Chapter 3: inflammation and repair Flashcards
1
Q
in acute respiratory distress syndrome which immune cells are most involved
A
neutrophils
2
Q
in asthma, which immune cells are most involved
A
Eosinophils, IgE ab
3
Q
in glomerulonephritis which immune cells are most involved
A
Ab and complement; neutrophils monocytes
4
Q
in septic shock which immune components are most involved
A
cytokines
5
Q
in arthritis which immune cells are most involved
A
lymphocytes macrophages; ab?
6
Q
in atherosclerosis which immune cells are most involved
A
macrophages; lymphocytes
7
Q
in pulmonary fibrosis which immune cells are most involved
A
macrophages; fibroblasts
8
Q
five R’s of inflammatory response
A
recognition recruitment removal regulation resolution
9
Q
cardinal signs of inflammation
A
rubor tumor calor dolor functio laesa (loss of fxn)
10
Q
what can trigger inflammatory responses
A
infection***
tissue necrosis
foreign bodies
immune reactions
11
Q
three major components of acute inflammation
A
dilation of small vessels –> increase flow, but slow (stasis)
increasaed dpermeability
emigration of leukocytes
12
Q
what is exudation
what is an exudate and what does it indicate
A
escape of fluid proteins and blood cells from vascular system into interstitial tissue or body cavities
exudate – high protein
indication of increased permeability triggered by some sort of injury and ongoing inflammatory rxn
13
Q
define exudate transudate edema pus
A
exudate - high protein
transudate - low protein
edema - excess fluid in interstitial tissue or serous cavity
pus - purulent exudate w/ neutrophils, debris of dead cells, microbes
14
Q
what induces increased vascular permeability
A
histamine
kinins
15
Q
key players in the steps of leukocyte recruitment rolling activation adhesion transmigration
A
rolling- selectins (P, E, L – on leukocytes)
activation - chemokines/cytokines – increase affinity of integrins (TNF?, IL-1?)
adhesion - integrins (ICAM-1, VCAM-1)
transmigration - PECAM-1 (CD31)
chemokines usually presented bound to proteoglycans
16
Q
what causes margination
A
in early inflammation, blood flow increases, but is slow (stasis)
wall shear stress dereases
more white blood cells assume positions closer to walls of endothelium
leads to rolling
17
Q
where does transmigration of leukocytes mainly occur
A
post capillary venules
18
Q
what is the main exogenous chemoattractant
A
N-formylmethionine (start codon for bacterial DNA)
19
Q
what are some endogenous chemoattractants (3)
A
cytokines
complement
arachidonic acid metabolites (LTB4)
all bind to specific GPCRs
20
Q
what is one of the most successful therapies for treating chronic inflammatory diseases
A
agents that block TNF
21
Q
steps of phagocytosis
A
recognition and attachment
engulfment
killing or degradation
22
Q
types of phagocytic receptors
ligand?
A
mannose-binding – mannose sugar on microbial cell walls
scavenger – usually acetylated LDL molecules
opsonin binding – c3b, IgG
23
Q
describe engulfment
A
after recognition, phagocyte’s pseudopodia surround the particle and pinches off part of its PM to form a phagosome
phagosomes fuse with lysosomes to form phagolysosomes
24
Q
where are ROS produced
A
within the lysosome/phagolysosome
25
what ROS do neutrophils utilize
myeloperoxidase (MPO)
26
which type of NOS is used in the killing of microbes
iNOS by M0 and N0
| activated by cytokines
27
effects of NO on cells
damages lipids, proteins, and nucleic acids of microbes and host cells
also relaxes vascular smooth m and promotes vasodilation
28
what two main types of granules do N0 have
```
smaller specific (secondary) granules
azurophil (primary) granules
```
primary includes the MPO
29
what regulates lysosomal enzymes
| what are some examples
antiproteases
a1-antitrypsin
a2-macroglobulin
30
what microbicidal granule content is utilized by eosinophils to combat multicell. ags
major basic protein
31
what are NETs
extracellular fibril network w/ high concentration of antimicrobial substances at sites of infection and prevent the spread of microbes by trapping them
produced by neutrophils
32
which T cells are most important in the contribution to acute inflammation
Th17
33
absence of effective Th17 responses can result in what
increased susceptibility to fungal and bacterial infections
| "cold abscesses"
34
in the termination of acute inflammatory responses, what occurs with active termination mechanism
switches arachidonic acid metabolite produced from proinflammatory leukotrienes (LTB4) to anti-inflammatory cytokines (TGF-b, IL-10)
35
most important mediators of acute inflammation
vasoactive amines, lipid products (prostaglandins and leukotrienes), cyto/chemokines, products of complement activation
36
examples of vasoactive amines (2)
histamine
serotonin
stored as preformed molecules in cells
among first to be released in inflammation
37
primary f(x) of serotonin as a vasoactive amine
vasoconstrictor in GI
38
arachidonic acid metabolites (2)
leukotrienes
| prostaglandins
39
what GPCR ligand can mediate virtually every step of inflammation
eicosanoids (leukotrienes and prostaglandins)
| lipoxins
40
actions of what enzymes generate prostaglandins
cyclooxygenases
| COX-1 and COX-2
41
which prostaglandins are involved in vasodilation?
