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Inflamation and Repair Flashcards

1
Q

What are the three major components of acute inflammation?

A
  • Dilation of small blood vessels leading to an increase in blood flow.
  • Increased permeability of the microvasculature allowing plasma proteins and leukocytes to leave the circulation.
  • Emigration of leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent.
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2
Q

Exudate vs Transudate

A
  • exudate - high protein concentration and contains cellular debris. Implies existence of an inflammatory process
  • transudate - low protein content (and mostly albumin), little or no cellular debris and low specific gravity. Essentially an ultrafiltrate of blood plasma produced as a result of hydrostatic or osmotic imbalance across the vessel wall.
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3
Q

Describe the four changes in vascular flow and caliber that occur in acute inflammation:

A
  • Vasodilation - mediators inc. histamine on smooth muscle. Involves arterioles then leads to opening of new capillary beds. Outcome of increased blood flow.
  • Increased permeability of the microvasculature.
  • Stasis of red cells due to loss of fluid, increased vessel diameter, concentration of red cells and increased viscosity of the blood.
  • Blood leukocytes accumulate along the vascular endothelium with stasis and endothelial cells express increased levels of adhesion molecules secondary to mediators produced at the site of injury/infection
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4
Q

What are two mechanisms responsible for the increased permeability of postcapillary venules in acute inflammation?

A
  • Contraction of endothelial cells (resulting in gaps). Mediators include histamine, bradykinin and leukotrines. Usually occurs rapidly and is short lived (15-30mins). Example of an exception to timing is sunburn
  • Endothelial injury resulting in necrosis and detachment. This can be direct or from neutrophils which have adhered to the endothelial cell. Lasts hours until damaged vessel is thrombosed or repaired.
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5
Q

How can reactive or inflammatory lymphandenitis (involving vessels which can appear as red streaks (lymphangitis) and enlarged, painful nodes) develop from tissue inflammation?

A

In inflammation lymph flow is increased (and the vessels proliferate) and leukocytes, cell debris and microbes can get into lymph. Inflammation of lymph nodes results in hyperplasia of lymphoid follicles and this with increased numbers of macrophages and lymphocytes can enlarge the node.

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6
Q

What mediates the the multistep process of leukocyte migration from the vessel lumen to the tissue?

A

Adhesion molecules and chemokines (a type of cytokine)

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7
Q

Name the three selectins involved in leukocyte “rolling”, where they are found and what regulates them

A
  • L-selectin, on leukocytes, always present.
  • E-selectin, on endothelium, expression induced by cytokines (IL-1, TNF).
  • P-selectin, platelets and endothelium, expression on endothelium induced by cytokines (IL-1, TNF), histamine or thrombin.
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8
Q

What triggers integrins on leukocytes to change from a low-affinity state to a high-affinity state allowing firm adhesion of leukocytes to the endothelium?

A

Chemokines from the site of injury displayed at high concentrations on endothelial proteoglycans bind to and activate rolling leukocytes. One of the consequences of activation is this change.

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9
Q

What is an example of an adhesion molecule present in the intercellular junctions between endothelial cells involved in the transmigration of leukocytes?

A

CD31(is a member of the immunoglobulin family)/PECAM-1 (platelet endothelial cell adhesion molecule)

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10
Q

Name some endogenous and exogenous chemoattractants for leukocytes respectively.

A
  • cytokines, particularly chemokines (e.g. IL-8), components of the complement system (e.g. C5a), arachidonic acid metabolites (e.g. leukotrine B4)
  • bacterial products including N-formylmethionine terminal amino acids and some lipids
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11
Q

In the inflammatory reaction, what are four exceptions to the stereotypic pattern of neutrophils predominating the for the first 6-24 hours followed by monocytes?

A
  • Pseudomonas bacteria - neutrophils dominate for several days
  • Viral infections - lymphocytes may be the first to arrive
  • Some hypersensitivity reactions - dominated by activated lymphocytes, macrophages and plasma cells
  • Helminthic infections and allergic reactions - eosinophils may be the main type
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12
Q

What are three types of receptors that enable phagocytes to bind and ingest microbes?

A

Mannose receptors, scavenger receptors and receptors for various opsonins e.g. IgG and C3b (complement)

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13
Q

Before discovering they bind a variety of microbes, what were macrophage scavenger receptors found to do?

A

Bind and mediate endocytosis of oxidised or acetylated LDL particles that do not interact with the conventional receptor.

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14
Q

Three methods of intracellular destruction of microbes are:

A
  • ROS
  • NO
  • Lysosomal enzymes and other lysosomal proteins
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15
Q

What is the respiratory burst?

