Inflammation and Tissue Healing - Physiology Flashcards
Inflammation Basic Definition
Non-specific defense and healing mechanism of the body to tissue damage and infection.
Causes of Cell Injury
- Ischemia (lack of blood supply)
- Infectious agents
- Immune reactions
- Genetic factors
- Nutritional factors
- Physical factors
- Chemical factors
Necrosis vs Apoptosis
Necrosis: causes inflammation, invariably pathologic (culmination of irreversible cell injury).
Apoptosis: no inflammation, physiologic )eliminating unwanted cells).
Phases of Inflammatory Reaction
- Recognition (tissue damage or infection)
- Recruitment (additional immune cells)
- Removal (what caused the problem e.g. pathogen)
- Resolution/repair (remove inflammation)
Operational Characteristics (Signs) of Inflammatory Response
Redness, pain, swelling, heat at the site of infection.
Recognition - PAMPs
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.
Recognition - DAMPs
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.
Scavenger Receptors
Few receptors, either release pro-inflammatory cytokines or eat the cell (phagocytosis of host cells undergoing apoptosis).
Recruitment
Phagocytotic macrophages often not enough to remove all pathogens → start an inflammatory response → recruitment of additional immune cells.
What are the effect of acute inflammation on surrounding blood vessels?
- Vasodilation increases local blood flow (heat & redness)
- Activation of endothelial cells.
- Increased vascular permeability(space between cells becomes bigger): exit of fluid and proteins from the blood (swelling and pain).
Order of Recruitment of Cells
1st: Neutrophils
2nd: Monocytes (in blood), differentiate into Macrophages (in tissue).
3rd: Lymphocytes
Chemotactic Agents
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
Removal - Protection Against Viral Infections
Soluble molecules for protection from viral infections.
Interferons induce both virally infected and noninfected cells to activate numerous antiviral defenses.
Removal - Compliment System
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.
Phagocytosis Definition
Engulfment and degradation of microbes and cellular debris - pathogens (bacteria, viruses), apoptotic bodies.
Removal - Phagocytosis
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.
Removal - Macrophages
Able to phagocyte dead cells and tissue debris. Responsible for cleaning up damaged tissue.
Resolution
An active process that suppresses the inflammatory reactions once the main objective is attained.
It ensures tissue repair and regain of physiological
function.
Resolution - Stop Recruitment
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.
Resolution - Efferocytosis
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).
Resolution - M1-like cells, M-2 like cells
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.
Resolution - Reestablishment of Tissue Functionality
Macrophages, stem cells and connective tissue cells prevent fibrosis.
M2-like cells orchestrate reparative processes:
- Proliferation of progenitor cells
- Influence ECM composition
- Angiogenesis
4 Phases of Tissue Healing
- Hemostasis & degeneration
- Inflammation
- Proliferation & migration
- Remodeling & maturation
Hemostasis and Degeneration
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
Inflammation - Tissue Healing
Remove threat (pathogen, debris)
Clear damaged tissue
Start healing process
Proliferation and Migration
Angiogenesis endothelial cells proliferate to form new blood vessels (to feed new cells).
Formation of granulation tissue (dense irregular connective tissue that fills gaps).
Remodeling and Maturation
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.
Tissue Regeneration
Depends on:
- Availability of stem cells
- Vascularization
- Length of inflammatory reaction
Tissue Regeneration - Cells
Permanent cells: irreplaceable. E.g. cardiomyocytes/neurons.
Stable cells: do not divide. Regenerative capacity.
Labile cells: constant division.
Tissue Healing - Primary/Secondary Intension
Healing by primary intension: much quicker, scarring minimal.
Healing by secondary intension: Edges not brought together, filled with granulation tissue.
Skeletal Muscle Tissue Injury
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.
Satellite Cells
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
Myoblasts
Satellite cells proliferate and differentiate into myoblast.
Can migrate and fuse with damaged muscle fiber or form new myotubes.
Muscle Tissue Healing - Beginning
1st step: hemostasis → anaphylatoxins trigger inflammatory response + activation of satellite cells → vasodilation and increased vascular permeability → Neutrophils and macrophages recruited.
Muscle Tissue Healing - Cells
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.
Myoblast Proliferation
IL-6 stimulates myoblast proliferation.
IL-10 stops myoblast proliferation and stimulate differentiation, fusion and growth of myotubes.
Fibroblasts
Regulate healing process.
Absence leads to premature differentiation (small muscle fibers).
Responsible for formation of connective tissue fibrosis.
Skeletal Muscle Fibrosis
Excessive production and deposition of collagenous ECM by myofibroblasts, compromising muscle fiber contractility, tissue architecture, and ultimately organ function.
The activity of immune cells during wound healing
- pro-inflammatory cells are recruited to the site of injury for defense and phagocytosis of necrotic tissues.
- 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. - Most immune cells exit the site of injury or are eliminated by apoptosis.
and the tissue homeostasis is restored
Regenerative Capacity - Bone/Muscle/Tendon
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
