Fa: Pathology - Inflammation - 2

Front 1

What is the most common location for leukocyte extravasation?

Back 1

Post-capillary venules (sites of tissue injury and inflammation)

Front 2

What are the four steps of leukocyte extravasation?

Back 2

1. Margination and rolling
2. Tight-binding
3. Diapedesis
4. Migration

Front 3

What mediates the first step of leukocyte extravasation?

Back 3

Margination and Rolling:
- E-selectin binds Sialyl-Lewis
- P-selectin binds Sialyl-Lewis
- GlyCAM-1, CD34 bind L-selectin

Front 4

What mediates the second step of leukocyte extravasation, after margination and rolling?

Back 4

Tight-Binding
- ICAM-1 (CD54) binds CD11/18 integrins (LFA-1, Mac-1)
- VCAM-1 (CD106) binds VLA-4 integrin

Front 5

What mediates the third step of leukocyte extravasation, after tight-binding?

Back 5

Diapedesis - leukocyte travels between endothelial cells and exits blood vessel
- PECAM-1 (CD31) binds PECAM-1 (CD31)

Front 6

What mediates the fourth step of leukocyte extravasation, after diapedesis?

Back 6

Migration - leukocyte travels through interstitium to site of injury or infection guided by chemotactic signals

Front 7

What chemotactic products are release in response to bacteria to stimulate leukocyte migration?

Back 7

- C5a
- IL-8
- LTB4
- Kallikrein
- Platelet-actvating factor

Front 8

What mediates margination and rolling in leukocyte extravasation?

Back 8

Vasculature / stroma:
- E-selectin
- P-selectin
- GlyCAM-1, CD34

Leukocyte:
- Sialyl-Lewis
- L-selectin

Front 9

What mediates tight binding in leukocyte extravasation?

Back 9

Vasculature / stroma:
- ICAM-1 (CD54)
- VCAM-1 (CD106)

Leukocyte:
- CD11/18 integrins (LFA-1, Mac-1)
- VLA-4 integrin

Front 10

What is the term for when a leukocyte travels between endothelial cells to exit a blood vessel?

Back 10

Diapedesis

Front 11

What mediates diapedesis in leukocyte extravasation?

Back 11

PECAM-1 (CD31) on both vasculature/stroma and leukocytes

Front 12

How do free radicals damage cells?

Back 12

- Lipid peroxidation
- Protein modification
- DNA breakage

Front 13

What can initiate free radical damage?

Back 13

- Radiation exposure (eg, cancer therapy)
- Metabolism of drugs (phase I)
- Redox reactions
- Nitric oxide
- Transition metals
- Leukocyte oxidative burst

Front 14

What enzymes can eliminate free radicals?

Back 14

- Catalase
- Superoxide dismutase
- Glutathione peroxidase

Front 15

Besides enzymes, what else can eliminate free radicals?

Back 15

- Spontaneous decay
- Antioxidants (eg, vitamins A, C, and E)

Front 16

What pathologies are caused by free radical injury?

Back 16

- Retinopathy of prematurity
- Bronchopulmonary dysplasia
- Carbon tetrachloride, leading to liver necrosis (fatty change)
- Acetaminophen overdose (fulminant hepatitis, renal papillary necrosis)
- Iron overload (hemochromatosis)
- Reperfusion injury (eg, superoxide), especially after thrombolytic therapy

Front 17

What free radical damage is associated with prematurity?

Back 17

Retinopathy

Front 18

How can the lungs be affected by free radical damage?

Back 18

Bronchopulmonary Dysplasia

Front 19

What are the effects of carbon tetrachloride?

Back 19

Free radical damage → liver necrosis (fatty change)

Front 20

What are the free radical effects of acetaminophen overdose?

Back 20

Overdose → fulminant hepatitis and renal papillary necrosis

Front 21

What mediates reperfusion injury?

Back 21

Superoxide, especially after thrombolytic therapy

Front 22

What is the most common pulmonary complication after exposure to fire?

