Tissue Repair & Chronic Inflammation Flashcards
0
Q
What type of injury does a scar become produced from
A
Prolonged and severe injury
1
Q
Briefly explain scarring
A
Damage to connective tissue & intra cellular matrix which holds the tissue together and comes from a more prolonged and severe injury
2
Q
What is normal homeostasis
A
A balance of proliferation and apoptosis
3
Q
When an injury occurs, which two routes can a cell take
A
- regeneration
Or - repair
4
Q
Which further two routes can a cell take other than regeneration
A
- renewing tissues
Or - stable tissues
5
Q
What happens to renewing tissues
A
Complete regeneration:
Epidermis, GI tract epithelium, hematopoletic system
6
Q
What happens to stable tissues
A
Compensatory growth of eg liver and kidney
7
Q
Which further two routes can a cell take other than repair
A
- wound
Or - chronic inflammation
8
Q
What happens to a tissue which forms a wound
A
Wound healing and scar formation (cannot compensate for injury)
9
Q
What happens to a tissue during chronic inflammation
A
Fibrosis
10
Q
Why would a tissue be unable to repair
A
If the injury persists and has to do with the type of injury, how severe it is and the time course of the injury
11
Q
What happens to the tissue if the injury is mild
A
Tissue can heal without scarring as the scaffolding and connective tissue of cells remains intact
12
Q
What happens to a cells which are unable to regenerate fully
A
Scarring
if injury persists eg from liver damage due to drinking
13
Q
What type of cells are labile cells
A
Cells which divide and proliferate throughout life
14
Q
What are labile cells derived from
A
Adult stem cells
15
Q
What type of cells have a set life span
A
Labile cells
16
Q
Give examples of labile cells
A
- Gut epithelium
- Corneal epithelium
- Blood cells
17
Q
What example of cell is able to regrow and replenish at a mitotic rate
A
Epithelial cells
18
Q
What is the name of corneal stem cells
A
Palisades of Vogt
19
Q
What do palisades of Vogt do
A
Power our corneal stem cells and produce continual supply of corneal epithelial cells
20
Q
Where are labile cells found within the cornea
A
Around the limbus
21
Q
What do stable cells do
A
Usually divide slowly but if damaged can increase rate of cell division so can get tissue repair
22
Q
Name examples of stable cells (can heal and grow but don’t usually turn over)
A
Hepatocytes eg liver Fibroblasts Vascular endothelial cells Smooth muscle cells Osteoblasts eg when bones break Renal tubular epithelial cells eg kidney
23
Q
Where can pockets of stem cells which have the same effect of epithelial stem cells (to replenish) be found within the body
A
Gut & skin
24
What are permanent cells
Cells that cannot divide but may be capable of some cellular repair if the nucleus and Golgi are not impaired
25
Name examples of permanent cells
Neurons in retina (cannot get new cells to grow so if they're gone they're gone)
&
Cardiac myocytes
26
What needs to be initiated in order for cell growth and replenishment
The growth cycle
27
What is the growth cycle
To switch the cell on to divide and multiply
28
What can the growth cycle be done by
Particular signalling molecules eg growth factors
Or
Integrin signalling pathways
Can switch on mitotic pathway to replenish cells which have been killed
29
What do growth factors/chemical switches regulate
Cell proliferation
30
What are the three types of growth factors
Autocrine
Paracrine
Hormones
31
Explain the autocrine growth factor
Self signalling
| Comes from the cell and binds to the receptor which initiates cell division
32
Explain the paracrine growth factor
Comes from damaged cell
| Sends signals to adjacent cell telling them to divide and replace them
33
Explain the hormone growth factor
Signals to distant tissue to repair parts of the body such as muscle or bone peripheral tissue
Eg growth hormone
34
Where are receptors for signal transduction found
On the cell
35
Name three types of receptors for signalling transduction
1. Intrinsic kinase activity
2. G-protein coupled receptors
3. Receptors lacking intrinsic kinase activity
36
What is intrinsic kinase activity
Growth factors which bind to the receptor and activate kinases
37
Give examples of intrinsic kinase activity growth factors
PI3-kinase
Mitogenic activated protein kinase (MAP)
PLC-y
38
What do kinases do
Activate transcription factors that regulate the cell cycle
| ie phosphorelation & dephosphorelation coupling switches receptors on & off
39
Give examples of G protein coupled receptors
```
Serotonin
Vasopressin
Histamine (activated by G protein & increases vasodilation)
Glucagon
Corticotrophin
```
40
As part of the G protein coupled receptors, what is cAMP and calcium important for
Tight junction formation
Ion channels
Transcription factors
41
Give examples of receptors lacking intrinsic kinase activity
Interleukins
Interferons
Growth hormones
Prolactin
42
What do receptors lacking intrinsic kinase activity activate
JAK (Janus kinase family) activate transcription factors that shuttle to the nucleus
43
Receptors lacking intrinsic kinase activity don't rely on...
