Inflammation and Tissue Healing - Physiology

Question 1

Inflammation Basic Definition

Answer 1

Non-specific defense and healing mechanism of the body to tissue damage and infection.

Question 2

Causes of Cell Injury

Answer 2

• Ischemia (lack of blood supply)
• Infectious agents
• Immune reactions
• Genetic factors
• Nutritional factors
• Physical factors
• Chemical factors

Question 3

Necrosis vs Apoptosis

Answer 3

Necrosis: causes inflammation, invariably pathologic (culmination of irreversible cell injury).
Apoptosis: no inflammation, physiologic )eliminating unwanted cells).

Question 4

Phases of Inflammatory Reaction

Answer 4

1. Recognition (tissue damage or infection)
2. Recruitment (additional immune cells)
3. Removal (what caused the problem e.g. pathogen)
4. Resolution/repair (remove inflammation)

Question 5

Operational Characteristics (Signs) of Inflammatory Response

Answer 5

Redness, pain, swelling, heat at the site of infection.

Question 6

Recognition - PAMPs

Answer 6

Innate immunity uses limited nr of pattern recognition receptors (PRRs) to spot pathogens.
Pathogen-associated molecular patterns (PAMPs): structural features expressed by microbes but not by host. Recognized by PRRs.
→ Synthesis and secretion of pro-inflammatory cytokines.

Question 7

Recognition - DAMPs

Answer 7

Innate immunity uses a limited number of pattern recognition receptors (PRRs) to spot damaged cells.
Danger-associated molecular patterns: Exposure of molecules from injured tissue, such as nuclear or cytosolic protein. If cell explodes, receptor is exposed.

Question 8

Scavenger Receptors

Answer 8

Few receptors, either release pro-inflammatory cytokines or eat the cell (phagocytosis of host cells undergoing apoptosis).

Question 9

Recruitment

Answer 9

Phagocytotic macrophages often not enough to remove all pathogens → start an inflammatory response → recruitment of additional immune cells.

Question 10

What are the effect of acute inflammation on surrounding blood vessels?

Answer 10

1. Vasodilation increases local blood flow (heat & redness)
2. Activation of endothelial cells.
3. Increased vascular permeability(space between cells becomes bigger): exit of fluid and proteins from the blood (swelling and pain).

Question 11

Order of Recruitment of Cells

Answer 11

1st: Neutrophils
2nd: Monocytes (in blood), differentiate into Macrophages (in tissue).
3rd: Lymphocytes

Question 12

Chemotactic Agents

Answer 12

Cause cells to move into a particular direction.
Chemotaxis tells cells to go to site of infection.
IL-8 chemotactic for neutrophils.
IL-12 chemotactic for NK cells

Question 13

Removal - Protection Against Viral Infections

Answer 13

Soluble molecules for protection from viral infections.

Interferons induce both virally infected and noninfected cells to activate numerous antiviral defenses.

Question 14

Removal - Compliment System

Answer 14

Enzymes and proteins providing protection against pathogens. Series of Plasma Proteins.

• Opsonization: Facilitate phagocytosis.
• Anaphylatoxins: Chemoattractant effect. Increase inflammation - Pro inflammatory mediators.
• Lytic death: Creates holes in cell membrane and induces death.

Question 15

Phagocytosis Definition

Answer 15

Engulfment and degradation of microbes and cellular debris - pathogens (bacteria, viruses), apoptotic bodies.

Question 16

Removal - Phagocytosis

Answer 16

PRR binds to PAMP or DAMP, or binding of
complement receptor or antibody receptor to an opsonized microbe → Engulfment → bacteria trapped within phagosomes → broken down by digestive enzymes through fusion of lysosomes.

Question 17

Removal - Macrophages

Answer 17

Able to phagocyte dead cells and tissue debris. Responsible for cleaning up damaged tissue.

Question 18

Resolution

Answer 18

An active process that suppresses the inflammatory reactions once the main objective is attained.
It ensures tissue repair and regain of physiological
function.

Question 19

Resolution - Stop Recruitment

Answer 19

Termination of neutrophil influx: prerequisite for resolution of inflammation.
Clearance of neutrophils: undergo apoptosis. Secrete annexin A1 → inhibit recruitment, promote apoptosis and clearance. Find me signals, eat me signals.

Question 20

Resolution - Efferocytosis

Answer 20

Apoptotic neutrophils cleared by macrophages via efferocytosis → causes a switch in macrophages to a anti-inflammatory pro healing cell (from M-1 like cells to M-2 like cells).

Question 21

Resolution - M1-like cells, M-2 like cells

Answer 21

Macrophages
M1-like cells: pro-inflammatory mediator, early phase of repair → phagocytosis of neutrophils.
M2-like cells: Express anti-inflammatory mediator and produce of growth factors. Later stage of repair.

