6 Inflammation & Repair III - Repair Flashcards
What is the term for the systemic effects of inflammation?
Acute phase reaction (or system inflammatory response)
What are the most important mediators of systemic inflammation? Be specific.
Cytokines
TNF, IL-1, & IL-6 (same trio as in the local acute inflammatory response)
What blood tests can be used to show an acute phase reaction is happening in a patient? Will the levels be elevated or depressed?
C-reactive protein (CRP)
erythrocyte sedimentation rate (ESR)
Both elevated
What are all the systemic manifestations of an acute phase reaction?
- Fever
- Elevated plasma levels of acute-phase proteins
- Increased WBC count
- Increased HR & BP
- Chills, rigors
- Anorexia, somnolence, & malaise
What is/are the key mediator(s) for fever?
TNF
IL-1
What is the basic process causing a fever?
It is in response to pyrogens which stimulate prostaglandin synthesis
What is/are the key mediator(s) for elevated plasma levels of acute-phase proteins?
IL-6
What is/are the key mediator(s) for increased WBC count?
TNF
IL-1
T/F
The population of WBCs increased in an acute phase reaction is neutrophils (PMNs).
False
The population of WBCs increased varies
What is another term for systemic inflammatory response syndrome? What are the presenting signs of this?
Sepsis
- Hypotension
- Poor organ perfusion
- Disseminated intravascular coagulation (May progress to shock and multiorgan failure)
What are the mediators of systemic inflammatory response syndrome?
TNF (most important)
IL-1
IL-12
What cytokines contributes to these local and systemic inflammatory effects?
- Increased permeability of blood vessels (local)
- Increased expression of adhesion molecules by vascular endothelium (local)
- Leukocyte production (systemic) & activation (local)
- Fever (systemic) -Low cardiac output (systemic)
- Increased clot formation (systemic)
- Insulin resistance in multiple tissues (systemic)
- Shock (systemic) (top mediator in this effect)
TNF
What cytokines contributes to these local and systemic inflammatory effects?
- Increased expression of adhesion molecules by vascular endothelium (local)
- Leukocyte production (systemic) & activation (local)
- Increased chemokine production
- Fever (systemic)
- Insulin resistance in multiple tissues (systemic)
- Shock (systemic)
IL-1
What cytokines contributes to these local and systemic inflammatory effects?
- Increased chemokine production
- Fever
- Increased production of acute phase proteins
- Increased leukocyte production
IL-6
What anti-inflammatory mediators downregulate acute inflammation?
Increased lipoxin
NO production by endothelium
Anti-inflammatory cytokine secretion (eg TGF)
What are the 3 possible outcomes of acute inflammation?
1-Complete restitution - no permanent damage and function regained
2-Healing by tissue replacement - fibrosis
3-Progression to chronic inflammation persistence of injurious agent interference with healing process autoimmunity
What are the 2 possible outcomes of chronic inflammation?
1-Resolution - inflammation subsides and repair occurs
2-Progressive tissue damage, repair, & scar formation (simultaneous)
The inflammatory response not only serves to eliminate the insult and tissue damage, but also sets into motion the process of ___________.
Repair
What are the 2 mechanisms of tissue repair (healing)?
Regeneration
Scar formation
-Often both mechanisms contribute to repair
What is regeneration (mechanism of tissue repair)?
Tissues that are able to replace damaged cells return to a normal state.
What is scar formation (mechanism of tissue repair)?
Occurs when the injured tissue is incapable of regeneration or if the supporting structures (eg basement membrane) are severely damaged. Process of deposition of fibrous tissue
What tissues are capable of regeneration?
Skin, GI epithelium, liver
What basic factors are necessary for regeneration to occur?
Cell proliferation
Growth factors
Integrity of extracellular matrix
What cell types proliferate during tissue repair?
Remnants of injured tissue
Vascular endothelial cells
Fibroblasts
What are the 3 types of tissues (based on proliferative capacity)? What is an example of each?