Phosphorylation and dephosphorylation coupling eg MAP kinase
44
What does mitogenic protein activated kinase use to activate mitosis
Phosphorylation
45
What happens in the IP3 pathway
IP3 binds to the IP3 receptor in the endoplasmic reticulum
Which increases intracellular calcium
Intracellular calcium effects transcription and translation as well as fluid transport
And activates calcium getting chloride channels
Cells under stress are swollen so it gets rid of fluid
46
What does the MAP kinase pathway activate
Transcription and translation
47
What does the JAK/STAT pathway regulate
Growth initiation
48
What are cyclic amp and what do they affect
Families of G proteins
| Which also affect transcription and translation
49
What are G protein coupled receptors found in
Rod outer segments eg rhodopsin and cyclic Gmp
50
List the properties of extra cellular matrix & cell matrix interactions
- mechanical support & anchorage for cell migration (needs collagen or fibrin to hold on to to move along)
- control cell growth through intergrin cellular receptors
- maintain cell differentiation via intergrin receptors
- scaffold for tissue renewal which requires as basement membrane if BM damaged results in a scar
- establishes tissue micro environment (barrier)
- storage & regulation of growth factors for rapid deployment is EGF, FGF
51
What is the extra cellular matrix important for
Cell stability and vitality
52
What do we get if the extra cellular matrix breaks
Scarring
53
What does the integrin cellular receptors integrate between
Cell membrane and its basement membrane of its partner
54
What does the maintenance of cell differentiation via intergrin receptors go into
Another cell type
If you take a cell away from its environment it will differentiate into some other cell type eg fibroblasts or immature cells
55
What happens to the cell without scaffolding
No tissue repair or renewal
56
If JAKs doesn't rely on phosphorylation, what do they respond to
Cytokines
Which regulates growth differentiation and cell movement where all the receptors help to increase cell tight junctions, divide and become motile which increases fluid permeability etc
57
What happens to cells which are moved away from their micro environment eg removed from their basement membrane
Dedifferentiate and can't maintain their identity
58
What happens to an RPE cell which has been moved from its micro environment
Lacks micro villi
Lacks differentiation
No regularity
No hexagonal shape
59
What are proteoglycans important for
Signalling proteins for cell differentiation
60
Name some examples of basement membranes
Type 4 collagen
Laminin
Proteoglycan
61
What do integrin receptors do
Anchor the cell down to eg collagen fibres to maintain cell communication and differentiation
62
What do integrins interconnect with in generic tissues
The basement membrane
Also
With the cellular matrix and fibroblasts
63
What do proteoglycans form
Extracellular matrix
64
What are proteoglycans attached by to connect with fibroblasts
Integrins
65
What is the interstitial matrix composed of
Fibrillar collagens
Elastin
Proteoglycan and
Hyaluronan
66
Describe the connection between integrin receptors to a cell nucleus
Direct lines like spiders webs with cytoskeletal attachments to the cell nucleus
67
What is the significance of intergrin receptors connecting to the cell nucleus via cytoskeletal attachments
If there's disruption to intergrin receptors, the signal will go to the cytoskeletal attachments
68
Why do integrin receptors attach to the cytoskeletal attachments
So there's a physical communication between the extra cellular environment and integrin receptors to the cell nucleus, which maintains differentiation and protein attachment, migration and form of the cell
69
What does damage to the extracellular matrix release
bFGF
70
Which two things do heparin sulfate bind together
Fibroblast growth factor to FGF receptor
71
Name one thing the extra cellular matrix contains which is readily accessible incase of damage
Growth factors
72
Describe what happens if there has been damage to the extracellular matrix
We get free fibroblast growth factors floating around which signals to the cell that the extracellular matrix has been damaged, so it needs to create more fibroblasts (which locks things down with heparin sulfate complex bFGF) so when it's smashed FGF is exposed and without heparin sulfate can signal to the cell nucleus to say the extracellular matrix has been damaged