Question 22

Resolution - Reestablishment of Tissue Functionality

Answer 22

Macrophages, stem cells and connective tissue cells prevent fibrosis.
M2-like cells orchestrate reparative processes:
- Proliferation of progenitor cells
- Influence ECM composition
- Angiogenesis

Question 23

4 Phases of Tissue Healing

Answer 23

1. Hemostasis & degeneration
2. Inflammation
3. Proliferation & migration
4. Remodeling & maturation

Question 24

Hemostasis and Degeneration

Answer 24

Hemostasis: stop the bleeding
- Formation of a platelet clot
- Activation of coagulation cascade
- Formation of a blood clot
Degeneration:
- Formation of a hematoma
- Necrosis of cells => inflammation

Question 25

Inflammation - Tissue Healing

Answer 25

Remove threat (pathogen, debris)
Clear damaged tissue
Start healing process

Question 26

Proliferation and Migration

Answer 26

Angiogenesis endothelial cells proliferate to form new blood vessels (to feed new cells).
Formation of granulation tissue (dense irregular connective tissue that fills gaps).

Question 27

Remodeling and Maturation

Answer 27

Tissue is remodeled and become smoother, lighter and less dense:

• Reduced number of fibroblast and capillaries
• Contraction of healing tissue (myofibroblasts): wound’s margins get closer.

Question 28

Tissue Regeneration

Answer 28

Depends on:

• Availability of stem cells
• Vascularization
• Length of inflammatory reaction

Question 29

Tissue Regeneration - Cells

Answer 29

Permanent cells: irreplaceable. E.g. cardiomyocytes/neurons.
Stable cells: do not divide. Regenerative capacity.
Labile cells: constant division.

Question 30

Tissue Healing - Primary/Secondary Intension

Answer 30

Healing by primary intension: much quicker, scarring minimal.
Healing by secondary intension: Edges not brought together, filled with granulation tissue.

Question 31

Skeletal Muscle Tissue Injury

Answer 31

If injury is minor, the healing process restores a functional tissue.
If a trauma exceeds the intrinsic regenerative capacity of the muscle => formation of fibrotic scar tissue. Never gains full functional integrity.

Question 32

Satellite Cells

Answer 32

Stem cells of skeletal muscle, able to differentiate into muscle fibers.
Inflammation has key role in regulation of satellite cell function → remove necrotic and damaged areas.
Activated in case of muscle damage

Question 33

Myoblasts

Answer 33

Satellite cells proliferate and differentiate into myoblast.

Can migrate and fuse with damaged muscle fiber or form new myotubes.

Question 34

Muscle Tissue Healing - Beginning

Answer 34

1st step: hemostasis → anaphylatoxins trigger inflammatory response + activation of satellite cells → vasodilation and increased vascular permeability → Neutrophils and macrophages recruited.

Question 35

Muscle Tissue Healing - Cells

Answer 35

1st: Neutrophils (within 2h).
2nd: M1 macrophages: Secrete cytokines, growth factors, pro-inflammatory mediators (stimulate myoblast proliferation).
Both responsible for phagocytosis.
Switch from phenotype M1 to M2(anti-inflammatory) sustain fiber reconstruction.

Question 36

Myoblast Proliferation

Answer 36

IL-6 stimulates myoblast proliferation.

IL-10 stops myoblast proliferation and stimulate differentiation, fusion and growth of myotubes.

Question 37

Fibroblasts

Answer 37

Regulate healing process.
Absence leads to premature differentiation (small muscle fibers).
Responsible for formation of connective tissue fibrosis.

Question 38

Skeletal Muscle Fibrosis

Answer 38

Excessive production and deposition of collagenous ECM by myofibroblasts, compromising muscle fiber contractility, tissue architecture, and ultimately organ function.

Question 39

The activity of immune cells during wound healing

Answer 39

1. pro-inflammatory cells are recruited to the site of injury for defense and phagocytosis of necrotic tissues.
2. the pro-inflammatory response is dampened via anti-inflammatory macrophages. Immune cells also directly participate in stimulating angiogenesis, myofibroblast activation, and tissue progenitor cell
   proliferation.
3. Most immune cells exit the site of injury or are eliminated by apoptosis.
   and the tissue homeostasis is restored

Question 40

Regenerative Capacity - Bone/Muscle/Tendon

Answer 40

Linked to availability of progenitor cells within the tissues.
Bone:
- High regenerative capacity
- High availability of progenitor and immune cells
- Low overshooting of inflammation
- High vascularization in mature tissue
Muscle:
- Medium regenerative capacity
- Medium availability of progenitor and immune cells
- Medium overshooting of inflammation
- Medium vascularization in mature tissue
Tendon:
- Low regenerative capacity
- Low availability of progenitor and immune cells
- High overshooting of inflammation
- Low vascularization in mature tissue