Back 22

Inhalation Injury:
- Inhalation of products of combustion (eg, carbon particles, toxic fumes) → chemical tracheobronchitis, edema, and pneumonia

Front 23

How long does it take for wound healing to get a majority of the tensile strength back to the tissue? What percentage of tensile strength?

Back 23

Takes ~3 months following wound formation to get 70-80% of the tensile strength back (little additional strength will be regained after that)

Front 24

What are the pathologic types of scars?

Back 24

- Hypertrophic scars
- Keloid scars

Front 25

Which type of scar has greater collagen synthesis?

Back 25

- Keloid Scars: ↑↑↑ collagen synthesis
- Hypertrophic Scars: ↑ collagen synthesis

Front 26

What is the arrangement of collagen in hypertrophic vs keloid scars?

Back 26

- Hypertrophic: parallel collagen
- Keloid: disorganized collagen

Front 27

What is the extent of a hypertrophic vs keloid scars?

Back 27

- Hypertrophic: confined to borders of original wound
- Keloid: extends beyond the borders of the original wound

Front 28

Do hypertrophic scars tend to recur following resection? vs keloid scars?

Back 28

- Hypertrophic scars infrequently recur following resection
- Keloid scars frequently recur following resection

Front 29

What types of scars are these? Characteristics?

Back 29

Keloid Scars
- ↑ collagen synthesis
- Parallel collagen arrangement
- Scar is confined to borders of original wound
- Infrequently recurs following resection

Front 30

What types of scars are these? Characteristics?

Back 30

Keloid Scars
- ↑↑↑ collagen synthesis
- Disorganized collagen arrangement
- Scar extends beyond the borders of the original wound
- Frequently recurs following resection

Front 31

Who is at higher risk for keloid scars?

Back 31

African-Americans

Front 32

What are the tissue mediators of wound healing?

Back 32

- PDGF
- FGF
- EGF
- TGF-β
- Metalloproteinases

Front 33

What is the source of PDGF? Function?

Back 33

PDGF is secreted by activated platelets and macrophages
- Induces vascular remodeling and smooth muscle cell migration
- Stimulates fibroblast growth for collagen synthesis

Front 34

What is the function of FGF?

Back 34

Stimulates all aspects of angiogenesis

Front 35

What is the function of EGF?

Back 35

Stimulates cell growth via tyrosine kinases (eg, EGFR as expressed by ERBB2)

Front 36

What is the function of TGF-β?

Back 36

- Angiogenesis
- Fibrosis
- Cell cycle arrest

Front 37

What is the function of metalloproteinases?

Back 37

Tissue remodeling

Front 38

What factor induces vascular remodeling and smooth muscle cell migration?

Back 38

PDGF (from activated platelets and macrophages)

Front 39

What factor stimulates fibroblast growth for collagen synthesis?

Back 39

PDGF (from activated platelets and macrophages)

Front 40

What factor stimulates all aspects of angiogenesis?

Back 40

FGF

Front 41

What factor stimulates cell growth via tyrosine kinases?

Back 41

EGF - via EGFR, as expressed by ERBB2

Front 42

What enzyme is involved in tissue remodeling?

Back 42

Metalloproteinases

Front 43

What are the phases of wound healing?

Back 43

1. Inflammatory (immediate)
2. Proliferative (2-3 days after wound)
3. Remodeling (1 week after wound)

Front 44

What is the immediate phase of wound healing? Mediators?

Back 44

Inflammatory Phase
- Mediated by platelets, neutrophils, macrophages

Front 45

What is the phase of wound healing that occurs 2-3 days after a wound? Mediators?

Back 45

Proliferative Phase
- Fibroblasts
- Myofibroblasts
- Endothelial cells
- Keratinocytes
- Macrophages

Front 46

What is the phase of wound healing that occurs 1 week after a wound? Mediators?

Back 46

Remodeling Phase
- Fibroblasts

Front 47

What are the characteristics of the inflammatory phase of wound healing?