73
Which two responses occur after an injury
Cellular and vascular
74
What two things can happen following a cellular and vascular response from and injury
Acute injury (stimulus removed)
Or
Persistent tissue damage
75
Which two routes can a cell take following acute injury (stimulus removed)
Either
1. Parenchymal cell death - intact tissue framework ie superficial wounds and some inflammatory processes
2. Parenchymal cell death - damaged tissue framework ie deep wounds to proteoglycans and collagen
76
What happens as a result of parenchymal cell death - intact tissue framework
Regeneration (restitution of normal structure)
if matrix is intact (labile/stable tissue) eg liver regeneration after partial hepatectomy, superficial skin wounds, resorption of exudate in lobar pneumonia
77
What happens as a result of parenchymal cell death - damaged tissue framework
Repair ie scar formation
| Eg deep excisional wounds, myocardial infarction
78
What is persistent tissue damage
An ongoing infection or auto immune change or ongoing ingestion of toxic particles ie chronic inflammation = fibrosis tissue scar
79
What happens as a result of persistent tissue damage
Fibrosis ie tissue scar eg chronic inflammatory diseases (cirrhosis, chronic pancreatitis, pulmonary fibrosis)
80
List the actions of a macrophage
1. Debridement removal of injured tissue & debris
2. Anti microbial activity
3. Chemotaxis and proliferation of fibroblasts and keratinocytes
4. Angiogenesis
5. Deposition and remodelling of ECM
81
Give examples of debridement removal of injured tissue and debris
- phagocytosis of dead/necrotic tissue
- collagenase
- elastin (both help to break down & mush up area)
82
Give examples of antimicrobial activity
- nitric acid
| - ROS (generate reactive oxygen species & o3)
83
Give examples of chemotaxis and proliferation of fibroblasts and keratinocytes
- PDGF
- TGF-b
- TNF
- IL-1
- KGF-7
(Release growth factors to bring fibroblasts to the area to help with wound healing especially TNF/tumour necrosis factor which is important for signalling to fibroblasts)
84
Give examples of deposition and remodelling of ECM
- TGF-b
- PDGF
- TNF
- OPN
- IL-1 (clearing away debris from basement membrane, so involved in remodelling & rebuilding the area & clearing it up)
- collagenase
- MMPs (rebuilding area)
85
What occurs from 0-6 days after wounding
Inflammation (initial phase)
- clot formation
- chemotaxis (brings macrophages)
86
What occurs from 6-12 days after wounding
Proliferation (macrophages go on to proliferation of fibroblasts)
- re-epilelialisation (new blood vessels grow)
- angiogenesis and granulation tissue
- provisional matrix (extracellular)
87
What occurs 12-16 days after wounding
```
Maturation (scar formation)
- collagen deposition
- collagen matrix
- wound contraction
In maturation, overtime granulation dissolves which results in more permanent damage to tissue and healing leads to maturation
```
88
What happens as inflammation and wound healing begin together
1. Increased neutrophils- bacterial killing and clearing of damaged tissues
2. Increased macrophages - wound healing - growth factors
- EGF - epidermal growth factor (released for epithelial growth)
- FGF - fibroblast growth factor (is increased)
- TGF - transforming growth factor (helps differentiation, transforms cell type from one to the other)
89
What happens during tissue repair
1. Acute inflammation
2. Angiogenesis
3. Migration and proliferation of fibroblasts
4. Scar formation
5. Remodelling of connective tissue
90
why does angiogenesis occur
- the wound edge is ischaemic
the usual vascular architecture is damaged
- thus the healing process cannot proceed without a sufficient blood flow
- macrophages secrete angiogenesis factor
VEGF = vascular endothelial growth factor
91
give example of eye diseases where VEGF is involved
- ARMD - produces new blood vessels in wet form
| - diabetic retinopathy
92
when does angiogenesis being during tissue repair
in the first few days
93
how does angiogenesis work
- endothelial cells proliferate to form capillary buds at the wound surface
- buds form loops which eventually fuse to form a new capillary bed
94
when can angiogenesis be delayed
if there is vascular disease (e.g. diabetes), necrosis or steroid therapy
95
what do macrophages form if you get a cut
