APPP 19 and 20: Inflammation / Tissue Repair and Wound Healing Flashcards

1
Q

What is inflammation?

A

protective response to eliminate the cause of cell injury and to remove damaged products/cells

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2
Q

What are the 2 major functions of inflammation?

A
  • stop the attack
  • repair the damage
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3
Q

What are the triggers of inflammation? (4)

A
  • infection (bacterial, fungal, toxin)
  • injury, foreign bodies, trauma
  • immunological (immune reactions, autoimmune conditions)
  • chemical agents and radiation
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4
Q

What are the 3 types of inflammation?

A
  • acute inflammation
  • systemic inflammation (ie. septic shock)
  • chronic inflammation (ie. allergy, autoimmune disease)
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5
Q

What is acute inflammation and what does it cause?

A

tissue injury caused by physical or chemical agent or pathogenic microorganism

  • capillary widening → increased blood flow
  • increased capillary permeability → release of fluid
  • attraction of white blood cells → migration of white blood cells to injury
  • systemic response → fever and proliferation of white blood cells
  • these all result in heat, redness, tenderness, swelling, and pain
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6
Q

What are the stages of acute inflammation?

A
  1. recognition of danger
  2. vasodilation and increase vascular permeability
  3. chemotaxis
  4. systemic response
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7
Q

Stages of Acute Inflammation

  1. Recognition of Danger
A
  • tissue resident immune cells (mast cells of macrophages) recognize damage signals through PRRs (such as toll-like receptors)
  • recognize pathogen factors (PAMPs) and cells in stress (DNA, heat shock proteins)
  • release stored chemicals – mast cells release histamine + NO, platelets release serotonin
  • inflammatory response is initiated
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8
Q

Stages of Acute Inflammation

2a. Vasodilation

A
  • earliest response mediated by histamine and nitric oxide (NO)
  • dilation of blood vessels starts at arteriole → capillary → venule
  • stasis occurs when enlarged vessels pack with cells – assists leukocyte migration along vessel endothelium (normally, blood flows too fast for directed leukocyte movement)
  • increase blood flow to wound sites causes local tissue erythema (redness) and warmth, swelling, painfulness
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9
Q

Stages of Acute Inflammation

2b. Increase Vascular Permeability

A
  • endothelial cells respond to histamine and cytokine release
  • contraction and retraction of endothelial cells allow protein-rich exudate to cross into interstitial tissue
  • results in reduced osmotic pressure in blood and increased osmotic pressure in interstitial space
  • leakage of fluid out of blood vessels leads to edema
  • when infection is present, edema can spread to nearby lymph channels and lymph nodes (lymphadenopathy)
  • increase delivery of immune cells and mediators, and clotting factors
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10
Q

Stages of Acute Inflammation

  1. Recruitment of Immune Cells – Chemotaxis

What are the WBC migration steps? (3)

A
  • rolling: loose, intermittent contact with endothelium
  • adhesion: tight, constant contact with endothelium
  • transmigration: WBCs cross endothelial layer through gaps created by contracted endothelial cells
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11
Q

Stages of Acute Inflammation

  1. Recruitment of Immune Cells – Chemotaxis

Leukocytes are recruited to the site of insult in different phases. What are these 2 phases?

A

6-24 hours post-injury:

  • dominated by neutrophils
  • first responders, fast arrival
  • phagocytes, apoptosis after response

24-48 hours post-injury

  • finds monocytes (→ macrophages, APC)
  • finds lymphocytes (sometimes eosinophils)
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12
Q

Acute Inflammation Mediators

What are the 4 pre-formed mediators released by mast cell degranulation?

A
  • histamine
  • cytokines: TNF-a, IL-1, IL-6
  • chemokines for neutrophils and eosinophils
  • enzymes: tryptase, chymase, cathepsin
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13
Q

Acute Inflammation Mediators

What does histamine do?

A
  • vasodilation, causing increased swelling or fluid in mucosa

in other tissues:

  • bronchiole constriction = wheezing
  • constriction of smooth muscles in intestine = cramps, diarrhea
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14
Q

Acute Inflammation Mediators

What do enzymes do?

A

responsible for changes in connective tissue matrix, tissue breakdown

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15
Q

Acute Inflammation Mediators

What are the 2 secondary mediators synthesized and secreted upon mast cell activation?

A
  • eiconsanoids: leukotrienes, prostaglandins, and thromboxanes
  • Th2 cytokines: Il-4, IL-5, IL-13, GM-CSF
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16
Q

Acute Inflammation Mediators

What do eiconsaoids do?

A
  • slower reacting substances, but longer-lasting effects
  • increase vascular permeability
  • platelet aggregation
  • bronchiole constriction
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17
Q

What are the 5 cardinal signs of inflammation and what are their mechanisms?

A
  • redness (rubor) – increase blood flow
  • heat (calor) – increase blood flow, exudation of fluid, release of inflammatory mediators
  • swelling (tumor) – exudation of fluid
  • pain (dolor) – release of chemical mediators, stretching of pain receptor and nerves by exudates
  • loss of function (functio laesa) – pain, disruption of tissue structure
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18
Q

What are the 6 types of inflammatory exudate and their biological content?

