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High Yield Pathoma > Ch. 2 - Inflammation, Inflammatory Disorders, and Wound Healing > Flashcards

Ch. 2 - Inflammation, Inflammatory Disorders, and Wound Healing Flashcards

1
Q

What is characterized by acute inflammation?

A

edema and neutrophils

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2
Q

What are the two stimuli that stimulate inflammation?

A

infection or tissue necrosis

-goal is to eliminate pathogen or clear necrotic debris

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3
Q

When do neutrophils normally arrive in inflammation?

A

within 24h - immediate response with limited speficity

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4
Q

What is the function of TLRs?

A

They are are present on cells of the innate immune system and are activated by pathogen-associated molecular patterns (PAMPs) that are commonly shared by microbes

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5
Q

What TLR on macrophages recognizes the PAMP LPS on gram negative bacteria?

A

CD14

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6
Q

What does TLR activation upregulate?

A

NF-kB - TF that activates immune mediators

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7
Q

What are the derivatives of arachidonic acid and what releases it from cells?

A

AA –> phospholipase A –> COX or 5-lipoxygenase

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8
Q

What are the products of COX?

A

PGI2, PGD2, and PGE2 which mediate vasodilation and vascular permeability
-PGE2 also mediates pain

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9
Q

Where do vasodilation and vascular permeability occur?

A

vasodilation: arterioles

vascular permeability: post-venule capillary

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10
Q

What are the products of 5-lipoxygnease and their functions?

A

LTB4: attracts and activates neutrophils

LTC4, LTD4, LT4: vasoconstriction, bronchospasm, and increased vascular permeability

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11
Q

What are the 4 molecules that attract and activate neutrophils?

A

LTB4, C5a, IL-8, bacterial products

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12
Q

How do LTB4, D4, and E4 exert their functions?

A

they cause contraction of smooth muscle

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13
Q

What are the 3 mechanisms of mast cell activation

A

1) tissue trauma
2) complement proteins C3a and C5a
3) cross-linking of cell-surface IgE by antigen

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14
Q

What is the immediate response of mast cells?

A

release of preformed histamine granules which leads to vasodialtion of arterioles and vascular permeability at post-capillary venules

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15
Q

What is the delayed response of mast cells?

A

production of arachidonic acid metabolites, particularly leukotrienes

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16
Q

What are the 3 pathways of complement?

A

1) classical: C1 binds to IgG or IgM which is bound to antigen (GM classical cars)
2) alternative: microbial products directly activat e complicate
3) Mannose-binding lectin: MBL binds mannose on microorganisms and activates complement

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17
Q

What are the key products of complement?

A

1) C3a and Ca: trigger mast cell degranulation
2) C5a: chemotactic for neutrophils
3) C3b: opsonin for phagocytosis
4) MAC: lyses microbes by creating holes in the cell membrane

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18
Q

What is Hageman factor?

A

-inflammatory proinflammatory protein produced in the liver that is activated upon exposure to subendothelial or tissue collagen

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19
Q

What pathologic process does Hageman factor play a large role in?

A

gram negative sepsis and DIC

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20
Q

What does Hageman factor activate?

A
  • coagulation and fibrinolytic system
  • complement
  • kinins ystem: cleaves HMWK to bradykinin, which mediates vasodilation, increased vascular permeability, and pain (bradykinin and PGE2)
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21
Q

What is the mechanism that mediates redness and warmth in acute inflammation?

A
  • d/t vasodilation, which results in increased blood flow
  • occurs via relaxation of arteriolar smooth muscle
  • key mediators are histamin, PGs, and bradykinin
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22
Q

What is the mechanism that mediates swelling in acute inflammation?

A
  • d/t leakage of fluid from postcapillary venules into interstitial space
  • key mediators: histamine and tissue damage
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23
Q

What is the mechanism that mediates pain?

A

bradykinin and PGE2 sensitizes sensory nerve endings

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24
Q

What is the mechanism that mediates fever?

A
  • pyrogens cause cause macrophages to release IL-1 and TNF
  • increase COX activity in perivascular cells of hypothalamus
  • increased PGE2 raises temperature setpoint
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25
Q

What are the three phases of acute inflammation?

A

1) fluid phase
2) neutrophil phase ~24h
3) macrophage phase ~2-3d

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26
Q

What happens to heavy particles during vasodilation?