new VEGF (angiogenesis from pre-existing vessels)
96
what do new VEGFs cause
new blood vessels to grow, sprouting off the broken one
| ie ischaemic signals to grow new blood vessels producing a mature network
97
what are the blood vessels of the immature network like
leaky
98
what do the leaky blood vessels form
a bruise
99
why do the leaky blood vessels form a bruise
they are not well formed and are immature, pooling of blood from leaky vessels
100
what are EPCs
endothelial precursor cells
| flow around in the blood and circulate around the body
101
what are EPCs derived from
stem cells of bone marrow
102
what do EPCs do
find a leak, and will initiate angiogenesis, if they bump into an area of breakage or leakage, they will bud & form capillaries called angiogenesis
103
what does fibroblast proliferation do
rebuilds scaffolding to enable epithelial cells and endothelial cells to migrate and regrow to new tissue
104
what can fibroblast proliferation lay down
collagen, fibrin, fibronectin
| and have actin myosin contractile components so acts as a glue to help repair our wound
105
when does fibroblast proliferation begin after wound
2 days
106
what do cells migrate from during fibroblast proliferation
from neighbouring connective tissue
107
during fibroblast proliferation, what do growth factors from macrophages and platelets stimulate
collagen production by fibroblasts and proteoglycans
108
what do fibroblasts form
granulation tissue
109
what is granulation tissue the area of
area of scarring
| with fibrosis and soft tissue made up of fibroblasts & macrophages & proteoglycans i.e. a spongy tissue
110
what does fibroblast proliferation depend on
the vascular supply and having nutrients such as collagen, zinc, copper to that area to sustain proliferation and synthesis of basement membrane (e.g. need to produce their own membrane and scaffold)
111
what do fibroblasts which have formed their granulation tissue consist of
new blood vessels and proliferating fibroblasts
112
what does leaky, high permeable granulation tissue end up to be
scar tissue
113
what do a lot more blood vessels =
angiogenesis packed full of arithrocytes
114
what is the connective tissue formation the synthesis of
collagen by fibroblasts
115
what does connective tissue formation require
nutrients - blood supply
116
which nutrients does the connective tissue require during formation
amino acids
zinc copper iron
vitamin A & E
117
what is the interstitial matrix synthesis produced by
fibroblasts
118
what is the interstitial matrix made out of
granulation tissue
119
what does the interstitial matrix affect
the architecture and strength of collagen fibres
120
what is secreted during interstitial matrix synthesis
proteoglycans (GAGS + protein core)
121
what do the secreted proteoglycans (GAGS & protein core) bind to during interstitial matrix synthesis
collagen fibres, to form a rigid scar as proteoglycan content decreases (ie amount of proteoglycans decrease with more collagen in the area)
122
what happens when the amount of proteoglycans decreases with more collagen in the area
start to get contractions of fibres in the fibroblasts which pull the wound together
123
during epithelialisation, what is in constant renewal
the squamous stratified epithelium
124
what happens to the epithelial cells from adjacent basement membranes during epithelialisation
detach divide and migrate across the wound
125
what won't epithelial cells form without
a basement membrane
126
what do the epithelial cells form when formed via adjacent membranes during epithelialisation
form a monolayer of epithelial cells
127
what initiates the response of epithelialisation
epithelial growth factor (EGF), derived from macrophages platelets initiate the response
128
what happens following epithelialisation
wound contraction
129
what happens during wound contraction
movement of wound edges towards the centre
130
what does wound contraction occur through
generation of forces in the contractile elements of the fibroblasts towards the centre of the wound
131
what happens as the wound contracts during wound contraction
collagen and proteoglycans are secreted that lock the new tissue in place
132
what aligns near the wound during wound contraction
fibroblasts
133
what is wound remodelling also known as
scar maturation
134
when does wound remodelling occur
> 3 weeks after injury