A

The reduction of oxygen to superoxide anion O2.- by the multicomponent enzyme NADPH oxidase (phagocyte oxidase) triggered by activating signals accompanying phagocytosis.

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16
Q

What does the enzyme myeloperoxidase (MPO), found in the azurophilic granules of neutrophils, do?

A

Converts H2O2 to hypochlorite (HOCl.) which is a potent antimicrobial that works through halogenation

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17
Q

How is arginine converted to peroxynitrite (ONOO-)?

A

NO is produced from arginine by the action of nitric oxide synthase (NOS). In the macrophage this then reacts with superoxide (O2.-) to generate ONOO-.

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18
Q

Relate the function of a1-antitrypsin to how it’s deficiency puts patients at risk of emphysema

A

a1-antitrypsin is the major inhibitor of neutrophil elastase which can be released as part of the inflammatory response from lysosomal granules. Uncontrolled elastase activity can destroy the elastic support fibres in the lung

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19
Q

What are neutrophil extracellular traps (NETs)

A

A viscous meshwork of nuclear chromatin that binds and concentrates granule proteins such as antimicrobial peptides and enzymes, keeping them to the site of infection. They also trap microbes, helping prevent spread. Requires the death of the neutrophil through the rupture of the nuclear envelope and release of chromatin.

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20
Q

Briefly describe three ways leukocytes can cause damage to normal cells and tissues

A
  • as part of normal defence adjacent tissues suffer collateral damage. Difficult to eradicate infections like TB can lead to more damage from leukocytes than the microbe itself.
  • when inflammatory response is inappropriately directed against host tissues
  • when the host reacts excessively against usually harmless environmental substances
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21
Q

What is frustrated phagocytosis?

A

When phagocytes encounter materials that can not be easily ingested (e.g. too big), strong activation and release of lysosomal enzymes into the extracellular environment is triggered

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22
Q

What are two active mechanisms involved in terminating inflammation?

A
  • switch in type of arachidonic acid metabolite produced from leukotrines to lipoxins
  • liberation of antiinflammatory cytokines e.g. TGF-B and IL10 from macrophages and other cells
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23
Q

The two major vasoactive amines, which are stored as preformed molecules allowing early release during inflammatory are what, and have what functions?

A
  • Histamine - causes dilation of arterioles and increases the permeability of venules
  • Serotonin - primary function is a neurotransmitter in the CNS and GI tract. Is a vasoconstrictor, unclear of importance of this in inflammation
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24
Q

What are three important stimuli which trigger the release of histamine by mast cell degranulation?

A
  • physical injury (inc cold and heat)
  • binding of antigen to IgE antibodies displayed on the mast cell surface
  • products of complement called anaphylatoxins (C3a and C5a)
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25
Q

Where is inactive (esterified) arachidonic acid found?

A

In membrane phospholipids. (Predominantly phospholipase A2 actions release)

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26
Q

Which eicosanoids are produced by which enzyme, cyclooxygenases (COX-1 and COX-2) and lipoxygenases, acting on arachidonic acid respectively?

A
  • prostaglandins
  • leukotrines and lipoxins
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27
Q

Divide the prostaglandins PGI2 (prostacyclin), PGD2, TXA2 (Thromboxane A2) and PGE2 into three groups based on function;
1- Causes vasodilation, inhibits platelet aggregation
2- Causes vasoconstriction, promotes platelet aggregation
3- Causes vasodilation, increased vascular permeability, leukocyte chemotaxis

A

1- PGI2
2- TXA2
3- PGE2 (not chemotaxis) and PGD2

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28
Q

What symptoms/signs of inflammation are prostaglandins involved in the pathogenesis of?

A

Pain and fever

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29
Q

Identify which of the following leukotrienes is not cysteinyl containing, so not able to cause intense vasoconstriction, bronchospasm and increased permeability of venules (more so than histamine), and state what it does do:
LTB4, LTC4, LTD4, LTE4

A

LTB4
Potent chemotactic agent and activator of neutrophils

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30
Q

Lipoxins require neutrophils to make the precursor then platelets to mature them. How do they suppress inflammation?

A

By inhibiting neutrophil chemotaxis and adhesion to the endothelium

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31
Q

What are the three most important roles of TNF and IL-1 in inflammation?
Pg88/9

A
  • Endothelial activation
  • Activation of leukocytes and other cells
  • Induction of the systemic acute-phase response
32
Q

TNF and IL-1 are both mainly produced by activated macrophages and dendritic cells. What are some other cells that produce one or the other?