A

heavy particles moves to the periphery - margination

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27
Q

Describe step 1 - margination.

A

vasodilation slows blood flow in the postcapillary venules (same place as fluid)
-cells marginate from center of flow to periphery

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28
Q

Describe step 2 - rolling.

A

selectin “speed bumps” are upregulated on endothelin cells

1) P-selectins: released from Weibel-Palade bodies and mediated by histamin
2) E-selectin: induced by TNF and IL-1
- selectins bind sialyl Lewis X on leukocytes
- interaction results in rolling of leukocytes along vessel walls

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29
Q

Describe step 3 - adhesion.

A
  • cellular adhesion molecules are upregulated on endothelium by TNF and IL-1
  • integrins upregulated on leukocytes by C5a and LTB4
  • interaction between CAMs and integrins result in firm adhesion of leukocytes to vessel wall
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30
Q

What is leukocyte adhesion deficiency?

A

autosomal recessive defect of integrins (CD18)

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31
Q

What are the clinical findings of leukocyte adhesion deficiency?

A
  • delayed separation of umbilical cord
  • increased circulating neutrophils
  • recurrent bacterial infection that lack pus formation
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32
Q

Why do you see increased circulating neutrophils in LAD?

A

neutrophils are unable to tightly adhere to cell adhesion molecules in the margination pool, so they fall into the blood vessels more easily

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33
Q

Describe step 4 - transmigration and chemotaxis.

A
  • leukocytes transmigrate across endothelium of postcapillary venules and move toward chemical attractants (chemotaxis(
  • neutrophils are attracted by IL-8, LTB4, C5a, and bacterial products
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34
Q

Describe step 5 - phagocytosis.

A
  • consumption of pathogens or necrotic tissue and enhanced by opsonins (IgG and C3b)
  • psuedopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes, to produce phagolysosomes
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35
Q

What is defective in Chediak-Higashi syndrome?

A
  • autosomal recessive protein trafficking defect charcterized by impaired phagolysosome formation
  • it is a microtubule defect that can’t fuse phagosome and lysosome
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36
Q

What are the clinical features of Chediak-Higashi?

A
  • increased risk of pyogenic infections
  • neutropenia
  • giant granules in leukocytes
  • defective primary hemostasis
  • albinism
  • peripheral neuropathy
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37
Q

What are the 2 types of step 6 - destruction of phagocytosed material?

A

1) O2-depending killing (most effective)

2) O2-independent killing

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38
Q

What is the mechanism of O-2 dependent killing?

A

HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes

  • O2 –> O2*- via NADPH oxidase
  • O2*- –> H2O2 via SOD
  • H2O2–> HOCl via MPO
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39
Q

What is defective in Chronic Granulomatous Disease?

A
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40
Q

What type of organisms are pts with CGD most susceptible to and why?

A
  • catalase + organisms
  • most bacteria produce H2O2 which can be used by the host to make bleach
  • bacteria with catalase will neutralize its own H2O2, so the host can’t kill these infections
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41
Q

What are 5 important catalase-positive bacteria that CGD pts are susceptible to?

A
  1. S. aureus
  2. P. cepacia
  3. S. marcescens
  4. Nocardia
  5. Aspergillus
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42
Q

How is the nitroblue tetrazolium test used in CGD?

A
  • it tests the ability of O2–> O2*- via NADPH

- it will turn blue in normal pts, but will remain colorless in CGD

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43
Q

What is defective in MPO deficiency and how does it present clinically?

A
  • results in defective conversion of H2O2 to HOCl
  • pts are at increased risk for candida infections, but most are asymptomatic
  • NBT test is normal
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44
Q

How does O2-independent killing work?

A

-occurs via enzymes present in leukocyte secondary granules (i.e. lysozome and major basic protein)

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45
Q

Describe step 7 - resolution.

A

-neutrophils undergo apoptosis and disappear within 24h after resolution of inflammatory stimulus

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46
Q

What are macrophages derived from?

A

monocytes in the blood

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47
Q

What is the mechanism of macrophage killing?

A

destroy phagocytosed material using enzymes in secondary granules, i.e. lysozome

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48
Q

What are the major functions of macrophages?