| can persist for months to years
135
what does increased collagen cross linking = during wound remodelling
increased strength
136
what is wound remodelling a regression of
surface capillary network
137
what is decreased during wound remodelling
proteoglycan content and thus water content
138
briefly list the stages of wound healing e.g. form a burn
- epithelium is removed from burn
- bruised area = leaky blood vessels
- which are replaced by proteoglycans and new blood vessels are grown
- keratin on the skin forms a scar
139
what is chronic inflammation
ongoing inflammation with attempts of wound healing or
| unregulated injury/repair in a perpetual cycle
140
list the outcomes of acute inflammation
1. resolution
2. healing by connective tissue replacement (is damaged)
3. progression to chronic inflammation (ongoing healing)
141
how long can chronic inflammation go on for
weeks, months, years
142
what steps does the tissue go through with chronic inflammation
- repair
- inflammation
- injury (ongoing)
all co-exist
143
what are the causes of chronic inflammation
- persistent infections
- immune mediated
- prolonged exposure to toxin
144
give examples of persistent infections which cause chronic inflammation
viral
| fungal
145
give examples of immune mediated causes of chronic inflammation
- autoimmune disease e.g. MS, RA, SLE
| - unregulated immune response to antigen e.g. environmental (asthma), bacterial (IBS)
146
what is IBS caused from
bugs in the gut of chronic inflammation & scarring
147
give examples of prolonged exposure to toxin as causes of chronic inflammation
- exogenous - silica, asbestosis
| - endogenous - atherosclerosis/lipids
148
what is atherosclerosis
hypertension - chronic inflammation of arterial walls
149
list the morphologic features of chronic inflammation
- infiltration
- tissue destruction
- attempts at healing
150
what are the morphologic features of infiltration during chronic inflammation
macrophages/lymphocytes (T-B)/plasma cells (Ab)
151
what is tissue destruction induced by of morphological features during chronic inflammation
persistent offending agent or by the inflammatory cells
152
what are the attempts at healing of morphological features during chronic inflammation
- connective tissue replacement
- angiogenesis
- fibrosis
153
what does chronic =
changes to tissues which causes damage
154
what are chronic inflammatory cells
- macrophages/lymphocytes/plasma cells
155
what forms constellation to tissues
T & B cells
156
what are the names of macrophages which have formed from stem cells in the bone marrow
monoblasts
157
what are the name of macrophages in the blood
monocyte
158
what are the name of macrophages in the tissues
macrophage
159
what is the name of macrophages in the CNS
microglia
160
what is the name of macrophages in the liver
kupffer cells
161
what are the name of macrophages in the lungs
alveolar macrophages
162
what are the name of macrophages in the bone
osteoclasts
163
what role does M1 macrophages have
a destructive role which releases cytokines and interleukins to damage the tissue and cause inflammation, M1 cells are associated with
- reactive oxygen and nitrogen species
- proteases
- cytokines, including cheekiness
- coagulation factors
- AA metabolites
164
what are M1 cells inhibited by
interleukin 4 & 13
165
what is a pale macrophage
an activated macrophage where the DNA is coiled
166
what are M2 macrophages involved in
```
reduce inflammatory cytokines
involved in repair and
making epithelial cells grow
- growth factors (PDGF, FGF, TGFbeta)
- fibrogenic cytokines
- angiogenic factors (FGF)
- remodelling collagenases
```
167
what is the two varieties of macrophages M1 and M2 for
balancing wound healing
168
what are macrophages activated by
T-cells
169
what are activated via macrophages
cytokines (IL-40
170
what do macrophages persist in
chronic inflammation
171
what do macrophages continue through tissue repair
tissue injury and fibrosis
172
what are the other cells apart from macrophages, in chronic inflammation
lymphocytes: T & B cells
173
what do macrophages attract
lymphocytes (IL 12 or present antigen)
174
what do T-cells recruit
monocytes/macrophages (TNF-IL17)
175
what happens to the reaction when T cells are involved
reaction becomes chronic/severe
176
why does the reaction become more severe when T cells are involved
as T cells and macrophages co-stimulate each other
