Chronic Inflammation and Wound Healing 1 Flashcards
1
Q
what are the functions of the skin?
A
- protection
- temperature regulation
- Immunity
- Sensory receptors
2
Q
what is the superficial outer layer of the skin?
A
Epidermis
3
Q
what is the structure of the epidermis?
A
5 layers/strata of keratinocytes
4
Q
what cells are found in the epidermis?
A
Melanocytes
Langerhans cells
5
Q
what is the dermis?
A
deeper ‘true’ skin
6
Q
what is the structure of the dermis?
A
Papillary and reticular layers
7
Q
what cell types are found in the dermis?
A
fibroblasts, collagen, elastic and reticular fibres
8
Q
what are found in the dermis?
A
Nerve endings, hair follicles, glands, lymphatics, blood vessels
9
Q
what is found in the hypodermis?
A
adipose tissue, macrophages
10
Q
what is the main cell in the epidermis?
A
keratinocyte
11
Q
what separates the epidermis from the dermis?
A
a basement membrane
12
Q
what is the function of melanocytes in the basal layer?
A
transfer pigment into keratinocytes
13
Q
when do the cells of the epidermis become differentiated?
A
Cells become terminally differentiated as they move to surface [takes 2-4 weeks]
14
Q
what sort of tissue is the dermis?
A
Dense irregular connective tissue
15
Q
what affects skin integrity?
A
Age Nutrition Circulation Hormonal status hydration Environment Mobility Assault Disease processes Sensation
16
Q
what is a wound?
A
Alteration in skin’s integrity
17
Q
what can cause a wound?
A
Injury
Disease
Environmental assault
Surgery
18
Q
what does wound healing consist of?
A
Highly regulated & synchronised process of cell: Proliferation Differentiation Migration Angiogenesis Production of granulation tissue
19
Q
what granulation tissues are produced in wound healing?
A
fibroblasts, epithelial, endothelial, inflammatory cells
20
Q
what happens during wound healing?
A
Co-ordinated breakdown, synthesis & remodelling of ECM
21
Q
what are the phases of cutaneous wound healing?
A
Inflammatory Phase
Proliferative Phase
Remodelling Phase
22
Q
what happens in the inflammatory phase of wound healing?
A
Following injury, damage to local blood vessels leads to platelet aggregation & clot formation. This phase also sees recruitment of neutrophils & macrophages
23
Q
what happens in the proliferative phase of cutaneous wound healing?
A
During this phase granulation tissue is formed as fibroblasts proliferate & secrete collagen. Re-epithelialisation over new granulation tissue also occurs
24
Q
what happens in the remodelling phase of cutaneous wound healing?
A
This phase occurs over weeks to months as granulation tissue is replaced by a mature connective tissue scar
25
how does an acute wound heal?
An acute wound progresses through hemostasis, inflammation, repair and remodeling to replace provisional wound matrix with mature scar tissue
26
what regulates acute wound healing?
Cytokines, proteases and growth factors regulate these phases
27
what happens to cause a chronic wound?
sequential healing is interrupted
28
what happens during hemostasis?
```
Initial injury or trauma
Clot formation
Platelet activation
Platelet release of factors
Fibrin matrix
```
29
when does inflammation occur?
3-7 days after injury
30
what are the features of inflammation?
Rubor [redness]
Calor [heat]
Tumor [swelling]
Dolor [pain]
31
why does vasodilation occur during inflammation?
Neutrophil and macrophage influx
32
what is the first process in wound healing?
inflammation
33
what are the cells involved in inflammation?
```
leukocytes
Neutrophils
Monocytes
Macrophages
Lymphocytes
Mast cells
```
34
what are the inflammatory mediators?
```
Prostaglandins
Histamine
Interleukins
TNF alpha
Matrixmetalloproteases [MMPs]
```
35
what is the first cell to arrive at the site of inflammation?
neutrophils
36
what are the specialised functions of neutrophils?
phagocytosis and destruction of invading microorganisms particularly bacteria
37
what do the factors released by neutrophils in a clot do?
amplify aggregation response
initiate coagulation cascade
act as chemoattractants for cells
38
what activates the transmigration of neutrophils?
Activated by pro-inflammatory cytokines e.g. IL-1b TNF-a, IFN-g
39
where do neutrophils migrate to?
Neutrophils transmigrate across endothelium
40
what happens when Neutrophils transmigrate across endothelium?
Increased expression of adhesion molecules e.g. P-& E-selectins, ICAMs
41
what are macrophages?
professional phagocytes
42
what do macrophages do?
Remove senescent, dead and damaged cells
| Remove large microorganisms
43
how are macrophages formed?
Macrophages mature in the tissue from circulating monocytes
44
when do monocytes and macrophages appear?
within 2 days of injury
45
how is monocyte and macrophage infiltration regulated?
regulated by gradient of chemotactic GFs & pro-inflammatory cytokines secreted by platelets, keratinocytes, fibroblasts & leukocytes
46
what is the importance of GFs –TGF-b, TGF-a, bFGF, PDGF & VEGF ?
promote cell proliferation and ECM synthesis
47
what is the function of lymphocytes?
to enable adaptive or acquired immunity
48
what is the role of B-lymphocytes?
B lymphocytes remain in the bone marrow & secrete antibodies
49
what is the function of T lymphocytes?