| vasoconstriction?
dilation: prostacyclin, PGE1/2, PGD2
constriction: thromboxane A2 (TxA2)
42
which prostaglandin is a potent inhibitor of platelet aggregation
prostacyclin (PGI2)
43
leukotrienes are produced by the actions of which enzymes?
| what processes are they involved in
lipoxygenase
involved in vascular and smooth m reactions and leukocyte recruitment
44
which leukotriene is involved in chemotaxis and leukocyte adhesion
LTB4
45
what are the functions of LTC4, LTD4, LTE4
vasoconstriction, increased vascular permeability of venules, bronchospasm
46
f(x) of lipoxins
suppress inflammation by inhibiting the recruitment of leukocytes
47
what do platelets do in the process of lipoxin synthesis
convert intermediates created by neutrophils into lipoxins
48
which chemokine receptors act as coreceptors for HIV and thus are involved in binding and entry of the virus into cells
CXCR-4 and CCR-5
49
three main functions of complement
inflammation
opsonization and phagocytosis
cell lysis
50
of the inflammation mediators in the complement pathway, which is strongest
C3a>C5a>C4a
51
what is another function of C5a that will further increase inflammatory responses
activates lipoxygenase pathway of AA metabolism --> leukotrienes in N0 and monocytes
52
important regulatory proteins for the complement pathway
C1 INH - blocks C1 activation
DAF - prevents formation of C3 convertases (C4b2a, C3bBb)
CD59 - prevents formation of MAC
DAF and CD59 are linked by a glycophosphatidyl (GPI) anchor
53
hereditary angioedema
inherited deficiency of C1 INH
54
paroxysmal nocturnal hemoglobinuria
acquired deficiency of enzyme that creates GPI anchors btw DAF and CD59
55
functions of PAF
platelet aggregation
vasoconstriction bronchospasm
in low concentrations induces vasodilation and increased venular permeability
56
how are bradykinins produced
cleavage of kininogen by kallikrein
57
effects of bradykinin
increase vascular permeability, contraction of smooth m, vasodilation, pain when injected into the skin
58
morphologic patterns of acute inflammation and examples
serous inflammation - skin blister from burn
fibrous inflammation - fibrinous pericarditis
purulent inflammation - acute appendicitis/abscess
ulcers - bed sores
59
pyogenic definition
pus producing
60
most frequent cause of purulent inflammation
bacterial infections that cause liquefactive necrosis -- staph
61
most common sites to encounter ulcers
mucosa of mouth, stomach, intestines, or genitourinary tract
| skin and subQ tissue of LE in older pts w/ circulatory disturbances
62
ulcers definition
local defect or excavation of the surface of an organ or tissue that is produced by sloughing of inflamed necrotic tissue
63
acute stage of ulcer
polymorphonuclear infiltration and vascular dilation
64
chronic stage of ulcer
margin and base develop fibroblastic prolif, scarring, and accumulation of lymphocytes, m0, and plasma cells
65
outcomes of acute inflammation (3)
complete resolution
healing by CT replacement
chronic inflammation
66
when does scarring or fibrosis occur (3)
| outcome of acute inflammation
after substantial tissue destruction
when tissues injured are incapable of regen
abundant fibrin exudation in tissue or serous cavities that cannot be adequately cleared
67
what is organization
| scarring or fibrosis
