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HL 20536 - Sports and Exercise Medicine > What do we Mean by Inflammation (Scott et al., 2004) --> (week 19) > Flashcards

What do we Mean by Inflammation (Scott et al., 2004) --> (week 19) Flashcards

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1
Q

what are platelets essential for?

A

coagulation, inflammation and repair

store and dynamically express a repertoire of membrane bound and secreted products involved in pain, haemostasis, WBC recruitment, regulation of vascular tone…

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2
Q

how are platelets signalled?

A
  • signals from extracellular matrix

- signals from various cell types

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3
Q

what is the first step of platelets in inflammation? (4 points)

A
  • circulating platelets contact collagen in cell vessel walls
  • specific receptors on platelet walls (e.g. - integrin) bind to collagen and trigger platelet adhesion
  • platelets then re-organise cytoskeleton to form procoagulant spines
  • release seretonin and ADP which recruits more platelets and helps form a platelet plug stabilised by strands of fibrin
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4
Q

what is the second step of platelets in inflammation? (2 points)

A
  • activated platelets synthesis and release arachidonic acid metabolite meditating further platelet activation and aggregation
  • platelet aggregation in the thrombus is mediated by von Willebrand factor
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5
Q

what is the third step of platelets in inflammation ?

A

the endothelium can neg influence platelet function by releasing prostaglandins (PDI2 and PGE2) and nitric oxide, which are vasodilatory and have an inhibitory effect on platelets, thereby preventing uncontrolled thrombosis

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6
Q

platelets are crucial factors in influencing other cells repairability. these include

A

transforming growth factor beta (TGFB)

platelet derived growth factor (PDGF)

endothelium growth factor (EGF)

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7
Q

explain the function of ‘transforming growth factor beta’ (TGFB)

(3 points)

A
  • TGFB binds to specific receptors on specific cells to enhance o inhibit inflammatory functions
  • although TGFB inhibits production of chamotaxic mediators, it is itself moderately chamotaxic for monocytes and neutrophils, but not monocytes
  • TGBF causes fibroblast proliferation, matrix secretion, and improved biomechanical function
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8
Q

explain the function of both ‘platelet derived growth factor’ (PDGF) and ‘endothelium growth factor’ (EGF)

A
  • PDGF and EGF are potent stimulators of mitosis in mesenchymal cell types, particularly smooth muscle cells, enhancing proliferation and angiogenesis
  • PDGF accelerates would healing when applied topically, especially in combination with EGF
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9
Q

what is the first function of the endothelium in injury (3 points)

A
  • regulate pain, coagulate blood, recruit and passage inflammatory cells
  • exposed to factors released by platelets, macrophages, and other immune cells, which induce endothelial cells to proliferate and remodel their surrounding extracellular matrix increasing vessel network to supply scar tissue
  • neovessels gradually disappear from scar tissue vi apoptosis
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10
Q

what is the second function of the endothelium in injury (4 points)

A
  • generate anti-coagulative signals (e.g. - ADPase)
  • after injury respond to pro-inflammatory signals, enhancing coagulation (e.g. - inc^ up-regulation of tissue factor)
  • activated platelets express CD40 ligands on CSM binding to CD$) receptors on endo increasing expression of leukocyte adhesive molecules
  • e-selectin expressed on luminal side of endo recruiting leukocytes by slowing their movement through endo
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11
Q

how do endothelial cells respond to IL-1? (3 points)

A
  • IL-1 is a pro-inflammatory mediator
  • in response to IL-1, paracrine and autocrine stimulation causes endo cells to up-regulate chemokine expression and adhesion molecules inc^ recruitment of immune cells
  • IL-1 also induces ‘matrix metalloproteinase’ (MMP) expression in fibroblasts facilitating inflammatory cell penetration of endothelium
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12
Q

how does TNF-a effect the endothelium during inflammation/injury ?

A

TNF-a released by endo cells and activated macrophages and overlaps many functions of IL-1

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13
Q

how does IL-6 effect the endothelium during inflammation/injury ?

A

IL-6 is a prototypical ‘pleiotropic’ mediator. it is both a pro and anti-inflammatory mediator and regulates a vast array of cellular functions

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14
Q

what role does the endothelium play in angiogenesis ?

A

‘endothelial growth factor’ (EGF) is a potent angiogenic factor which secreted in higher amounts later in the reparative stage by diverse cell types, especially macrophages

this response remodels the extracellular matrix, proliferation and migration of cells

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15
Q

what is the role of the endothelium in tendinosis (Ohberg & Alfredson., 1991)

A
  • biopsies of tendinosis occasionally display areas of perivascular inflammatory cell invasion, indiating the endo may have become activated earlier on, but not confirmed
  • animal models suggest that neurovascular ingrowth is a late appearing feature of tendinitis
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16
Q

what is the relationship of ROS and neutrophils in inflammation ? (3 points)

A
  • neutrophils bacterial toxicity comes from their ability to release high levels of reactive oxygen species (e.g. - superoxide)
  • these ROS are non-specifically toxic, so may destroy surrounding tissue and immune cells
  • neutrophils undergo apoptosis and exposure to phosphatidylserine - marking them for phagocytosis
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17
Q

what is the main function of neutrophils?