T lymphocytes kill virus infected cells & regulate the activities of other white blood cells
50
what is the most frequent leukocyte in the remodelling phase?
T cells
51
what are chemokines important for?
lymphocyte chemotaxis & function
52
what is the role of mast cells in inflammation?
source of pro-inflammatory mediators and cytokines that promote inflammation and vascular changes important in tissue repair
Important cell in secretion of histamine
53
where are mast cells found?
within the connective tissue
54
what do mast cells rely on?
heavily on degranulation
55
what is degranulation?
secretion of stored vesicles/granules into the extracellular space
56
what is the purpose of degranulation?
Immune cells use this process to release signaling or effector molecules critical in wound healing
57
what cells are involved in proliferation?
fibroblasts
58
what do chemoattractants do?
Secrete EMC
Collagen
Elastin
Fibronectin
59
what is the role of the matrix scaffold?
Communication between fibroblasts & ECM
60
what happens in proliferation - angiogenesis?
```
Fragmentation of basement membrane
Migration of endothelial cells
Proliferation
Capillary tube formation
Granulation tissue
```
61
what happens in epithelialisation?
```
Detachment of basal keratinocytes
Migration
Proliferation
Differentiation
New epithelium has fewer basal cells, lacks rete pegs and more susceptible to malignant transformation
```
62
when does maturation and remodelling start?
commences when the wound is closed
63
when does maturation and remodelling end?
when scar is remodelled
64
how long can the maturation and remodelling phase last?
up to 2 years
65
what decreases after the remodelling phase?
cellularity
| vascularity
66
how much of the original tensile strength is left after remodelling?
80%
67
what happens during maturation and remodelling?
Collagen synthesis-lysis balance
Collagenases, proteolytic enzymes, metalloproteases [MMPs]
Maturation of collagen fibers by cross-linking
Increased tensile strength
68
what is granulation tissue replaced by during remodelling?
mature connective tissue
69
what is fibronectin and type 3 collagen replaced by during remodelling?
type 1 collagen
70
why do embryos heal without scarring?
high levels of TGF-b-3
71
what is the difference between an embryonic wound and an adult wound?
Adult wounds have low levels of TGF-b-3 and high levels of TGF-b-1 & TGF-b-2
whereas embryos have high levels of TGF-b-3
72
what are examples of excess degradation of ECM?
```
Chronic wounds
Dermal photoaging
Atherosclerosis
Rheumatoid arthritis
Cancer invasion
Metastasis
```
73
why does inflammation continue in chronic wounds?
- neutrophils remain overactive
| - proteases break down new tissue and destroy growth factors
74
what leads to chronic, non-healing wounds?
loss of regulation of Co-ordinated breakdown, synthesis & remodelling of ECM
75
why might ulcers fail remain in chronic inflammatory phase?
tissue hypoxia
bacterial components
foreign bodies
necrotic tissue
76
which MMPs are high in chronic dermal wounds?
MMP-2, MMP-9
77
what is the link between diabetes and TGF-b?
Plasma glucose concentrations modulate TGF-b
78
what is the relationship between chronic wounds and proteases?
Unbalanced proteolytic activity
79
what are MMPs?
- matrix metalloproteases
| Zinc-dependent endopeptidases
80
what are the 4 subdivisions of MMPs?
Collagenases (collagen)
Stromelysin (b.mem, laminin, fibronectin)
Gelatinases (elastin)
Membrane-type (MT-MMP)
81
what happens to the concentrations of MMP in normal tissues?
they are expressed at low levels
82
when is production of MMPs increased?
Production & activation increased when tissue remodelling required
83
which MMPs are collagenases?
MMP-1
| MMP-8
84
which MMPs are gelatinises?
MMP-2
| MMP-9
85
which MMPs are stromelysins?
MMP-3
MMP-10
MMP-11
86
what are TIMPs?
tissue inhibitors of metalloproteinases
87
how are TIMPs controlled?
down regulated by proinflammatory cytokines
88
when are TIMPs produced?
excess of MMP activity
89
what happens when TIMPs are produced?
Mediators crucial for repair are degraded & inactivated by wound proteases
Fibronectin
PDGF
VEGF
90
what are a source of ROS in chronic wounds?
Neutrophils & senescent fibroblasts
91
what are the impacts of ROS'?
Damage cell membranes & structural proteins (ECM)
```
Affect signalling pathways - activation of transcription factors control:
proinflammatory cytokines (IL-1,-6, TFN-a)
Proteolytic enzymes (MMPs)
```
92
what is a consequence of ROS?
Disturbed oxidant/antioxidant balance – amplifies persistent inflammatory state of chronic wounds
93
what are biofilms?
bacterial communities surrounded by polysaccharide matrix
94
why are chronic wounds an ideal environment for biofilms?
Wound remains open for a prolonged period of time - increasing odds of bacterial infection
Wound bed provides surface for growth
Poor blood flow & hypoxia discourage native defences
Wounds inoculated with bacteria form biofilms
95
what are some characteristics of biofilms?
Often polymicrobial and resistant to antimicrobials
96
true or false - chronic wounds are a risk for neoplastic progression
true
97
when is the incidence of squamous cell carcinoma increased?
in chronic leg ulcers
98
what are malignant progressions in chronic wounds associated with?
changes in MMPs
Increase in MMPs 7, 12 & 13
Decrease in MMP 19