CT growing into the area of damage or exudate and converting it into a mass of fibrous tissue
68
what accounts for the signs and symptoms of the inflammatory response
vascular and cellular reactions
69
causes of chronic inflammation (3)
persistent infections
hypersensitivity diseases
prolonged exposure to potentially toxic agents, endogenous or exogenous
70
morphologic features of chronic inflammation
infiltration with mononuclear cells - m0, lymphocytes, plasma cells
tissue destruction - induced by persistent offending agent or by inflammatory cells
attempts at healing - by CT replacement of damaged tissue, accomplished by angiogenesis and fibrosis
71
dominant cell type in most chronic inflammatory reaction
macrophages
72
specific macrophages
liver - kuppfer
spleen and LNs - sinus histiocytes
CNS - microglial
lungs - alveolar macrophages
73
where do macrophages develop from
bone marrow, fetal liver, yolk sac
74
half-life of tissue macrophage
several months or years
75
half-life of blood monocytes
~1 day
76
what stimulates classical macrophage activation
microbes, IFN-gamma
77
what do M1 macrophages produce
ROS, NO, inflammatory cytokines (1, 12, 23)
78
what stimulates alternatively activated macrophages
IL-4, IL-13
79
principal function of M2 macrophages
tissue repair
80
what do M2 macrophages produce
GFs, TGF-beta, IL-10
81
functions of macrophages in general (4)
phagocytose
tissue repair (scar formation and fibrosis)
secrete mediators of inflammation (TNF, IL-1, eicosanoids)
APC to T-cells and respond to signals from T-cells
82
what does each type of T-cell secrete
Th1 - IFN-gamma --> classical M0 activation
Th2 - IL-4, 5, 13 --> alternative M0 activation
Th17 - IL-17 --> N0 and monocyte recruitment
83
which T-cell helps in defense against helminths
Th2 --> IL-4, 5, 13 --> IgE and Eosinophil recruitment
84
which T-cells are involved in defense against virus/bacteria
Th1, Th17
85
what is responsible for granulomatous inflammation
T and B lymphocytes
86
what are tertiary lymph nodes
clusters of accumulated lymphocytes, APCs, and plasma cells
87
in which conditions can tertiary LNs be seen
some chronic inflammatory rxns
long-standing RA
hashimoto thyroiditis
88
which cell type binds to IgE in allergic responses
Mast cells
have FceRI
release histamine and prostaglandins
89
what is granuloma formation
a cellular attempt to contain an offending agent that is difficult to eradicate
90
what is a granulomatous inflammation
form of chronic inflammation characterized by collections of activated M0, often with T lymphocytes, and sometimes associated with central necrosis
91
what are epithelioid cells
activated M0s that develop abundant cytoplasm and begin to resemble epithelial cells (granulomatous inflammation)
92
what are giant cells
fused activated M0
| multinuclear
93
two types of granulomas
foreign body granuloma
| immune granuloma
94
foreign body granuloma
caused by foreign body
can form around talc (IVD use), sutures, other large fibers
do NOT produce inflammatory or immune response
95
immune granuloma
caused by variety of agents capable of inducing persistent T cell-mediated immune response
occurs with microbes particularly hard to kill
96
when looking at a granuloma, what is the first disease you need to rule out
TB
97
diseases with granulomatous inflammation
```
TB
leprosy
syphilis
cat-scratch disease
sarcoidosis
crohn disease - U.S!!