A
  • They manage the next step of the acute inflammation process; employing one of the following:
    1) resolution and healing (via IL-10 and TGF-B)
    2) continued acute inflammation (via IL-8)
    3) abscess (walled off area of acute inflammation)
    4) chronic inflammation
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49
Q

How will lymphocytes appear in chronic inflammation?

A

mononuclear cells

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50
Q

How will plasma cells appear in chronic inflammation?

A

cells with nuclei pushed to the periphery

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51
Q

What are stimuli for chronic inflammation?

A
  • persistent infection (most common)
  • infection with viruses, mycobacteria, parasites, and fungi
  • autoimmune disease
  • foreign material
  • some cancers
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52
Q

Where are T cells produced?

A

bone marrow

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53
Q

Where are T cells developed?

A

thymus

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54
Q

What does T cell activation require?

A

1) binding of antigen/MHC complex

2) additional 2nd signal

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55
Q

What is the first activation signal for T cells?

A

Extracellular antigen is phagocytosed, processed, and presented via MHC II (APCs)

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56
Q

What is the second activation signal for T cells?

A

B7 on APC binds CD28 on CD4+ T cells

28/7=4

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57
Q

What do Th1 cells activate?

A
  • IL2: T-cell growth factor and CD8+ T cell activator
  • IFN-g: macrophage activator
  • helps CD8+ T cells
58
Q

What do Th2 cells activate?

A
  • IL-4: class switching of IgG –> IgE
  • IL-5: eosinophil chemotaxis and activation, maturation of B cells to plasma cells, and clas switching to IgA
  • IL-10: inhibits Th1 phenotype
59
Q

How are CD8+ T cells activated?

A

1st signal: intracellular antigen is processed and presented on MHC I
2nd signal” IL-2 from CD4+ Th1 cell
-cytotoxic T cells are activated for killing

60
Q

What is the key enzyme that activates apoptosis?

A

caspases

61
Q

How does cytotoxic killing occur?

A
  • secretion of perforins and granzymes that induce apoptosis of the target cell
  • expression of FasL, binds Fas on target cells, activating apoptosis
62
Q

What is the first signal for B-cell activation?

A

B-cell antigen presentation to CD4+ helper T cells via MHC II

63
Q

What is the second signal for B-cell activation?

A

CD40 receptor on B cell binds CD40L on helper T cell

64
Q

What is the result of B cell activation?

A

IL-4 and IL-5: B-cell istoype switching, hypermutation, and plasma cell maturation

65
Q

What is the key characteristic of a granuloma?

A

epithelioid histiocytes: macrophages with abundant pink cytoplasm

66
Q

What surrounds granulomas?

A

giant cells and a rim of lymphocytes

67
Q

How are noncaseating granulomas different from caseating granulomas?

A

they lack central necrosis

68
Q

What are 5 examples of noncaseating granulomas?

A

reaction to foreign material, sarcoidosis, Beryllium exposure, Crohn disease, and cat scratch disease (stellate-shaped granuloma)

69
Q

What is the histological hallmark of ulcerative colitis?

A

crypt abscess

70
Q

What is the histologic hallmark of crohn disease?

A

noncaseating granuloma

71
Q

What are the key differentials for caseating granulomas and what stains do you use for each?

A

TB and fungus
AFB: TB
GMS: fungus

72
Q

What are the steps involved in granuloma formation?

A

1) macrophages present antigen via MHC II to CD4+ hepler T cells
2) macrophages secrete IL-12, inducing CD4+ helper cells to differentiate into Th1 subtype
3) Th1 cells secrete IFN-g, which converts macrophages to epithelioid histiocytes and giant cells

73
Q

What do macrophages secrete to induce CD4+ –> Th1?

A

IL-12

74
Q

What do Th1 secrete to convert macrophages into epithelioid histiocytes and giant cells?

A

IFN-g

75
Q

What is the genetic defect of DiGeorge syndrome?

A

d/t 22q11 microdeletion leading to developmental failure of 3rd and 4th pharyngeal pouch

76
Q

What are the clinical findings of DiGeorge syndrome?

A
  • T-cell deficiency (lack of thymus)
  • hypocalcemia (lack of parathyroids)
  • abnormalities of heart, great vessels, and face
77
Q

What are the major etiologies of SCID?

