Ch. 2 - Inflammation, Inflammatory Disorders, and Wound Healing Flashcards
(141 cards)
1
Q
What is characterized by acute inflammation?
A
edema and neutrophils
2
Q
What are the two stimuli that stimulate inflammation?
A
infection or tissue necrosis
-goal is to eliminate pathogen or clear necrotic debris
3
Q
When do neutrophils normally arrive in inflammation?
A
within 24h - immediate response with limited speficity
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
5
Q
What TLR on macrophages recognizes the PAMP LPS on gram negative bacteria?
A
CD14
6
Q
What does TLR activation upregulate?
A
NF-kB - TF that activates immune mediators
7
Q
What are the derivatives of arachidonic acid and what releases it from cells?
A
AA –> phospholipase A –> COX or 5-lipoxygenase
8
Q
What are the products of COX?
A
PGI2, PGD2, and PGE2 which mediate vasodilation and vascular permeability
-PGE2 also mediates pain
9
Q
Where do vasodilation and vascular permeability occur?
A
vasodilation: arterioles
vascular permeability: post-venule capillary
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
11
Q
What are the 4 molecules that attract and activate neutrophils?
A
LTB4, C5a, IL-8, bacterial products
12
Q
How do LTB4, D4, and E4 exert their functions?
A
they cause contraction of smooth muscle
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
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
15
Q
What is the delayed response of mast cells?
A
production of arachidonic acid metabolites, particularly leukotrienes
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
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
18
Q
What is Hageman factor?
A
-inflammatory proinflammatory protein produced in the liver that is activated upon exposure to subendothelial or tissue collagen
19
Q
What pathologic process does Hageman factor play a large role in?
A
gram negative sepsis and DIC
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)
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
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
23
Q
What is the mechanism that mediates pain?
A
bradykinin and PGE2 sensitizes sensory nerve endings
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
25
What are the three phases of acute inflammation?
1) fluid phase
2) neutrophil phase ~24h
3) macrophage phase ~2-3d
26
What happens to heavy particles during vasodilation?
heavy particles moves to the periphery - margination
27
Describe step 1 - margination.
vasodilation slows blood flow in the postcapillary venules (same place as fluid)
-cells marginate from center of flow to periphery
28
Describe step 2 - rolling.
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
29
Describe step 3 - adhesion.
- 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
30
What is leukocyte adhesion deficiency?
autosomal recessive defect of integrins (CD18)
31
What are the clinical findings of leukocyte adhesion deficiency?
- delayed separation of umbilical cord
- increased circulating neutrophils
- recurrent bacterial infection that lack pus formation
32
Why do you see increased circulating neutrophils in LAD?
neutrophils are unable to tightly adhere to cell adhesion molecules in the margination pool, so they fall into the blood vessels more easily
33
Describe step 4 - transmigration and chemotaxis.
- leukocytes transmigrate across endothelium of postcapillary venules and move toward chemical attractants (chemotaxis(
- neutrophils are attracted by IL-8, LTB4, C5a, and bacterial products
34
Describe step 5 - phagocytosis.
- 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
35
What is defective in Chediak-Higashi syndrome?
- autosomal recessive protein trafficking defect charcterized by impaired phagolysosome formation
- it is a microtubule defect that can't fuse phagosome and lysosome
36
What are the clinical features of Chediak-Higashi?
- increased risk of pyogenic infections
- neutropenia
- giant granules in leukocytes
- defective primary hemostasis
- albinism
- peripheral neuropathy
37
What are the 2 types of step 6 - destruction of phagocytosed material?
1) O2-depending killing (most effective)
| 2) O2-independent killing
38
What is the mechanism of O-2 dependent killing?
HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes
- O2 --> O2*- via NADPH oxidase
- O2*- --> H2O2 via SOD
- H2O2--> HOCl via MPO
39
What is defective in Chronic Granulomatous Disease?
-poor O2-dependent killing d/t NADPH oxidase defect (XLR or AR)
-
40
What type of organisms are pts with CGD most susceptible to and why?
- 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
41
What are 5 important catalase-positive bacteria that CGD pts are susceptible to?
1. S. aureus
2. P. cepacia
3. S. marcescens
4. Nocardia
5. Aspergillus
42
How is the nitroblue tetrazolium test used in CGD?
- it tests the ability of O2--> O2*- via NADPH
| - it will turn blue in normal pts, but will remain colorless in CGD
43
What is defective in MPO deficiency and how does it present clinically?
- results in defective conversion of H2O2 to HOCl
- pts are at increased risk for candida infections, but most are asymptomatic
- NBT test is normal
44
How does O2-independent killing work?
-occurs via enzymes present in leukocyte secondary granules (i.e. lysozome and major basic protein)
45
Describe step 7 - resolution.
