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POM > Lecture 3 > Flashcards

Lecture 3 Flashcards

1
Q

What are the elements of Acute Inflammation?

A

First- Body’s immediate response to tissue injury
WBC/leukocytes leaving BV to go into the tissue
Dynamic process evolving over time
“-itis” pathlologies + sunburn, cancer, infection
Intertwines with cell injury and healing
Stereotyped process, Irrespective of the tissue involved - Atherosclerosis -sees plaque as injury and inflammes

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2
Q

What are the 6x triggers of Acute inflammation?

A

FIT PIN
1. Infections: Bacterial, viral, parasitic. and Microbal toxins
2. Trauma (blunt and penetrating)
3. Physical and Chemical agents.
4. Tissue Necrosis (from any cause)- Most powerful
5. Foreign bodies (splinters, dirt, sauces). Activate inflammation via local bodies(esp. Macrophages) sensing them
6. Immune/Hypersensitivity reactions
Endothelial cells. Release Proinflammatory signals- Tumor-necrosis signals. Bring in WBC and turn on Inflammation

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3
Q

What is the most potent activator of inflammation?

A

Tissue Necrosis

Death by Necrosis, releasing cytoplasmic contents

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4
Q

What are the Steps to Acute Inflammation?

A
  1. Triggering
  2. Blood flow and Permeability changes - changes in smooth muscle and endothelial cells
  3. Endothelial cells changes it’s signalling cascades and gene expression, including changes adhesion molecule regulation (bind WBCs)
  4. Neutrophils signalling and gene expression changes, adhesion to endothelial cells and migration into tissues
  5. Neutrophil activation, survival, function and death
  6. Inflammation subsides. OR Inflammation continues with other Leukocyte types (macrophages and lymphocytes) entering the tissue (Chronic inflammation)
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5
Q

What is the role of Endothelial cells to acute inflammation?

A

Gate Keepers
-Line blood vessels
First cell types effected
Complex signalling mechanisms are activated inside Endothelial cells
TNF alpha (Tumornecrosis factor alpha) bind to TNF endothelial receptors on BV going through inflamed areas, NFkB Neucleofactor Kapa B Transcription factors activated. Turns on other inflammatory genes

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6
Q

What are examples of Inflammatory Associated genes?

A

Activated Cell Adhesion molecules -surface of endothelial cells
Activated Anti-apoptosis molecules
Activated Cytokine and Chemokines - activate WBC
Activated Coagulation factors - Blood clotting
Activated PRo- angiogenesis factors - promote BV growth - clean up of inflammation
Decrease in Cytoskeleton stabilizer
Increase/Decrease in many signalling molecules

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7
Q

What is a result of Inflammation associated gene expression and signalling changes in endothelial cells?

A

Shape change
Smooth muscle surrounding endothelial cells change contractility
Blood flow and permeability changes
1. Hyperaemia = Increased blood flow
2. Exudation = Loss of fluid and protein
3. Fibrous exudate and tissue oedema(tissue swelling)
4. Blood flow slower around vessel edges. Stasis and Leukocyte margination in POST-capillary venules
Permeability : Endothelial cells pull away from neighbours creating channels for protein and fluid exudate can flow into the tissue

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8
Q

What are the elements of Neutrophil adhesion and migration in tissues?

A
  1. Macrophages release Cytokines, or may have ingested dead cells
  2. Turning on of Endothelial cells
  3. Decreased blood flow
  4. Exudate (protein and fluid combo) entering the tissue
  5. Endothelial cells pumping out cytokines and growth factors, which act on macrophages and circulating neutrophils
  6. “Velcro” molecules/Selectins on endothelial and leukocyte put onto surface. Neutrophils attach and causes them to “roll along the surface” of endothelial cels. (tennis ball rolling down velcro wall)
  7. Leukocytes slow down and adhere firmly due to Endothelial addressins and Leukocyte Integrins.
  8. Diapaedesis: Leukocytes migrate into the tissue, squeezing between adjacent endothelial cells.
  9. Neutrophils carry out function in tissue
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9
Q

What is the role of selectin-selectin adhesion?

A

Selectin inhibited. (anti-selectins)
No rolling. Leukocytes/neutrophils dont have a chance to slow down and firmly adhere to integrins and then crawl through endothelial layer

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10
Q

What is the role of neutrophils in acute inflammation?