A
  • serous – cell-free plasma (ie. skin blisters, pericarditis)
  • fibrinous – with increased fibrinogen for wound repair (ie. adhesions following surgery)
  • mucinous – thick clear gel-like mucous provides physical barrier and aid targeting of infectious materials (ie. runny nose with common cold)
  • purulent – thick, coloured pus containing WBCs (ie. abscesses, boils, cellulitis)
  • sanguineous – fresh bleeding (ie. hematoma)
  • mixed types – mixture of the above (ie. serosanguineous, mucopurulent)
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19
Q

Describe the steps of the inflammatory response.

A
  1. bacteria and other pathogens enter wound
  2. platelets form blood release blood-clotting proteins at wound site
  3. mast cells secrete factors that mediate dilation and constriction of blood vessels – delivery of blood, plasma, and cells to injured area increases
  4. neutrophils secrete factors that kill and degrade pathogens
  5. neutrophils and macrophages remove pathogens by phagocytosis
  6. macrophages secrete cytokines, which attract immune system cells to the site and activate cells involved in tissue repair
  7. inflammatory response continues until the foreign material is eliminated and the wound is repaired
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20
Q

Mast cells are the source of which mediators of inflammation?

A

histamine, others

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21
Q

Macrophages are the source of which mediators of inflammation?

A

cytokines, others

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22
Q

Endothelium is the source of which mediators of inflammation?

A

NO, cytokines, others

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23
Q

What plasma proteins are sources of mediators of inflammation?

A
  • complement
  • clotting factors and kininogens
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24
Q

What are the 4 outcomes of acute inflammation?

A
  • resolution
  • abscess formation
  • fibrosis (scar) formation
  • chronic inflammation
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25
Q

Outcomes of Acute Inflammation

Resolution

A
  • damaging agent removed and damages repair
  • organ regeneration and full function restored (normal function)
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26
Q

Outcomes of Acute Inflammation

Abscess Formation

A
  • walled off collection of pus (neutrophils and necrotic tissues)
  • may need to reabsorption or necrosis
27
Q

Outcomes of Acute Inflammation

Fibrosis (Scar) Formation

A
  • excessive or abnormal connective tissue (fibrosis)
  • hard, non-functional tissue, no organ regeneration (loss of function)
28
Q

What causes systemic inflammation?

A

spill-over effects – local inflammation mediators and/or toxins reaching systemic circulation

29
Q

What are common clinical signs and symptoms of systemic inflammation?

A
  • pyrexia (fever)
  • tachycardia (increase heart rate)
  • rigors (chill)
  • diaphoresis (sweating)
  • leukocytosis (increase WBC counts)
  • lethargy, confusion, hypoxia
30
Q

What is the spectrum of systemic inflammation?

A
  • infection
  • SIRS (systemic inflammatory response syndrome)
  • sepsis (SIRS + infection)
  • severe sepsis (sepsis + end organ damage)
  • septic shock (severe sepsis + hypotension)
  • death
31
Q

What is sepsis?

A

body’s inflammation response to a severe infection

32
Q

What is SIRS (systemic inflammatory response syndrome)?

A
  • caused by infection or trauma
  • contains all clinical signs of systemic inflammation
33
Q

What is septic shock?

A
  • most severe form of sepsis with bacteria/infectious agents in blood
  • end organ damage + hypotension
  • typically lead to death
34
Q

What are the differences between acute vs. chronic inflammation?

A

acute inflammation:

  • protection process to immediate danger
  • rapid onset (minutes)
  • exudates production and migration of WBC (neutrophils)
  • causes: infection immunological, trauma, foreign bodies

chronic inflammation:

  • sustained response to injurious stimuli
  • long time course: days to years
  • involves lymphocytes (B and T) and macrophages
  • causes: persistent viral or bacterial infection, autoimmune dysfunction, chronic diseases
35
Q

Acute vs. Chronic Inflammation

A

acute inflammation:

  • allergic reaction
  • chemical irritants
  • infection
  • trauma injury
  • burns
  • laceration, cuts, wounds
  • frostbite

chronic inflammation

  • cardiovascular disease
  • neurological disease
  • autoimmune disease
  • rheumatoid arthritis
  • cancer
  • luous
  • fibromyalgia
  • chronic fatigue syndrome
36
Q

How does chronic inflammation occur? (2)

A
  • may follow acute inflammation
  • may occur as a pathogenic process
37
Q

What are the the 2 types of chronic inflammation mediators?

A
  • macrophages
  • lymphocytes
38
Q

What are the macrophage chronic inflammation mediators? (5)

A
  • proteases
  • cytokines: TNF, IL-1 (activates lymphocytes)
  • nO
  • eicosanoids
  • angiogenesis and growth factors: platelet derived growth factor (PDGF)
  • fibroblast growth factor (FGF)
39
Q

What are the lymphocyte chronic inflammation mediators? (2)

A
  • cytokines: interferon 𝛾 (activates
    macrophage)
  • angiogenesis and growth factors: transformation growth factor beta (TGF𝛽), platelet derived growth factor (PDGF), fibroblast growth factor (FGF)
40
Q

Chronic Inflammation

What are granulomas?