-neutrophils undergo apoptosis and disappear within 24h after resolution of inflammatory stimulus
46
What are macrophages derived from?
monocytes in the blood
47
What is the mechanism of macrophage killing?
destroy phagocytosed material using enzymes in secondary granules, i.e. lysozome
48
What are the major functions of macrophages?
* 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
49
How will lymphocytes appear in chronic inflammation?
mononuclear cells
50
How will plasma cells appear in chronic inflammation?
cells with nuclei pushed to the periphery
51
What are stimuli for chronic inflammation?
- persistent infection (most common)
- infection with viruses, mycobacteria, parasites, and fungi
- autoimmune disease
- foreign material
- some cancers
52
Where are T cells produced?
bone marrow
53
Where are T cells developed?
thymus
54
What does T cell activation require?
1) binding of antigen/MHC complex
| 2) additional 2nd signal
55
What is the first activation signal for T cells?
Extracellular antigen is phagocytosed, processed, and presented via MHC II (APCs)
56
What is the second activation signal for T cells?
B7 on APC binds CD28 on CD4+ T cells
| 28/7=4
57
What do Th1 cells activate?
- IL2: T-cell growth factor and CD8+ T cell activator
- IFN-g: macrophage activator
* helps CD8+ T cells
58
What do Th2 cells activate?
- 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
How are CD8+ T cells activated?
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
What is the key enzyme that activates apoptosis?
caspases
61
How does cytotoxic killing occur?
- secretion of perforins and granzymes that induce apoptosis of the target cell
- expression of FasL, binds Fas on target cells, activating apoptosis
62
What is the first signal for B-cell activation?
B-cell antigen presentation to CD4+ helper T cells via MHC II
63
What is the second signal for B-cell activation?
CD40 receptor on B cell binds CD40L on helper T cell
64
What is the result of B cell activation?
IL-4 and IL-5: B-cell istoype switching, hypermutation, and plasma cell maturation
65
What is the key characteristic of a granuloma?
epithelioid histiocytes: macrophages with abundant pink cytoplasm
66
What surrounds granulomas?
giant cells and a rim of lymphocytes
67
How are noncaseating granulomas different from caseating granulomas?
they lack central necrosis
68
What are 5 examples of noncaseating granulomas?
reaction to foreign material, sarcoidosis, Beryllium exposure, Crohn disease, and cat scratch disease (stellate-shaped granuloma)
69
What is the histological hallmark of ulcerative colitis?
crypt abscess
70
What is the histologic hallmark of crohn disease?
noncaseating granuloma
71
What are the key differentials for caseating granulomas and what stains do you use for each?
TB and fungus
AFB: TB
GMS: fungus
72
What are the steps involved in granuloma formation?
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
What do macrophages secrete to induce CD4+ --> Th1?
IL-12
74
What do Th1 secrete to convert macrophages into epithelioid histiocytes and giant cells?
IFN-g
75
What is the genetic defect of DiGeorge syndrome?
d/t 22q11 microdeletion leading to developmental failure of 3rd and 4th pharyngeal pouch
76
What are the clinical findings of DiGeorge syndrome?
- T-cell deficiency (lack of thymus)
- hypocalcemia (lack of parathyroids)
- abnormalities of heart, great vessels, and face
77
What are the major etiologies of SCID?
- cytokine receptor defects
- adenosine deaminase deficiency****
- MHC class II deficiency
78
What are the clinical manifestations of SCID?
- susceptibility to fyngal, viral, bacterial, and protozoal infections including opportunistic infections and live vaccines
- Tx: sterile isolation and stem cell transplant
79
What is the defect in X-linked agammaglobulinemia?
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
What is the clinical manifestaton of X-linked agammaglobulinemia?
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
What is the defect in CVID?
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
Which 3 infections are X-linked agammaglobulinemia and CVID both at risk for?
bacterial, enterovirus, and Giardia
83
What are pts with IgA deficiency most at risk for?
mucosal infections, especially viral
| *most common
84
Which GI disease is most associated with IgA deficiency?
Celiac disease
85
What is the defect in hyper IgM syndrome?
```
d/t mutated CD40L or CD40 receptor (2nd signal)
-cytokines (IL-4 and IL-5) necessary for Ig class switching not produced
```
86
What are pts with hyper IgM syndrome most at risk for?
low IgA, IgG, and IgE result in recurrent pyogenic infections, especially at mucosal sites
87
Why are IgM levels high in hyper IgM syndrome?
because the first signal is intact (MHC II-CD4+ TCR)
88
What is the triad of Wiskott-Aldrich syndrome?
1) thrombocytopenia
2) eczema
3) recurrent infections
*d/t mutation in WASP protein
89
What is the presentation of C5-C9 complement deficiency?
increased risk for Neisseria infection
90
What is the presentation of C1 inhibitor deficiency?
hereditary angioedema characterized by edema of skin (especially periorbital) and mucosal surfaces
91
What type of hypersensitivity reactions are present in SLE?