A
  • cytokine receptor defects
  • adenosine deaminase deficiency**
  • MHC class II deficiency
78
Q

What are the clinical manifestations of SCID?

A
  • susceptibility to fyngal, viral, bacterial, and protozoal infections including opportunistic infections and live vaccines
  • Tx: sterile isolation and stem cell transplant
79
Q

What is the defect in X-linked agammaglobulinemia?

A

complete lack of immunoglobulin d/t disordered B-cell maturation in which naive B cells cannot mature to plasma cells
(aka Bruton tyrosine kinase)

80
Q

What is the clinical manifestaton of X-linked agammaglobulinemia?

A

presents after 6mo of life with recurrent bacterial, enterovirus, and Giardia infections; live vaccines (i.e. polio) must be avoided

*no IgA - no mucosal protection

81
Q

What is the defect in CVID?

A

low Ig d/t B-cell or helper T-cell defects which increase the risk for bacterial, enterovirus, and Giardia infections, usually late in childhood with increased risk for autoimmune disease and lymphoma

82
Q

Which 3 infections are X-linked agammaglobulinemia and CVID both at risk for?

A

bacterial, enterovirus, and Giardia

83
Q

What are pts with IgA deficiency most at risk for?

A

mucosal infections, especially viral

*most common

84
Q

Which GI disease is most associated with IgA deficiency?

A

Celiac disease

85
Q

What is the defect in hyper IgM syndrome?

A 
d/t mutated CD40L or CD40 receptor (2nd signal)
-cytokines (IL-4 and IL-5) necessary for Ig class switching not produced
86
Q

What are pts with hyper IgM syndrome most at risk for?

A

low IgA, IgG, and IgE result in recurrent pyogenic infections, especially at mucosal sites

87
Q

Why are IgM levels high in hyper IgM syndrome?

A

because the first signal is intact (MHC II-CD4+ TCR)

88
Q

What is the triad of Wiskott-Aldrich syndrome?

A

1) thrombocytopenia
2) eczema
3) recurrent infections

*d/t mutation in WASP protein

89
Q

What is the presentation of C5-C9 complement deficiency?

A

increased risk for Neisseria infection

90
Q

What is the presentation of C1 inhibitor deficiency?

A

hereditary angioedema characterized by edema of skin (especially periorbital) and mucosal surfaces

91
Q

What type of hypersensitivity reactions are present in SLE?

A

Type II (cytotoxic) and Type III (antigen-antibody complex)

92
Q

What is the most common feature of SLE?

A

renal damage - diffuse proliferative glomerulonephritis is the most common injury

93
Q

What kind of endocarditis is present in SLE?

A

Libman-Sacks: vegetations on both side of the valve

94
Q

What kind of blood disorders can SLE present with?

A

anemia, thrombocytopenia, or leukopenia

95
Q

What are the most common causes of death in SLE?

A

renal failure and infections

96
Q

What are the sensitive and specific markers for SLE?

A

sensitive: ANA
specific: anti-dsDNA

97
Q

What marker is associated with drug-induced SLE?

A

antihistone Ab

98
Q

What drugs are associated with SLE?

A

hydralazine, isoniazid, procainamide, and phenytoin (HIPP)

99
Q

What is the clinical significane of antiphospholipid syndrome associated with SLE?

A

autoAbs against proteins boudn against phospholipids

  • anticardiolipin: false VDRL
  • lupus anticoagulant: falsely-elevated PTT (actually hypercoagulable)
100
Q

What are the complications of antiphospholipid syndrome?

A

arterial and venous thrombosis

DVT, hepatic v, thrombosis, placental thrombosis, and stroke

101
Q

What is Sjogren syndrome?

A

autoimmune destruction of lacrimal and salivary glands d/t lymphocyte mediate (Type IV HSR) with fibrosis

102
Q

What is the clinical presentation of Sjogren?

A

dry eyes, dry mouth, and recurrent dental caries in older woman

103
Q

What is the marker for Sjogren syndrome?

A

anti-ribonucleoprotein antibodies

104
Q

What other AI disease is most associated with Sjogren?

A

rheumatoid arhtrits

105
Q

What is most likely present if a pt with Sjogren presents with a unilateral enlargement of parotid late in disease course?

A

B-cell lymphoma

106
Q

What is Scleroderma?