```
98
TB
```
caused by mycobacterium tuberculosis
caseating granuloma (tubercle)
```
99
leprosy
mycobacterium leprae
| noncaseating granuloma
100
Syphilis
treponema pallidum
| gumma: microscopic to grossly visible lesion, enclosing wall of histiocytes
101
cat-scratch disease
gram-negative bacillus
| rounded or stellate granuloma central granular debris and recognizable N0; giant cells uncommon
102
sarcoidosis
unknown etiology
| noncaseating granuloma w/ abundant activate M0
103
Crohn disease
immune reaction against intestinal bacteria, possibly self Ags
occasional noncaseating granulomas in the wall of the intestine, with dense chronic inflammatory infiltrate
104
important mediators of the acute-phase reaction
IL-1, IL-6, TNF
105
exogenous pyrogen
bacterial products (LPS)
106
endogenous pyrogens
IL-1, TNF --> increase COX --> increase in prostaglandins
107
what can stimulate the production of neurotransmitters that reset the temperature set point at a higher level
prostaglandins (PGE2)
108
how do NSAIDs (aspirin) reduce fever
inhibit production of prostaglandins
109
examples of acute-phase proteins (3)
C-reactive protein (CRP)
fibrinogen
serum amyloid A (SAA)
110
what is the basis for the erythrocyte sedimentation rate
fibrinogen binds to red cells and causes them to form stacks (rouleaux) that sediment more quickly than RBCs at unit gravity
111
what can cause secondary amyloidosis
prolonged production of acute-phase proteins (especially SAA) in states of chronic inflammation
112
how does CRP and SAA work
attaches to cell walls
| opsonize and fix complement
113
what should you think about if you see increased serum levels of CRP
increased risk of a MI in pts w/ coronary artery disease
114
what does chronically elevated levels of hepcidin do to the body
reduces amount of iron available
| responsible for anemia associated with chronic inflammation
115
what are leukemoid reactions
extreme elevations of leukocytes
116
what is important to distinguish from when a pt presents with a leukemoid reaction
leukemia
| blood counts are similar in both
117
what is leukocytosis
increased leukocyte count (--> 15,000 or 20,000; can get to 40,000-100,000)
118
initial source of elevated leukocytes in leukocytosis
bone marrow postmitotic reserve pool
| associated with rise of more immature neutrophils known as left shift
119
what is left shift
presence of more immature neutrophils responding to inflammatory events?
120
other manifestations of acute-phase response
increased P and BP
decreased sweating
```
rigors
chills
anorexia
somnolence
malaise
probably bc of actions of cytokines on the brain
```
121
clinical triad of septic shock
- disseminated intravascular coagulation
- hypotensive shock
- metabolic disturbances including insulin resistance and hyperglycemia
122
what happens in sepsis
production of enormous amounts of several cytokines (TNF and IL-1 most notably)
123
two reactions of repair
regeneration by proliferation of residual cells and maturation of tissue stem cells
deposition of CT to form a scar
124
what is it called if extensive deposition of collagen occurs in an area with inflammatory exudate
organization
125
what determines a tissue's ability to repair themselves
their intrinsic proliferative capacity
126
types of proliferative tissue (3)
labile - continuously dividing
stabile - quiescent; minimally proliferative
permanent - terminally differentiated; nonproliferative
127
what drives cell proliferation
growth factors and extracellular matrix signals
128
in terms of cell proliferation and repair, what is the f(x) of satellite cells
helps skeletal m regenerative ability
129
sources of the growth factors for cell proliferation
M0**** activated by tissue injury
epithelial
stromal cells
130
two major mechanisms of liver regeneration
proliferation of remaining hepatocytes
| repopulation from progenitor cells
131
what triggers hepatocyte proliferation in a regenerating liver
cytokines and polypeptide growth factors
132
stages of hepatocyte proliferation
| description
priming phase - IL-6 secreted mainly by kuppfer (resident M0) make hepatocytes more receptive to GFs
growth factor stage - HGF and TGF-alpha act on primed cells to mmove them out of G0 --> G1 (takes several hours bc hepatocytes are quiescent)
termination stage - cells return to their quiescent states
133
when is regeneration from progenitor cells the dominant form of liver regeneration
in times where liver hepatocyte proliferation capabilities are limited
ex. chronic liver injury
134
steps in scar formation
angiogenesis
formation of granulation tissue
remodeling of connective tissue
135
what growth factor drives angiogenesis