A

operate assuming the injury is infected –> function as phagocytes and kill bacteria

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18
Q

what is the response time of neutrophils in injury

A

the first line of phagocytosis –> occurs within a couple of hours (released passively with platelets from the injured vessel)

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19
Q

what is the relationship between platelets and neutrophils in inflammation?

A
  • platelets release platelet basic factor which is processed by neutrophils to ‘neutrophil activating protein 2’
  • this rapidly attracts neutrophils by its affinity for their CXCR2 receptor (Gillitzer et al., 2001)
  • because ‘neutrophil activating protein 2’ is a chemotaxin for neutrophils, but not for macrophages, its early presence may explain neutrophil predominance in early inflammation
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20
Q

neutrophils release enzymes belonging to two families which support roles in tissue debridement and clot resorption. what are the two families ?

A

1) MMP’s

2) serine proteinases (e.g. - urokinase-type plasminogen activator)

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21
Q

what is the effect of ‘urokinase-type plasminogen activator’ in inflammation (2 points)

A
  • converts plasminogen into plasmin, which can degrade fibrous clots (essential for healing)
  • working with gelatinase B, together they degrade most components of the extracellular matrix
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22
Q

what is the final part neutrophils play in inflammation?

A
  • play no part in the repair of sterile tissue, removing them in the hours post injury is a key therapeutic technique
  • they appear to have a more negative effect if they remain present
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23
Q

when are macrophages and monocytes most dominant in the immune response ?

A

24-48 hours post injury

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24
Q

where and how are macrophages recruited and released?

A

macrophages are recruited by chemokines (e.g.- MCP-1) and released by activated endothelium and fibroblasts

25
Q

what are many of the signals that activate macrophages ?

A

TNF-a, IL-1, and tissue hypoxia

26
Q

what are the uses of macrophages in inflammation?

A
  • versatile cell which can secrete > 100 pro-inflammatory mediators –> creates a positive feedback loop to amplify their response
  • play a key role in coagulation, expressing tissue factors and prothrombinase on their surface
  • also secrete factors for tissue regeneration
27
Q

what types of tissue have macrophages been shown to be dominant in the healing process?

A

bursa, ligaments, synovium, muscle, intervertebral discs

28
Q

state 2 facts about macrophages in tendon recovery

A

1) macrophages can be observed phagocytosing collagens and cellular debris
2) however, they are quite scarce in surgical biopsies of tendinitis and even tendon rupture (Yuan et al., 2002)

29
Q

what are fibroblasts a marker of?

A

proliferation of fibroblasts and the secretion of increased amounts of provisional matrix and scar tissue are markers of the later repair processes

30
Q

what is the function of fibroblasts in injury?

A
  • migrate into fibrin clot and synthesise a hyaluronan rich matrix
  • fibroblast activation in the area of the former clot may partially be attributed to the activity of clot associated proteinases
31
Q

when are T-lymphocytes predominant in injury?

A

predominant in the remodelling phase of injury; most dominant cell by day 14

32
Q

what proliferates t-lymphocytes during injury?

A

IL-1

33
Q

what recruits T-lymphocytes during injury?

A

recruited to areas by INF-y 10 and monokine induced interferon gamma (Mig)

34
Q

what is the impact of t-lymphocyte depletion in healing?

A

delays healing, reduces collagen secretion, more fragile scar tissue (Efron et al., 1990)

35
Q

what injuries have t-lymphocytes been shown to be most active in?

A

bursal biopsies and rotator cuff pathology, in which synovial and vascular hyperplasia are predominant (Santavirta et al., 1992)

36
Q

fibroblasts proliferate in response to a number of different signals. these include:

A

IL-1
IL-4
IL-6
TNF-a

37
Q

fibroblasts are released from a number of different locations. these include:

A
  • platelets
  • endothelial cells
  • macrophages
  • other fibroblasts
38
Q

what is the use of fibroblasts in the later stages of inflammation (3 points)

A
  • characterised by proliferation of local collagen secreting fibroblasts and their contractile offspring (myofibroblasts)
  • myofibroblasts may differ as contain actin which allows contractile properties to be used in tissue healing
  • myofibroblasts disappear from wounds via apoptosis
39
Q

what can fibroblasts secrete

A
  • inflammatory mediators in response to mechanical loading (e.g. - PGE2 in response to stretching)
  • however, recent work has shown that tensile loading of human patellar tendon fibroblasts in vitro leads to down regulation of the major pro-inflammatory cytokines, including IL-1 (Wang., 2003)
40
Q

what is the main function of mast cells in inflammation?