A

Fist leukocyte cell type to enter inflamed tissues

Main leukocyte of acute inflammation

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11
Q

What activates neutrophils causing them to move into the tissue?

A
  1. Contact with Endothelial clel surface molecules
  2. Soluble signals: IL-1 Interlukin 1 and TNF-a Tumour Necrosis Factor Alpha
  3. Bacterial products which bind to neutrophil Toll-like receptors
  4. Chemotactic factors: C5a Complement 5a and Interlukin 8 IL-8. Bind to 7-transmembrane G-protein-coupled receptors on neutrophil surface
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12
Q

What is the killing potential of neutrophils?

A

Useful but limited killing potential

  1. Oxygen dependant mechanisms. Kill bacteria (read slide). More effective typically.
  2. Oxygen independant mechanisms (lysosome, lactoferrin and defensins)

Hypoxia promotes/adapts neutrophil survival. In hostile environment, No BF, bacterial toxins, little O2, Little Growth factors.
Much more powerful Macrophages are called in if neutrophils cannot resolve inflammation themselves.

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13
Q

What is the adaption of neutrophils to survive in hostile environments?

A

O2 dependant gene expression changes allow neutrophils to resist apoptosis in hypoxic damaged tissues
Turn on transcription factors. Hypoxia, HIF system and/or NFkB activity increased. Which turn on Pro-survival target transcripts (proteins) –> allows survival against apoptosis

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14
Q

What are the 5x Local Hallmarks/ clinical manifestations of acute inflammation?

A
  1. Redness (rubor)- due to hyperremia, dilated vessles and increased BF
  2. Swelling (tumor) -oedema - fluids moving through permeable endothelial cell junctions
  3. Heat (calor)- increased BF and stimulation of local nerve endings by products ad causes of inflammation
  4. Pain (dolor)- increased BF and stimulation of local nerve endings by products ad causes of inflammation
  5. Loss of Function (functio laesa)
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15
Q

What are the 4x Systemic effects of acute inflammation?

A

Brain, Bone Marrow, Liver, Adrenal Glands

  1. Pyrexia (fever): mediated by inflammatory mediators such as IL-1 and TNF-a which have systemic effects when in circulation
  2. Leukocytosis: increased production and release of leukocytes from the bone marrow- likely that more cells will be needed to go into the tissue
  3. Acute Phase Proteins from liver- acute phase response
  4. Endocrine changes (activation of glucocorticoid steroid hormones)
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16
Q

What are Acute phase reactions in response to IL-1 and TNF-a?

A

Changes in entire Gamet of molecules secreted by liver, and changes to liver function

  1. Fever
  2. Increased sleepiness
  3. Decreased Appetite
  4. Increased Acute Phase Proteins
  5. Hemodynamic effects (shock)
  6. Neutrophilia
17
Q

What are the Effects of Fibroblasts in response to IL-1 and TNF-a?

A

Fibroblasts are multifunctional structural cells. immotile. secondary repair.
Activated by systemic effects from molecules released from inflammed sites.
1. Inreased Proliferation
2. Increased Collagen synthesis
3. Increased Collagenase
4. Increase Protease
5. Increase PGE synthesis

18
Q

What are the Negative effects of acute inflammation?

A

Harmful if occurs inappropriately or inadequately controlled
Inappropriate inflammatory reactions underlie:
1. Rheumatoid arthritis
2. Atherosclerosis
3. Hypersensitivity to insect bites, drugs and toxins
4. Hyper-immune reactions/ Cytokine storms- large amounts of interferon/ TNFa and IL1 inflammatory signalling molecules into Blood stream

19
Q

What happens when the cause of inflammation is not removed/resolved?

A

Chronic inflammation. Neutrophils will bring in other Leukocyte types to enter the tissue
- Mainly Macrophages and Lymphocytes
Generally:
Inflammatory effects on BV (hyperemia and edema) peaks after few hours
Neutrophils enter after 12-36 hours and peak after a day or so
Macrophages and Lymphocytes bought in by Neutrophils after 2-4 days
-will hang around for as long as needed for repair

20
Q

What are the elements of Monocytes/Macrophages response to chronic inflammation?