A

accumulations of mononuclear WBC (macrophage and lymphocytes), epithelioid cells and multi-nucleated giant cells in injured/damaged tissues

  • associated with mycobacterial (TB) or fungal infections
  • chronic injury caused by foreign agents such as silica
41
Q

Autoimmune Problem

A
  • internal threat
  • immune over-reaction (hypersensitivity)
  • ie. Hashimoto’s thyroiditis, rheumatoid arthritis, lupus, inflammatory bowel disease, type I diabetes
42
Q

Allergic Reaction

A
  • external reaction
  • immune over-reaction (hypersensitivity)
  • ie. food sensitivities, allergies, eczema, asthma, sinusitis
43
Q

Cancer

A
  • internal threat
  • immune under-reaction (immunodeficiency)
  • ie. hepatitis, HIV, shingles, TB
44
Q

Infection

A
  • external threat
  • immune under-reaction (immunodeficiency)
  • ie. bacteria, mold/fungus, parasites, viruses
45
Q

What is tissue repair?

A

regeneration of parenchymal tissue, or replacement of damaged tissue with scar if complete repair is not possible

46
Q

What is tissue regeneration?

A

replacement of damaged cells with no scar formation

  • only possible in tissues that are able to replicate
  • tissues with high renewal rate: GI tract, skin
  • not possible in tissues with stable/post-mitotic cell population: kidney, heart
47
Q

What is tissue healing?

A

some replacement of cells combined with scarring and fibrosis

48
Q

What are the 5 mediators of tissue repair?

A
  • epidermal growth factor (EGF)
  • vascular endothelial growth factor (VEGF)
  • platelet derived growth factor (PDGF)
  • fibroblast growth factor (FGF)
  • transformation growth factor beta (TGF𝛽)
49
Q

What does epidermal growth factor (EGF) do?

A

stimulates granulation tissue formation

50
Q

What does vascular endothelial growth factor (VEGF) do?

A

stimulates formation of blood vessels

51
Q

What does platelet derived growth factor (PDGF) do?

A

promotes growth of fibroblasts and smooth muscle cells

52
Q

What does fibroblast growth factor (FGF) do?

A

stimulates formation of blood vessels and wound repair

53
Q

What does transformation growth factor beta (TGF𝛽) do?

A

promotes collagen deposition and ECM growth

54
Q

What are the steps in tissue repair?

A
  1. injury occurs and inflammation
  • clotting caused by clotting proteins and plasma proteins occurs, and scab is formed
  • removal of damaging agents (neutrophils/WBC)
  • removal of dead tissues (macrophages and others)
  1. new (granulation) tissue formation
  • deposition of extracellular matrix (fibroblasts)
  • formation of new blood vessels (endothelial cells) – restores vascular supply
  • production of extracellular matrix (ie. collagens)
  1. tissue remodeling
  • maturation and reorganization of fibrous tissues – restored epithelium thickens
  • wound contracture
55
Q

What are the two types of wound healing?

A
  • first intention
  • second intention
56
Q

What is first intention wound healing?

A
  • wound has clean edges
  • close proximity of margins
  • minimal tissue disruptions
  • outcome: no tissue loss, little or no scar
  • ie. surgical incision, clean cuts
57
Q

What is second intention wound healing?

A
  • wound has unclean, wide edges
  • extensive tissue disruption and necrosis
  • large, more prominent scar
  • ie. pressure ulcers, trauma that affects large areas
58
Q

Describe the wound healing timeline.

A
  • injury occurs and acute inflammatory response is induced
  • repair starts within 24 hours of onset of acute inflammation
  • 3-5 days: granulation tissues form, collagen deposition continues to week 2, edema and inflammatory cells disappear
  • 1 month: all inflammatory infiltrate is gone, scar consists of mature collagen
59
Q

Granulation Tissue

Where and when is pink, granular tissue formed?

A
  • occurs in all wounds
  • formed during the initial process of wound healing (first 24-72 hours), but also in chronic inflammation
60
Q

Granulation Tissue

What does granulation tissue consist of?

A
  • fibroblasts
  • extracellular matrix
  • newly formed blood vessels (angiogenesis by endothelial cells)
  • immune cells (specifically macrophages, but also other inflammatory cells)
61
Q

Granulation Tissue

Describe the structure of early granulation tissues.

A

leaky – allows passage of liquid and cells

62
Q

Granulation Tissue

Describe the structure of late granulation tissues.

A

as the wound heals, late granulation tissue dries up – replaced during the remodeling process (ie. replacement of temporary immature collagen with mature collagen)

63
Q

What are the 6 factors that delay/impair wound healing?

A
  • infection
  • necrotic debris
  • poor tissue perfusion and hypoxia
  • nutritional deficiency
  • physical trauma
  • drugs (glucocorticoids, immunosuppressives)