A

autoimune tissue damage with activation of fibroblasts and deposition of collagen (fibrosis) that is divided into diffuse and localized types

107
Q

How does diffuse scleroderma present?

A

skin and early visceral involvement, most often involves esophagus resulting in disordered motility and dysphagia

108
Q

What are the markers for diffuse scleroderma?

A

ANA and anti-DNA topoisomerase I (Scl-70) Ab

109
Q

What are the clinical features of the localized scleroderma type?

A 
CREST
Calcinosis/anti-Centromere Abs
Raynaud phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasias of skin
110
Q

What is the marker for localized scleroderma?

A

anti-Centromere Abs

111
Q

What is mixed connective tissue disease?

A

autoimmune-mediated tissue damage with mixed features of SLE, systemic sclerosis, and polymyositis

112
Q

What is the the marker associated with mixed connective tissue disease?

A

U1 ribonucleoprotein

113
Q

How does healing occur?

A

combo of regeneration and repair

114
Q

What is regeneration dependent on?

A

regenerative capacity

115
Q

What are 3 types of labile tissues?

A
  • small and large bowels (stem cells in mucosal crypts)
  • skin (stem cells in basal layer)
  • bone marrow (hematopoietic stem cells- CD34+)

*continuously cycle to regenerate tissue

116
Q

What are stable tissues and what is a classic example?

A
  • stable tissues are quiescent, but can reenter cell cycle
  • liver: liver can regeneratve by compensatory hyperplasia after partial resection
  • each hepatocyte produces additional cells and then reenters quiescence

*PCT of kidney is also an example

117
Q

What are 3 examples of permanent tissue?

A

myocardium, skeletal muscle, and neurons

118
Q

How do permanent tissues heal?

A

repair: replaces damaged tissue with fibrous scar

- occurs when regenerative stem cells are lost or when tissues lack regenerative capacity

119
Q

Why do you see a scar with deep cuts to the skin?

A

regenerative stem cells of skin have been loss so only repair can occur

120
Q

What is the initial phase of repair?

A

granulation tissue

121
Q

What are the three components of granulation tissue?

A

1) granulation tissue: deposit type III collagen
2) capillaries: provide nutrients
3) myofibroblasts: contract wound

122
Q

What is the final result of granulation tissue?

A

Scar: Type III collagen is replaced with Type I collagen

123
Q

Where is Type I collagen most common?

A

bONE

124
Q

where is Type ii collagen most common?

A

car2lige

125
Q

Where is Type III collagen most common?

A

pliable tissue: blood vessels, granulation tissues, embryonic tissue

126
Q

Where is Type IV collagen most common?

A

basement membrane

127
Q

What removes type III collagen?

A

collagenase which requires zinc as a cofactor

128
Q

What is an epithelial and fibroblast growth factor?

A

TGF-a

129
Q

What is an important fibroblast growth factor that inhibits inflammation?

A

TGF-B

130
Q

What is an endothelium, smooth muscle, and fibroblast growth factor?

A

PDGF

131
Q

What growth factor is involved in angiogenesis and skeletal development?

A

FGF

132
Q

What growth factor is involved in angiogenesis only?

A

VEGF

133
Q

What is cutaneous healing by primary intention?

A

wound edges are brought together with minimal scar formation

134
Q

What is the cutaneous healing by secondary intention?

A

edges are not approximated so granulation tissue fills in the defect

135
Q

What is responsible for reducing size of wound?

A

myofibroblast - have ability to contract wounds

136
Q

What is the m ost common cause of delayed wound healing?

A

infection

137
Q

What deficiencies can lead to delayed wound healing?

A

Vitamin C (hydroxylation), copper (lysyl oxidase), or zinc deficiency (required by collagenase)

138
Q

What is the function of Vitamin C?

A

hydroxylation of proline and lysine residues to allow for proper crosslinking in collagen molecules

139
Q

When is dehiscence most commonly seen?

A

rupture of a wound - most common after abdominal surgery

140
Q

What is hypertrophic scar?

A

excess production of type 1 collagen

141
Q

What is a keloid?

A

excess production of scar tissue out of proportion of the wound composed of type III collagen
-genetic predisposition in African Americans and commonly seen on earlobes

High Yield Pathoma (4 decks)

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