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Unit 9 > Week 1: Inflammation and Repair 2 > Flashcards

Week 1: Inflammation and Repair 2 Flashcards

1
Q

What type of disease is commonly associated with granulomas?

A

TB
Chrons disease

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2
Q

Describe the structure of a TB granuloma?

A

Central region composed of pathogens
and potentially necrotic tissue
Surrounded by a rim of macrophages that are attempting to phagocytose and deal with the pathogen
Followed by rims of epitheliod cells that act as a barrier to prevent the spread of pathogen out of granuloma
Finally surrounded by rims of B and T cells awaiting to response to infection, if antigen is successfully presented on MHC by a macrophage
May also contain foam cells, and giant cells within the inner layers.

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3
Q

Define granulomatous inflammation.

A

A form of chronic inflammation characterised by groupings of activated macrophages, sometimes accompanied by necrosis, fibrosis and T lymphocytes.
Response to an offending agent that is difficult to eradicate

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4
Q

What is the purpose of granuloma formation?

A

To contain an offending agent, either a peristent infection or persistent foreign body.

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5
Q

How are epitheliod cells formed?

A

In granulomas
Activated macrophages develop an abundant cytoplasm and interdigitated cell membranes.
May have elongated nuclei and increased e-cadherin to hold multiple epitheliod cell together
Thought to be a mesenchymal to epithelial transition

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6
Q

What pehontype of T cells is mainly present in granulomas?

A

CD4+ naive T helper cells
Differentiate into Th1 cells

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7
Q

What are the two main types of granulomas?

A

Foreign-body granulomas
Immune granuloma

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8
Q

What are the features of a foreign body granuloma?

A

Reaction to an inert foreign material such as silica or sutures
No T cell mediated response
So are typically smaller and consist of mainly activated macrophages

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9
Q

What are the features of immune granulomas?

A

Typically caused by infectious agents capable of causing a T cell mediated response
Normally myobacterial, fungal or parasitic in origin
Consists of macrophages, foam cells, multinucleated giant cell, T cells and B cells.

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10
Q

What are some examples of granulomas in non-infectious diseases where no foreign bodies are present?

A

Crohns disease - is an immune granuloma (where the specific antigen is not known- may be commensal or dietary), is non necrosing.
Sacoidosis - unknown aeitology

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11
Q

In granulomas, how do macrophages lookon histoligical imaging?

A

Large with a pale staining cytoplasm and a bean-shaped nucleus

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12
Q

How do multinucleate giant cells form in granulomas and what do they look like on histological images?

A

Formed by fusion of macrophages - hence large cytoplasm with multiple distinct nuclei
or may form from replicative stress so unable to undergo cytokinesis.

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13
Q

What are the key identifiable features of granulomas on a histological image?

A

Central pale staining area of macrophages
Multinucleate giant cells - very large cytoplasm and horse shoe of nuclei
Surrounded by a ring of lymphocytes

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14
Q

How might a foreign body granuloma be identified on a histological image?

A

Foreign body appears white/very pale
As refractile under polarised light

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15
Q

What is a caseating granuloma?
How does is form?

A

A granuloma with a central area of necrosis
Typical myobactreium tuberculosis infection
Centre appears soft and cheesy.
Necrosis occurs by free radical mediated pathways or by hypoxia mediated pathways.

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16
Q

What do caseating granulomas look like on a histological image?

A

Central necrosing section is pink and amorphous (smudged like appearance)
THen surrounded by a pale macrophage ring
Then potentially a lymphocyte ring

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17
Q

How do granulomatous inflammation heal?

A

Typically by fibrosis - resulting in tissue and organ damage
Some granulomas calcify due to large amounts of Ca2+ released in necrotic centres, this normally happens in the lung parenchyma, can be in a homogenous or laminated fashion.

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18
Q

What are the four stages of tissue repair?