A
  • T-lymphocytes and mast cells produce TNF
  • some epithelial cells produced IL-1
33
Q

An agonist to which cytokine is effective in the treatment of chronic inflammatory diseases?

A

TNF (Tumour necrosis factor)

34
Q

What are the four groups of chemokines and the primary cells they act on?

A
  • CXC - a subset including CXCL8 (IL-8) acts primarily on neutrophils
  • CC - monocytes, eosinophils, basophils and lymphocytes
  • C - lymphocytes
  • CX3C - only one known member - fractalkine (CX3CL1). Monocytes and T-cells
35
Q

What are the main functions of chemokines displayed attached to proteoglycans on the surface of endothelial cells and of chemokines in the ECM?

A
  • in acute inflammation stimulate leukocyte attachment to endothelium by increasing affinity of integrins
  • maintenance of tissue architecture by organising various cell types in different anatomical regions of the tissues
36
Q

Pair the following in terms of which antagonist to the cytokine will treat which disease:
IL-6, IL-17, Psoriasis, Juvenile arthritis

A
  • IL-6 and Juvenile arthritis
  • IL-17 and Psoriasis
37
Q

What are the three pathways through which C3 can be cleaved through activation of C3 convertase?
(This is the critical step in complement activation)

A
  • Classical pathway - triggered by binding of C1 to antibody (IgM or IgG) that has combined with antigen
  • Alternative pathway - triggered by microbial surface molecules (e.g. endotoxin, lipopolysaccharide(LPS)), complex polysaccharides, cobra venom and other substances, in the absence of antibody
  • Lectin pathway- plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1
38
Q

Of the complement components C3a, C3b, C4a, C5a, C5b, which,
1. Are called anaphylactoxins and stimulate histamine release from mast cells?
2. Act as opsonins when fixed to a microbial cell wall?
3. Activates the lipoxygenase pathway of arachidonic acid metabolism in neutrophils and monocytes?
4. Is a chemotactic agent for neutrophils, monocytes, eosinophils and basophils?
5. Binds with others of the same kind to form C5 convertase?
6. Binds the late components (C6-9), culminating in the formation of the membrane attack complex (multiple C9 molecules)

A
  1. C3a, C5a and C4a
  2. C3b
  3. C5a
  4. C5a
  5. C3b
  6. C5b
39
Q

What are the three main functions of the complement system?

A
  • Inflammation
  • Opsonization
  • Cell lysis (via membrane attack complex causing permeability to water and ions leading to osmotic lysis of the cell)
40
Q

Name four complement regulatory proteins, their functions and a disease associated with their deficiency:

A
  • C1 inhibitor. Blocks C1 activation. Hereditary angioedema
  • Decay accelerating factor. Prevents formation of C3 convertases. See CD59
  • CD59. Inhibits formation of membrane attack complexes. Deficiency of the enzyme that creates GPI (which anchors both CD59 and DAF to the plasma membrane) leads to paroxysmal nocturnal hemoglobinuria with excessive complement activation and lysis of red cells.
  • Complement factor H. Inhibits alternative pathway of activation by promoting cleavage and destruction of C3b and turnover of C3 convertases. Haemolytic uremic syndrome.
41
Q

Explain the differences between the exudates of serous inflammation, fibrinous inflammation and purulent inflammation

A
  • serous is cell poor, derived from plasma or secretions of mesothelial cells
  • fibrinous includes large molecules like fibrinogen and leads to formation and deposition of fibrin. Requires large vascular leakage or a local procoagulant state
  • purulent consists of neutrophils, the liquefied debris of necrotic cells and oedema fluid
42
Q

What is required for ulceration to occur?

A

Tissue necrosis and resultant inflammation existing on, or near, a surface

43
Q

What are the three typical possible outcomes of acute inflammation?

A
  • Complete resolution
  • Healing by connective tissue replacement (scaring or fibrosis)
  • Progression to chronic inflammation
44
Q

Define chronic inflammation

A

A response of prolonged duration (weeks or months) in which inflammation, tissue injury and attempts at repair coexist in varying combinations.

45
Q

What are three settings in which chronic inflammation can arise?

A
  • Persistent infections
  • Hypersensitivity diseases
  • Prolonged exposure to potentially toxic agents
46
Q

What is the morphology of chronic inflammation characterised by?

A
  • Infiltration with mononuclear cells
  • Tissue destruction
  • Attempts at healing with angiogenesis and fibrosis
47
Q

In what tissues do resident populations of specialised macrophages originating from progenitors in the yolk sac or fetal liver reside, and what are they called?