Back 47

Immediately after wound:
- Clot formation
- ↑ Vessel permeability and neutrophil migration into tissues
- Macrophages clear debris 2 days later

Front 48

What are the characteristics of the proliferative phase of wound healing?

Back 48

2-3 days after wound
- Deposition of granulation tissue and collagen
- Angiogenesis
- Epithelial cell proliferation
- Dissolution of clot
- Wound contraction (mediated by myofibroblasts)

Front 49

What are the characteristics of the remodeling phase of wound healing?

Back 49

1 week after wound
- Type III collagen replaced by type I collagen
- Increased tensile strength of tissue

Front 50

What bugs/pathologies can cause granulomas?

Back 50

- Bartonella henselae (cat scratch)
- Berylliosis
- Churg-Strauss syndrome
- Crohn disease
- Francisella tularensis
- Fungal infections (eg, histoplasmosis, blastomycosis)
- Granulomatosis with polyangiitis (Wegener)
- Listeria monocytogenes (granulomatosis infantisepticemia)
- M. leprae (leprosy; Hansen disease)
- M. tuberculosis
- Treponema pallidum (tertiary syphilis)
- Sarcoidosis
- Schistosomiasis

Front 51

What mediates the formation of a granuloma?

Back 51

- Th1 cells secrete γ-interferon, activating macrophages
- Macrophages release TNF-α, which induces and maintains granuloma formation

Front 52

What can the side effects of anti-TNF drugs be?

Back 52

Cause sequestering granulomas to breakdown, leading to disseminated disease

(TNF-α maintains granuloma formation)

Front 53

Which mediator activates macrophages? Source?

Back 53

γ-Interferon from Th1 cells

Front 54

What mediator from macrophages induces and maintains granuloma formation?

Back 54

TNF-α

Front 55

What do you need to check for before starting anti-TNF therapy? Why?

Back 55

Latent Tuberculosis
- Anti-TNF drugs can cause sequestering granulomas to breakdown, leading to disseminated disease

Front 56

Which is thicker/thinner: exudate or transudate?

Back 56

- Exudate (thick)
- Transudate (thin)

Front 57

What are the contents of an exudate?

Back 57

- Cellular
- Protein rich

Front 58

What are the contents of an transudate?

Back 58

- Hypocellular
- Protein-poor

Front 59

What is the relative specific gravity in an exudate vs transudate?

Back 59

- Exudate: >1.020 (thick)
- Transudate: <1.012 (thin)

Front 60

What can cause an exudate?

Back 60

- Lymphatic obstruction
- Inflammation / infection
- Malignancy

Front 61

What can cause a transudate?

Back 61

- ↑ Hydrostatic pressure (eg, CHF)
- ↓ Oncotic pressure (eg, cirrhosis)
- Na+ retention

Front 62

What is the Erythrocyte Sedimentation Rate a reflection of?

Back 62

- Products of inflammation (eg, fibrinogen) coat RBCs and cause aggregation
- When aggregated, RBCs fall at a faster rate within the test tube

Front 63

What can cause increased ESR?

Back 63

- Most anemias
- Infections
- Inflammation (eg, temporal arteritis)
- Cancer (eg, multiple myeloma)
- Pregnancy
- Autoimmune disorders (eg, SLE)

Front 64

What can cause decreased ESR?

Back 64

- Sickle cell (altered shape)
- Polycythemia (↑ RBCs "dilute" aggregation factors)
- CHF (unknown)

Front 65

What is one of the leading causes of fatality from toxicologic agents in children?

Back 65

Iron poisoning

Front 66

What is the mechanism of iron poisoning?

Back 66

Cell death due to peroxidation of membrane lipids

Front 67

What are the acute symptoms of iron poisoning?

Back 67

- Nausea
- Vomiting
- Gastric bleeding
- Lethargy

Front 68

What are the chronic symptoms of iron poisoning?