A

Homeostasis - immediate blood vessl constriction and activation of coagulation factors to prevent further blood loss
Inflammatory response - to fight off infection. MAcrophages and neutrophils migrate to area. MAcrophages release growth factors.
Proliferation - fibroblasts and endothelial cells proliferate, forming granulation tissue. Fibroblasts secrete collagen and ECM components
ECM reorganisation - MMPs aid this process by degrading the ECM. Type 3 collagen is replaced by type 1 collagen, collagen is also rearranged in a way (parallel arrangement) to better withstand tensile forces.

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19
Q

What are the two ways that a tissue may try to resolve damage/heal?

A

Scar formation
Regeneration
Typically process is a combination of both

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20
Q

What are the classifications of tissue based on how well tissue regenerates?

A

Labile tissue
Stable tissue
Permanenet tissue

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20
Q

What are the characteristics of labile tissue?

A

Highlt regenerative
From constantly proliferating mature cells
Or from stem cell population replacing damaged cells
Examples: epithelial tissue and HSC

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21
Q

What are the characteristics of stable tissue?

A

Quiescent tissue - meaning not currently in the cell cycle but may re-enter it if injured or depleted
Hence have a limited regneration capacity
Examples - endothelial cells, hepatocytes

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22
Q

What are the characteristics of permanent tissue?

A

Cells in tissue are permanently differentiated and unable to regenerate.
E.g neurons and cardiac mycocytes

23
Q

What is the basic process of regeneration at a tissue?

A

Macrophages at site of injury produce growth factors
Proliferation of exisiting functional cells
Stem cells in niches of tissue will differentiated into required lineages if needed
Fibroblast contribute to rebuilding of ECM.

24
Q

List the different growth factors involved in tissue repair.

A

TGF beta
Platelet derived growth factor
Vascular endothelial growth factor
Epidermal Growth Factor
Fibroblast Growth Factor

25
Q

What is the role of TGF beta as a growth factor?

A

Fibroblast migration
Collagen synthesis
Monocyte migration

26
Q

What is the role of PDGF as a growth factor?

A

Wound contraction
Monocyte migration and proliferation
Angiogenesis
Collagen synthesis
Fibroblast migration and proliferation

27
Q

What is the function of VEGF as a growth factor?

A

Angiogenesis

28
Q

What is the role of EGF in tissue repair?

A

Epithelial cell migration and proliferation
Fibroblast proliferation
MMP synthesis

29
Q

What is the role of fibroblast growth factor in tissue repair?

A

Fibroblast migration and proliferation
Epithelial migration and proliferation
MMP synthesis
Wound contraction

30
Q

How is the condition of the ECM relevant to tissue repair?

A

Cells use integrins to bind to the ECM, this interaction is responsible to cell signalling hence proliferation/survival
If the ECM is extensibly damaged, regardless of the tissue type, healing by scar formation not regeneration.

31
Q

What are the key featues of scar formation?

A

May be referred to a fibrosis (although other types exist)
Occurs when tissue is unable to regenerate
Normally from extensive or severe damage or in permanment tissue
Tissue does not return to functional state.

32
Q

Describe the process of scar formation?

A

Inflammation - eliminates offensive agent then resolves. M2 and pro-resolving efferocytosing macrophages release grwoth factors
Cell proliferation -
A) epithelial cells to cover up wound
B)Fibroblasts - deposit collagen and ECM components
c) Endothelial cells and pericytes - angiogensis, new vessels bud off old vessels
Granulation tissue forms
Granulation tissue is replaced by collagen deposits, which can be degraded by MMPs and rearranged to form a mature scar.

33
Q

What is granulation tissue?

A

Replaces a fibrin clot in repairing of chronic inflammation.
Consists of immature capillaries (active angiogenesis) and active fibroblasts.
Neo-matrix develops with depositions of fibronectin and hyaluronan.
Also includes inflammatory cells such as macrophages and lymphocytes depending on the stage of infection/inflammation.
Later stage myofibroblasts aid with wound contraction

34
Q

What is organisation?
In links to healing

A

The transformation of necrotic tissue of fibrin to a fibrous scar by the process of granulation tissue

35
Q

What processes occur within granulation tissue?