A

once activated, they quickly degranulate and activate nearby cells and stimulate neuropeptide-containing sensory nerves to generate a regional neurogenic inflammation via an axonal reflex

41
Q

what is the second function of mast cells in inflammation?

A
  • cause thrombin induced, histamine mediated increases in vascular permeability
  • when cells degranulate, they release tryptase which, with thrombin, activates the protease activator receptor 2 o the mast cells and sensory neurones
  • this activation results in further degranulation, contributing to a positive feedback loop
42
Q

what do mast cells secrete ?

A

a broad range of enzymes and mediators including TNF-a and TGFB

43
Q

what is the recruitment process of mast cells?

A
  • recruited to injury sites by MCP-1 where they are activated by hypoxia or inflammatory mediators
  • mast cells also accumulate near cells of angiogenesis (e.g. - ruptured tendon)
44
Q

explain how neurones can effect the immune cells

A

1) many immune cell effects are mediated by vasoconstrictive neuropeptides (e.g. - substance P, SP; and calcitonin gene related peptide, CGRP)
- they’re synthesised in dorsal root ganglia
- they’re then transported to axon terminals where they are stored in vesicles
- several enzymes in injured areas stimulate the release of SP and CGRP

45
Q

state, and explain, 3 functions of ‘substance P’ (SP)

A

1) important in neurogenic inflammation and repair
- can activate NK1 receptors on endothelial increasing NO production
2) can enhance inflammatory cell recruitment by up-regulating P-selectin on endothelial cell and by chemoattracting neutrophils and macrophages
3) SP also stimulates lymphocytes and fibroblasts to proliferate

46
Q

what has measuring inflammation in clinical researched usually relied on?

A

generally relied on subjective scales addressing pain, swelling, redness, or gross functional measures and volumetric measures of swelling

47
Q

what is the difficulty with measuring inflammation?

A

1) very difficult for researchers to determine the roles of specific cellular processes in clinical populations
2) biopsy tissue is rarely available in most conservatively managed patients, and measurement of cytokines in blood and urine is limited as it is virtually impossible to identify the main sources and targets of the mediator

48
Q

state a potential method but its issue for researching in clinical populations

A
  • radiolabelling WBC’s before exercising so accumulation can be detected in inflamed tissue
  • limited sensitivity and financial cost means its not often used in clinical research
49
Q

what are NSAID’s

A

non-steroidal anti-inflammatory drugs

NSAID’s are a diverse group of compounds that can inhibit one or more isoform of a COX (one of two enzymes that degrades arachidonic acid)

50
Q

what is the relationship between inflammatory cells and COX

A

activation of inflammatory cells up-regulates COX 2 expression with a corresponding increase in prostaglandins and thromboxanes

51
Q

what do NSAID’s usually inhibit?

A

COX 1 and COX2 - this lack of sensitivity is thought to account for the high levels of GI related problems from LT NSAID usage

52
Q

what are 2 issues with NSAID’s?

A

1) can reduce clotting ability

2) alleviate pain can mask the pain leading to an injury worsening

53
Q

is it clear of the effect NSAID’s have? (3 points)

A
  • unclear to whether NSAID’s have a positive or negative effect and needs to be carefully examined in clinicians
  • NSAID’s don’t influence a specific pathway or cell type
  • may be important to reserve their prescription for conditions that they’ve been shown to be effective in rather than assuming they’ll provide anti-inflammatory effects to all inflammation
54
Q

what did (Hutchins et al., 2002) find about NSAID’s

A
  • a small benefit in tissue repair with the use of NSAID’s

- also found collagen synthesis and mechanical strength in healing ligaments was improved with NSAID usage

55
Q

what is the main use of corticosteroids?

A

aimed at treating sport induced inflammation

56
Q

how do corticosteroids work?

A
  • they exert inhibitory effects by binding to intracellular receptors found in most cell types
  • the corticosteroid-receptor complex translocates to the nucleus and alters transcriptional activity (e.g. - suppressing collagen synthesis)
  • an inhibitor of phospholipase is up-regulated in cells exposed to corticosteroids, blocking the release of arachidonic acid from the cell membrane
57
Q

have corticosteroids had research backed benefits?

A
  • the benefits of corticosteroids have been seen to accelerate ham-string repair, although anecdotally (Synder., 1982)
58
Q

state 3 facts about the use of ultrasound use for inflammation

A

! ultrasound treatment has no documented anti-inflammatory action (Sopowit et al., 19950

2) causes fibroblast proliferation in injured skeletal muscle and enhances angiogenesis and bone deposition in healing fractures
- these effects may be due to increased expression of PDGF by endothelium and osteoblasts subjected to ultrasound (Rantenan et al., 1999)

HL 20536 - Sports and Exercise Medicine (10 decks)

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