A
  • Liver, Kupffer cells
  • CNS, microglial cells
  • Lungs, alveolar macrophages
48
Q

List four functions of macrophages

A
  • ingest and eliminate microbes and dead tissues
  • initiate tissue repair and are involved in scar formation and fibrosis
  • secrete mediators of inflammation like cytokines and eicosanoids
  • display antigens to T lymphocytes and respond to signals from T cells
49
Q

Explain classical macrophage activation

A

-Induced by microbial products e.g. endotoxin which engage TLRs and other sensors; T-cell derived signals, importantly IFN-y (cytokine); or foreign bodies.
- M1 produce NO, lysosomal enzymes and secrete cytokines that stimulate inflammation(IL-1, IL-12,IL-23, chemokines).

50
Q

Explain alternative macrophage activation

A
  • induced by cytokines like IL-4 and IL-13 produced by T lymphocytes and other cells
  • M2 function to terminate inflammation(e.g. by releasing IL-10 and TGF-B) and promote tissue repair(growth factors and TGF-B)
51
Q

Name three subsets of CD4+ T lymphocytes and the effects of the different cytokines produced

A
  • Th1. Produce IFN-y, activates macrophages by classical pathway
  • Th2. Secrete IL-4,-5 and -13, recruits and activates eosinophils as well as alternative pathway macrophage activation
  • Th17. Secrete IL-17 and other cytokines. Induce secretion of chemokines responsible for recruiting phagocytes
52
Q

Where could lymphoid follicles/tertiary lymphoid organs be found?

A
  • In the synovium of patients with long-standing RA
  • In the thyroid in Hashimoto thyroiditis
53
Q

What are some of the ways in which macrophages and T lymphocytes stimulate each other?

A
  • Macrophages display antigens, express membrane molecules called costimulators and produce cytokines e.g. IL-12
  • T lymphocytes produce cytokines which recruit and activate macrophages e.g. IL-17, IFN-y
54
Q

What is a highly catatonic protein found in eosinophilic granules?

A

Major basic protein

55
Q

Briefly describe the two types of granulomas

A
  • Foreign body granulomas - incited by inert FBs which induce inflammation in the absence of T cell mediated immune responses. Epithelioid and giant cells are apposed to the surface of the FB.
  • Immune granulomas - caused by agents capable of inducing a persistent T cell mediated response. Granulomas usually form when the agent is difficult to eradicate.
56
Q

List six examples of diseases that can have granulomatous inflammation

A
  • Tuberculosis
  • Leprosy
  • Syphilis
  • Cat-scratch disease
  • Sarcoidosis
  • Crohn’s disease
57
Q

Outline the pathway that leads to fever

A

(Start)Exogenous pyrogen e.g. LPS -> (Start)Endogenous pyrogens, principally TNF, IL-1 -> vascular and perivascular hypothalamus cells -> up-regulation cyclooxygenases -> increased prostaglandin production -> PGE2 particularly stimulates production of neurotransmitters by the hypothalamus that reset steady-state temp to a higher level by reducing heat loss and increasing generation

58
Q

What are two acute phase proteins which can result in altered blood counts, and how?

A
  • Hepcidin - reduces availability of iron to erythroid progenitors in the bone marrow -> anaemia of chronic inflammation
  • Thrombopoietin - is the major growth factor for megakaryocytes in the bone marrow -> thrombocytosis
59
Q

Name three of the best known acute-phase proteins, what stimulates their synthesis, and a function they have

A
  • CRP, IL-6, bind microbial cell walls (opsonins and fix complement) and as per SAA
  • Serum amyloid A (SAA), TNF/IL-1, bind chromatin possibly aiding in clearing necrotic nuclei and as per CRP
  • Fibrinogen, IL-6, bind red cells forming rouleaux that sediment more rapidly at unit gravity (basis of ESR measurement)
60
Q
  1. How high is the leukocyte count expected to get in inflammatory reactions and 2. at what levels does it become leukemoid?
A
  1. 15,000 to 20,000cells/mL
  2. 40,000 to 100,000cells/mL
61
Q

In leukocytosis, 1. what stimulates accelerated release of granulocytes from the bone marrow and 2. in prolonged infection what are the main cell types that induce proliferation of precursors in the bone marrow by increased production of colony-stimulating factors (cytokines)?

A
  1. Cytokines including TNF and IL-1
  2. Activated macrophages and marrow stromal cells
62
Q

What are the components of the clinical triad known as septic shock?
(Induced by high levels of TNF, IL-1 and other cytokines)

A

Disseminated intravascular coagulation, hypotensive shock, metabolic disturbances (including insulin resistance and hyperglycaemia)

63
Q

Divide the tissues of the body into three groups based on the ability they have to repair themselves, and give an example of each.

