull apart or dhisce)
  6. Poor perfusion
  7. Foreign bodies
  8. Type and extent of tissue injury
  9. Location
62
Q

What are the steps involved in cutaneous wound healing?

A
  • Inflammation
    • formation of blood clot
    • secretion of growth factors, cytokines and chemokines
    • cell migration
    • VEGF → increased permeability → edema
  • Proliferation of epithelial and other cells
    • 24-48 hours
    • neutrophil invasion
    • epithelial cells deposit basement membrane
    • Day 3 - macrophages & granulation tissue
    • collagen fibers along margins
    • Day 5 - neovascularization
  • Maturation of the connective tissue scar
63
Q

What is healing by first intention?

A

Epithelial regeneration.

64
Q

What is different about second intention wound healing?

A
  • larger tissue defect
  • larger fibrin clot
  • more intense inflammatory reaction
  • larger amounts of granulation tissue
  • wound contraction
  • greater mass of scar tissue
65
Q

How does the tensile strength of a healing skin wound changes over time?

A
  • 1 week after suture removal
    • wound strength is 10% of normal strength
  • Tensile strength increases rapidly over next four weeks due to increased collagen deposition and structural modification of collagen
    • type III → type I
    • cross-linking of collagen
    • increased fiber size
  • 70-80% would strength by 3 months
66
Q

What are some of the complications of tissue repair?

A
  • Inadequate formation of granulation tissue
    • wound dehiscence (wound rupture)
    • ulceration
  • Formation of a scar
  • Hypertrophic scars and Keloids
    • excessive accumulation of collagen
  • Exuberant granulation tissue
    • blocks re-epithelialization
67
Q

What are two disciplines of the practice of pathology?

A
  • Anatomic pathology
    • surgical
    • autopsy
    • cytopathology
  • Clinical pathology
    • laboratory test report
    • clinical chemistry
    • hematology
    • microbiology
    • blood bank
68
Q

What three key questions should one ask when ordering a laboratory test?

A

Why is the test being ordered?

What will I do with the results?

What are the consequences of not ordering the test?

69
Q

What are the five rationales discussed in the use of laboratory tests?

A
  1. Screening
  2. Diagnosis
  3. Appropriate therapy selection
  4. Monitoring
  5. Research
70
Q

Define accuracy.

A

Ability of the test to actually measure what it claims to measure correctly.

71
Q

Define precision.

A

Ability of the test to reproduce the same result when repeated.

72
Q

What is the key question for tests ordered for diagnosis or screening?

A

Does the test accurately distinguish between patients with the disease in question and those without the disease?

73
Q

Define prevalence.

A

The percent of individuals with the disease in the population being tested.

74
Q

Define specificity.

A

The probability that an individual without the disease will test negative.

(true negative)

75
Q

Define sensitivity.

A

The probability that an individual with the disease will test positive.

(true positives)

76
Q

Define positive predictive value (PPV).

A

Refers to the probability that a positive test correctly identifies an individual who actually has the disease.

PPV = true positives / all positives

77
Q

Define Negative Predictive Value (NPV).

A

Refers to the probability that a negative test correctly identifies an individual who does not have the disease.

NPV = true negatives / all negatives

78
Q

What is the effect of prevalence on the predictive value of a positive test?

A

Disease prevalence is the key factor in determining the utility of a test.

The usefulness of a positive test decreases as disease prevalence decreases.

79
Q
A

FOM - WLB (20 decks)

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