A

1.Macrophages release growth factors
2.Vascular endothelial cells proliferate in response, forming new blood vessels that sporut from existing ones (angiogenesis)
3. Fibroblasts migrate and proliferate when stimulate by growth factors and cytokines
4. Fibroblasts deposit ECM componenets, oringinall fibronectin which is gradually replaced by collagen
5. Cellularity decreases and progressive vascular regression
6. Myofibroblasts differentiate and contract scar
7. MMPs aid reorganisation of collagen to remodel the new connective tissue.

36
Q

What might a scar look like on a histological slide?

A

Epithelial layer may be present
Dense fibrous tissue with no specialised structures.
Highly dense collagen.

37
Q

What factors influence the efficiency of tissue repair?

A

Infection
Disease (diabetes)
Nutritional status
Glucocorticoids
Mechanical factors
Perfusion
Foreign bodies
Injury type and extent

38
Q

How does infection influence tissue repair?

A

Prolongs inflammation, may cause more damage

39
Q

How does diabetes influence tissue repair?

A

Poor perfusion, impaired leukocyte function, ongoing low level systemic inflammation

39
Q

How does nutritional status affect tissue repair?

A

Protein deficiency unable to make new components
Vitamin C deficiency - imapirs collagen synthesis

40
Q

How do glucorticoids impair tissue repair?

A

Immunosuppressant
Reduce inflammation (this can be useful or not)

40
Q

How does mechanical forces affect tissue repair?

A

Physical disruption of wound healing process

41
Q

How does poor perfusion affect the wound healing process?

A

Reduced delivery of raw material and cells

42
Q

What are some conditions caused by malfunctions in the wound healing process?

A

Hypertrophic scar
Keloids
Excess granulation tissue
Wound rupture or ulceration
Contracture

43
Q

What causes a hypertrophic scar?

A

Due to excessive collagen generation and deposition
Exists only within the original scar boundaries

44
Q

What causes a keloid?

A

Due to excessive collagen generation and deposition
Spreads outside the original scar boundaries

45
Q

What causes excessive granulation tissue?
Why is this problematic?

A

Infection not resolved/ problem in healing process
Can block further healing such as reepithelialisation

46
Q

What causes a wound rupture?

A

When the edges of the wound are pulled apart
Can be due to inadequate formation of granulation tissue or a scar, can be caused by repeated trauma or continuing infection

47
Q

What causes a contracture?

A

Excessive contraction of a scar leads to restriction in movement or a deformity.

48
Q

What are some causes of systemic low grade chronic inflammation?

A

Ageing - immunoscenescence and mitochondrial dysfunction
poor diet - excess adipose tissue and alters gut microbiome
Stress - prolonged elevation of cortisol promotes inflammation and impairs repair

49
Q

What are some consequences of systemic low grade inflammation?

A

Fatigue and raised blood pressure - other physiological sickness
Breakdown of immune tolerance leading to autoimmune disease
Dysregulation of normal cellular physiology, increase risk of metabolic disease and cancer.

50
Q

What diseases may be associated with systemic chronic inflammation?

A

Metabolic (type 2 diabetes)
Cardiovascular disease
Cancer
Depression
Auto-immune diseases
Neurodegenerative diseases
Osteoporosis
Immunosenescence

51
Q

What are foam cells?

A

Form in a granuloma - macrophages that accumulate oxidised lipids and dead material
Microbacteria may promote formation of foam cells as have a impaired immune function

52
Q

What is meant by tissue repair/healing?

A

restoration of tissue architecture and function after injury.
Occurs by regeneration or scar formation or a combination of both.

53
Q

What triggers cell proliferation in regeneration?

A

Signals from the extracellular matrix
Signals provided by growth factors (released from macrophages or epithelial cells.

54
Q

What type of granuloma tends to be caseating?

A

Typically immune granulomas, most likley a TB infections

Unit 9 (15 decks)

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