A
  • Labile (continuously dividing) tissues - can readily regenerate as long as the pool of stem cells is preserved. E.g. skin
  • Stable tissues - normally quiescent but capable of dividing in response to injury to a limited capacity. E.g. liver (which is an exception to the limited capacity rule),
  • Permanent tissues - insufficient proliferation capacity for tissue regeneration after injury. E.g. heart
64
Q

As well as growth factors, what can stimulate cell proliferation?

A

Signals from the cell’s integrins bound to ECM proteins

65
Q

What nature of injury to the liver leads to regeneration through proliferation of hepatocytes compared to through repopulation from progenitor cells?

A

If the proliferative capacity of the hepatocytes are intact, e.g after partial hepatectomy, then the same will proliferate. If this is impaired e.g. after chronic liver injury or inflammation, progenitor cells will contribute.

66
Q

What are the three stages of hepatocyte proliferation?

A
  1. Priming - cytokines like IL-6, mostly from Kupffer cells, act to make hepatocytes competent to receive and respond to growth factors.
  2. Growth factors e.g. HGF, TGF-a, produced by many cell types, stimulate metabolism and entry into the cell cycle. Hepatocyte replication is followed by nonparenchymal cells (Kupffer, endothelial and stellate)
  3. Termination where hepatocytes return to quiescence
67
Q

What are the steps of scar formation after tissue injury?

A
  1. Platelet plug formation (minutes)
  2. Inflammation (6-48 hours)
  3. Cell proliferation of epithelial cells, endothelial cells and fibroblasts (up to 10 days)
  4. Formation of granulation tissue
  5. Deposition of connective tissue
68
Q

What are the seven steps of angiogenesis?

A
  1. Vasodilation and increased permeability
  2. Separation of pericytes and breakdown of basement membrane
  3. Migration of endothelial cells
  4. Proliferation of endothelial cells
  5. Remodelling into capillary tubes
  6. Recruitment of periendothelial cells (pericytes for small capillaries, otherwise smooth muscle)
  7. Suppression of endothelial proliferation and migration, and deposition of basement membrane.
69
Q

In angiogenesis what do VEGFs, mostly VEGF-A, do?

A

Promotes vasodilation and increased vessel permeability, stimulates migration and proliferation of endothelial cells, stimulates expression of Notch ligands

70
Q

In angiogenesis, what do FGFs, mostly FGF-2 do?

A

Stimulate proliferation of endothelial cells, promote migration of macrophages and fibroblasts to the damaged area and stimulate epithelial cell migration to cover epidermal wounds.

71
Q

Match one from 1., with one from 2. (In relation to angiogenesis)
1. TGF-B, PDGF, angiopoietins 1 and 2
2. Angiogenesis and structural maturation of new vessels, suppresses endothelial cell proliferation and migration and enhances production of ECM proteins, recruits smooth muscle cells.

A
  • TGF-B - suppresses endothelial cell proliferation and migration and enhances production of ECM proteins
  • PDGF - recruits smooth muscle cells
  • angiopoietins 1 and 2 - Angiogenesis and structural maturation of new vessels
72
Q

What enzyme group in the ECM degrade it to allow remodelling and the extension of the vascular tube in angiogenesis?

A

Matrix metalloproteinases (MMPs)

73
Q

What does the Notch signalling pathway do?

A

Regulates the pattern of sprouting and branching of new vessels in angiogenesis

74
Q

What are the two steps of the laying down of connective tissue at a site of injury, and what is the most important cytokine for this?

A
  • Migration and proliferation of fibroblasts into the site
  • Deposition of ECM proteins produced by these cells
  • TGF-B
75
Q

In remodelling of connective tissue, what balance does ECM deposition depend on?

A

The balance between fibrogenic agents, MMPs and tissue inhibitors of metalloproteinases (TIMPs)

76
Q

What are some ways in which skin healing by secondary intention differ from healing by primary intention?

A
  • Greater potential for inflammatory mediated injury (as larger with more exudate, necrotic debris and fibrin)
  • More granulation tissue meaning more scar tissue (as larger deficit)
  • Replacement of provisional matrix of fibrin, plasma fibronectin and type III collagen with type I collagen after about two weeks
  • Wound contraction by myofibroblasts
77
Q

Give three clinical examples that are evidence of abnormalities in tissue repair

A

Venous leg ulcers, keloid, contractures

BPS (13 decks)

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