A

Macrophages= Monocytes in circulation and prior to differentiation
As Monocytes enter injured tissue they become Macrophages
-enter by rolling, adhering and squeezing through via Diapodesis
Macrophages have greater phagocytic and killing potential, than neutrophils. - One packaged debris into phagolysosomal organelles they can effectively kill the organelle contents
Macrophages interface closely with lymphocytes and other cell types
1. Activated Macrophage secrete signalling molecules (interferons, IL1)
2. Signalling molecules turn on Neutrophils and T lymphocytes
3. T-lymphocytes then secrete TNF and other factors which activate neutrophils. And interferons which feed back onto the macrophages.
Complex interconnected web of molecular signals between different leukocytes and endothelial cells

21
Q

Granuloma formation

A

Unusual example/Specific pattern of Chronic inflammation
-Body typically responds to inflammation in a generic manner. But This is a relatively non-specific response where the response is modified in certain instances:
Seen in TB tuberculosis and small number of other diseases (sarcoidosis)
When inflammatory body is having difficulty getting rid of cause of inflammation
Focus of chronic inflammation with:
1. Core of necrosis
2. Epithelioid Macrophages -Microscopic aggregation of macrophages that have transformed into epithelium like cells to better perform their function
3. Collar of Lymphocytes- surrounding the E. Macrophages
4. Macrophages often fuse together to form giant cells (to gain size) - able to do function better. Multiple nuclei. Able to ingest large foreign body

22
Q

What occurs after chronic inflammation?

A

Healing
Body’s attempt to restore the original structure and function of the tissue, as closely as possible
1. Cleaning up mess (neutrophils and macrophages)
2. Rebuilding original structure and function through a mix of Regeneration and repair
-Ideally Regeneration (individual cells types repopulated, typically by proliferation of stem cells)
- If regeneration cannot occur or is only partial. Repair (insufficient stem cells or some cells are terminally differentiated, without any stem cells to regenerate population from). Fibroblasts replace cells with lots of fibres (collagen) instead “filler”.

23
Q

What is the response if the cause of inflammation can be removed by neutrophils and macrophages?

A

Resolution

Tissue returns to normal

24
Q

What is the response if there are Stem cells Present to repopulate tissue cells?

A

Skin, gut, liver
Once mess has been cleaned up
Regeneration of Tissue structure and function is rebuilt
Return of some previous function

25
Q

What is the response if there is an insufficient ability of stem cells to regenerate initial cell types?

A

Repair
Fibrous collagen scar forms to replace damaged cells
Prior: Organisation into granulation tissue (as seen through microscope). Macrophages of chronic tissue secrete two types of Growth factors. 1. Bring in endothelial cells to form new vessels (vascular endothelial growth factor family) 2. Bring in fibroblasts to secrete collagen fibres for repair (fibroblast growth factor family)
Forms Non-functional Fibrous scar

26
Q

What is the time course of healing?

A

Inflammation 0.1-3 days
Granulation tissue 1 week build up
Fibres start to contract and align to lines of stress.(Wound Contraction) Wound matures and fibres remodelled to make tissue strong

27
Q

What are the Examples surrounding injury, acute inflammation, chronic inflammation, healing and repair?

A

Sunburn
Infection
Myocardial Infarction -Myocardial myocytes injured by lack of blood supply, die by necrosis. - No nucleus and RBC haemorage. Acute inflammation- neutrophils move in among dead cardio-myocyte cells and ingest. Adapted to survive in toxic conditions
Chronic inflammation: signals bring in macrophages and lymphocytes. Macrophages chew fibres to prepare tissue for regeneration. Stem cells number insufficient to complete repair. Macrophages initiate organisation, pulling in endothelial cells to form new BV and Fibroblasts which will form collagen fibres. (red lines= new BV) (pale wavy lines= collagen). Eventually Bv will regress and fibroblasts will go away with small maintenance crew to remain and realign collagen fibres according to tissue stress patterns.
-Extent of repair varies depending on amount of stem cells regeneration.

28
Q

What are 3x other clinical concepts that should be explored?

A
  1. Gout/acute pain and swelling of the knee
  2. Headache, morning stiffness and shoulder pain
  3. Inflammatory low back pain
29
Q

What is the key point to take from the lecture?

A

In most cases the process of inflammation will be almost the same
-nonspecific
Applied in similar ways to different contexts, in different types of inflammation triggers in different tissues

POM (33 decks)

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