Type II (cytotoxic) and Type III (antigen-antibody complex)
92
What is the most common feature of SLE?
renal damage - diffuse proliferative glomerulonephritis is the most common injury
93
What kind of endocarditis is present in SLE?
Libman-Sacks: vegetations on both side of the valve
94
What kind of blood disorders can SLE present with?
anemia, thrombocytopenia, or leukopenia
95
What are the most common causes of death in SLE?
renal failure and infections
96
What are the sensitive and specific markers for SLE?
sensitive: ANA
specific: anti-dsDNA
97
What marker is associated with drug-induced SLE?
antihistone Ab
98
What drugs are associated with SLE?
hydralazine, isoniazid, procainamide, and phenytoin (HIPP)
99
What is the clinical significane of antiphospholipid syndrome associated with SLE?
autoAbs against proteins boudn against phospholipids
- anticardiolipin: false VDRL
- lupus anticoagulant: falsely-elevated PTT (actually hypercoagulable)
100
What are the complications of antiphospholipid syndrome?
arterial and venous thrombosis
| DVT, hepatic v, thrombosis, placental thrombosis, and stroke
101
What is Sjogren syndrome?
autoimmune destruction of lacrimal and salivary glands d/t lymphocyte mediate (Type IV HSR) with fibrosis
102
What is the clinical presentation of Sjogren?
dry eyes, dry mouth, and recurrent dental caries in older woman
103
What is the marker for Sjogren syndrome?
anti-ribonucleoprotein antibodies
104
What other AI disease is most associated with Sjogren?
rheumatoid arhtrits
105
What is most likely present if a pt with Sjogren presents with a unilateral enlargement of parotid late in disease course?
B-cell lymphoma
106
What is Scleroderma?
autoimune tissue damage with activation of fibroblasts and deposition of collagen (fibrosis) that is divided into diffuse and localized types
107
How does diffuse scleroderma present?
skin and early visceral involvement, most often involves esophagus resulting in disordered motility and dysphagia
108
What are the markers for diffuse scleroderma?
ANA and anti-DNA topoisomerase I (Scl-70) Ab
109
What are the clinical features of the localized scleroderma type?
```
CREST
Calcinosis/anti-Centromere Abs
Raynaud phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasias of skin
```
110
What is the marker for localized scleroderma?
anti-Centromere Abs
111
What is mixed connective tissue disease?
autoimmune-mediated tissue damage with mixed features of SLE, systemic sclerosis, and polymyositis
112
What is the the marker associated with mixed connective tissue disease?
U1 ribonucleoprotein
113
How does healing occur?
combo of regeneration and repair
114
What is regeneration dependent on?
regenerative capacity
115
What are 3 types of labile tissues?
- 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
What are stable tissues and what is a classic example?
* 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
What are 3 examples of permanent tissue?
myocardium, skeletal muscle, and neurons
118
How do permanent tissues heal?
repair: replaces damaged tissue with fibrous scar
| - occurs when regenerative stem cells are lost or when tissues lack regenerative capacity
119
Why do you see a scar with deep cuts to the skin?
regenerative stem cells of skin have been loss so only repair can occur
120
What is the initial phase of repair?
granulation tissue
121
What are the three components of granulation tissue?
1) granulation tissue: deposit type III collagen
2) capillaries: provide nutrients
3) myofibroblasts: contract wound
122
What is the final result of granulation tissue?
Scar: Type III collagen is replaced with Type I collagen
123
Where is Type I collagen most common?
bONE
124
where is Type ii collagen most common?
car2lige
125
Where is Type III collagen most common?
pliable tissue: blood vessels, granulation tissues, embryonic tissue
126
Where is Type IV collagen most common?
basement membrane
127
What removes type III collagen?
collagenase which requires zinc as a cofactor
128
What is an epithelial and fibroblast growth factor?
TGF-a
129
What is an important fibroblast growth factor that inhibits inflammation?
TGF-B
130
What is an endothelium, smooth muscle, and fibroblast growth factor?
PDGF
131
What growth factor is involved in angiogenesis and skeletal development?
FGF
132
What growth factor is involved in angiogenesis only?
VEGF
133
What is cutaneous healing by primary intention?
wound edges are brought together with minimal scar formation
134
What is the cutaneous healing by secondary intention?
edges are not approximated so granulation tissue fills in the defect
135
What is responsible for reducing size of wound?
myofibroblast - have ability to contract wounds
136
What is the m ost common cause of delayed wound healing?
infection
137
What deficiencies can lead to delayed wound healing?
Vitamin C (hydroxylation), copper (lysyl oxidase), or zinc deficiency (required by collagenase)
138
What is the function of Vitamin C?
hydroxylation of proline and lysine residues to allow for proper crosslinking in collagen molecules
139
When is dehiscence most commonly seen?
rupture of a wound - most common after abdominal surgery
140
What is hypertrophic scar?
excess production of type 1 collagen
141
What is a keloid?
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