Back 68

- Metabolic acidosis
- Scarring leading to GI obstruction

Front 69

How do you treat a patient with iron poisoning?

Back 69

Chelation:
- IV deferoxamine
- Oral deferasirox

Dialysis

Front 70

What is the term for the abnormal aggregation of proteins (or their fragments) into β-pleated sheet structures? Implications?

Back 70

Amyloidosis → damage and apoptosis

Front 71

What are the common types of Amyloidsosi?

Back 71

- AL (primary)
- AA (secondary)
- Dialysis-related
- Heritable
- Age-related (senile) systemic
- Organ specific

Front 72

What causes AL (primary) amyloidosis? Associated with?

Back 72

- Deposition of proteins from Ig Light chains
- Can occur as a plasma cell disorder or associated with multiple myeloma

Front 73

What are the extent of the effects of AL (primary) amyloidosis?

Back 73

Often affects multiple organ systems, including:
- Renal (nephrotic syndrome)
- Cardiac (restrictive cardiomyopathy, arrhythmia)
- Hematologic (easy bruising)
- GI (hepatomegaly)
- Neurologic (neuropathy)

Front 74

What causes AA (secondary) amyloidosis? Associated with?

Back 74

Seen with chronic conditions:
- Rheumatoid arthritis
- IBD
- Spondyloarthropathy
- Protracted infection

Often multisystem

Front 75

What is AA (secondary) amyloidosis composed of?

Back 75

Fibrils composed of serum Amyloid A

Front 76

What are the extent of the effects of AA (secondary) amyloidosis?

Back 76

Often multisystem involvement like AL amyloidosis

Front 77

How does dialysis relate to amyloidosis?

Back 77

Dialysis-Related Amyloidosis:
- Fibrils composed of β2-microglobulin in patients with ESRD and/or on long-term dialysis

Front 78

How might dialysis-related amyloidosis present?

Back 78

Carpal tunnel syndrome

Front 79

What is the amyloidosis in patients on dialysis composed of?

Back 79

β2-microglobulin

Front 80

What are the characteristics of heritable amyloidosis? Cause?

Back 80

Heterogenous group of disorders
- Example is ATTR neurologic / cardiac amyloidosis due to transthyretin (TTR or prealbumin) gene mutation

Front 81

What causes age-related (senile) systemic amyloidosis?

Back 81

Deposition of normal (wild-type) transthyretin (TTR) in myocardium and other sites

Front 82

How does the rate of cardiac dysfunction compare in age-related amyloidosis and AL amyloidosis?

Back 82

Age-related amyloidosis has a slower progression of cardiac dysfunction relative to AL amyloidosis

Front 83

What is the most important form of organ-specific amyloidosis? Cause?

Back 83

Alzheimer Disease
- Deposition of amyloid-β protein cleaved from amyloid precursor protein (APP)

Front 84

What type of amyloidosis is associated with T2DM? Cause?

Back 84

Islet Amyloid Polypeptide (IAPP) - type of organ-specific amyloidosis
- Commonly seen in T2DM
- Caused by deposition of amylin in pancreatic islets

Front 85

What type of disease is caused by deposition of amylin in the pancreatic islets?

Back 85

Islet Amyloid Polypeptide (IAPP) - organ-specific amyloidosis commonly seen in patients with T2DM

Front 86

What does this image show?

Back 86

Amyloidosis:
- Congo red stain shows amyloid deposits within vessel walls

Front 87

What does this image show?

Back 87

Amyloidosis
- Congo red stain shows apple green birefringence under polarized light

Front 88

What is the name of the yellow-brown "wear and tear" pigment associated with normal aging?

Back 88

Lipofuscin
- Macrophages with granular yellow-brown pigment

Front 89

What is the cause of Lipofuscin deposition in macrophages?

Back 89

Formed by oxidation and polymerization of auto-phagocytosed organellar membranes

Front 90

Where will you find Lipofuscin in an autopsy of an elderly person?

Back 90

- Heart
- Liver
- Kidney
- Eye
- Other organs