| what is its f(x)
VEGF -- formation of blood vessels from pre-existing vessels also increases vascular permeability
stimulates both migration and proliferation of endothelial cells -- initiating capillary sprouting
stimulates NO production
136
what is granulation tissue formed by
migration and proliferation of fibroblasts and deposition of loose CT together w/ vessels and interspersed leukocytes
appears in about 3-5 days
137
histological appearance of granulation tissue
characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries, in a loose CT matrix often w/ inflammatory cells, mainly M0
138
f(x) of FGFs
stimulates the proliferation of endothelial cells
139
f(x) of PDGF
recruitment of smooth m cells
140
f(x) of angiopoietins 1 and 2
ang1 interacts with TKRs on endothelial cells called Tie2
play role in angiogenesis and structural maturation of new vessels
recruitment of pericytes and smooth m cells
141
notch signaling
works w/ VEGF through cross-talk -- regulates sprouting and branching of new vessels and ensures that new vessels have enough spacing to effectively supply healing tissue w/ blood
142
2 steps to deposition of connective tissue
migration and proliferation of fibroblasts into the site of injury
deposition of ECM proteins produced by these cells
143
what orchestrates the deposition of CT
cytokines and GFs
| PDGF, FGF-2, TGF-beta
144
what is the most important cytokine for deposition of CT
TGF-beta
145
how is TGF-beta regulated
post-transcriptional activation
rate of secretion
factors in the ECM (integrins) that enhance or diminish TGF-beta activity
146
f(x)s of TGF-beta
stimulate fibroblastmigration and proliferation
increased synthesis of collagen and fibronectin
decreases degradation of ECM due to inhibition of MMPs
plays role in fibrosis in lung, liver and kidneys following chronic inflammation
anti-inflammatory cytokine
147
what contributes to the contraction of a scar over time
myofibroblasts
148
what influences the outcome of the repair process
balance between synthesis and degradation of ECM proteins
149
f(x) of MMPs
degradation of collagens and other ECM components
150
f(x) of TIMPs
during scar formation, shuts down MMPs
151
factors that influence tissue repair
```
infection
diabetes
nutritional status
glucocorticoids (steroids) - weakness in scar due to inhibition of TGF-beta production = decreased fibrosis (not always a bad thing - corneal infections)
mechanical factors
poor perfusion
foreign bodies
type and extent of injury - types of cells involved (stabile/labile/ permanent)
location of injury
```
152
when does healing by first intention occur
when injury involves only epithelial layer (ex. healing of clean uninfected surgical incision approximated by sutures)
153
three connected processes of healing by first intention
inflammation
proliferation
maturation
154
when does healing by second intention occur
with more extensive tissue or cell loss -- large wounds, abscesses, ischemic necrosis, ulcerations
155
healing by first intention vs second intention
| whats different about the mechanisms
first intention - epithelial regen
second intention - combo of regen and scarring; inflammatory rxn is more intense, abundant granulation tissue, accumulation of ECM, wound contraction (myofibroblasts)
156
what is an important feature of healing by secondary intention
wound contraction
157
what causes the recovery of tensile strength of a wound
result of excess of collagen synthesis over degradation during first two months of healing
later, from cross-linking and increased fiber size after collagen synthesis stops
158
in lung kidney and liver, what are the main source of collagen
lung and kidney - myofibroblasts
| liver - stellate cells (liver cirrhosis)
159
wound dehiscence and ulceration are complications that arise due to what
inadequate formation of granulation tissue or formation of a scar
occurs most frequently in abdominal surgery -- due to incrased abd pressure
160
what can give rise to hypertrophic scars and keloids
excessive formation of the components of the repair process
161
keloid definition
if scar tissue grows beyond the boundaries of the original wound and does not regress
more common in african-americans
162
what is proud flesh
extra granulation
must be removed by cautery or surgical excision to allow for continuity of epithelium
163
what is it called if exuberant granulation occurs after removal of proud flesh
desmoid or aggressive fibromatoses (low grade neoplasms that lie btw malignant and benign)
164
most likely areas for contracture to occur
palms, soles, anterior aspect of the thorax
| commonly seen after burns, can affect joint mobility