1) Labile tissues - readily regenerate - hematopoietic cells in bone marrow, surface epithelia, GI epithelium
2) Stable tissues - minimal replicative activity (normally quiescent) - parenchyma of most solid organs, endothelial cells, fibroblasts, smooth muscle
3) Permanent tissues - non-proliferative - most neurons, cardiac muscle
Stem cells are characterized by & found in:
Characterized by self-renewal & asymmetric replication
Found in labile tissues
What are growth factors?
What cells produce growth factors related to tissue repair?
- Proteins that stimulate the survival and proliferation of particular cells; may also promote migration, differentiation, and other cellular responses
- Many produced by macrophages and lymphocytes; others by parenchymal or stromal cells in response to cell injury
Name the growth factors involved in repair (list from PP).
EGF
TGF-beta
HGF
VEGF
PDGF
FGFs
What are the 2 forms of extracellular matrix? What does each contain?
Interstitial matrix - fibrillar collagens, elastin, proteoglycan, and hyaluronan
Basement membrane - type IV collagen, laminin, and proteoglycan
What are the functions of the extracellular matrix?
- Provides mechanical support to tissues
- Acts as a substrate for cell growth and formation of tissue microenvironments
- Regulates cell proliferation and differentiation
- Required for tissue regeneration (otherwise scar formation occurs)
What is the process of regeneration in labile tissues? What signaling molecules are involved?
Injured cells are rapidly replaced by proliferation of residual cells and differentiation of tissue stem cells provided that the underlying basement membrane is intact
No known growth factors
What is the process of regeneration in stable tissues? What signaling molecules are involved?
Liver has the greatest ability to regenerate. After damage remaining hepatocytes proliferate.
Initiated by cytokines (TNF, IL-6) & mediated by growth factors (HGF, EGF, TGF-beta)
;)
What is the time course of inflammation and repair?
Inflammation 0.1 - 3 days
Granulation tissue 0.3 - 10 days
Wound contraction 3 - 30 days
Collagen accumulation/remodeling 3 - 100 days
What are the essential processes involved in scar formation?
- Inflammatory cell infiltration
- Angiogenesis
- Fibrogenesis (migration and proliferation of fibroblasts with deposition of extracellular matrix - mainly collagen; formation of granulation tissue)
- Maturation & remodeling (sometimes re-epithelialization)
Angiogenesis involves what processes?
What growth factors are necessary?
extracellular matrix interactions; endothelial cell migration, proliferation, and differentiation
VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor), Ang1, & Ang2
New vessels are leaky.
What is the result of leaky vessels?
What growth factor contributes to this?
Edema
VEGF
What are the 2 steps of fibrogenesis?
- migration & proliferation of fibroblasts
- deposition of ECM by fibroblasts
What growth factors are involved in fibrogenesis?
TGF-beta (transforming growth factor beta)
PDGF (platelet derived growth factor)
FGF (fibroblast growth factor)
cytokines - IL-1, IL-13
What is granulation tissue?
highly vascular tissue composed of small vessels, fibroblasts, few inflammatory cells
What is a granuloma?
inflammation characterized by epitheloid macrophages and giant cells
What is involed in tissue remodeling?
- balance of collagen synthesis and degradation
- synthesis of fibroblasts
- degradation by metalloproteinases
- collagenases, gelatinases, and stromelysins
- produced by fibroblasts, leukocytes, and some epithelial cells
- tightly controlled by growth factors, plasmin, and tissue inhibitors of metalloproteinases (TIMPs)
What 8 factors influence tissue repair?
Infection - most important cause of delay in healing
Nutrition
Glucocorticoids - anti-inflammatory effects -> weaker scar
Mechanical variables - pressure, torsion
Poor perfusion
Foreign bodies
Location of injury
Abberations of cell growth (keloid)
What is the difference between first intention and second intention healing?
First intention - eg surgical incision; leads to less prominent scar
Seconf intention - eg trauma, ulcer; leads to more significant scar
What are the 5 Rs of the inflammatory response?
- Recognition of the injurious agen
- Recruitment of leukocytes
- Removal of the agent
- Regulation of the response
- Resolution (repair)
What is the hallmark of inflammation?
Infiltration of tissue with any of the classes of leukocytes
- neutrophils - acute inflammation
- lymphocytes & monocytes - chronic inflammation
