Chronic Inflammation and Repair Flashcards
Some products released by macrophages
- Complement components (e.g., C1 to C5, properdin)
- Enzymes
- Cytokines, chemokines (IL-1, TNF, IL-8)
- Growth factors (PDGF, EGF, FGF, TGF-beta)
- Nitric Oxide
Actions of Chemokines
- Activate adhesion molecules
- Act thru G-protein coupled transmembrane receptors and caus Ca++ influx (actin effect)
- Inude Haptotaxis (Cell migration along surface gradients)
- Bind to proteoglycans and ECM
- Induce oxygen burst
Chronic Inflammation therapies
- Corticosteroids
- Non-steroidals and other anti-inflammatories
*NSAIDS, aspirin, COX-2 inhibitors
*Nutrition; vit. D, E, C and folic acid are anti-inflammatory, Omega 3 fatty acids, Resveratrol
- New therapies
*Pentoxifylline, thalidomide
*Infliximab, etanercept, adalimumab
Corticosteriods effect on chronic inflammation
- Decrease transcription rates for IL-6 and IL-1Beta
- Suppresses phospholipase A2, Cyclo-oxygenase 2, and NO synthase
Pentoxifylline and thalidomide effects
- Suppress the release of TNF-alpha from phagocytes
Infliximab, Etanercept and Adalimumab effects
- Block TNF-alpha, blocks the protein’s activity
Steps of the repair process (also known as organization)
- Macrophages phagocytize necrotic debris and foreign matrial
- At edges of damaged area proliferation of endothelia and fibroblasts
- Endothelial cells grow into damaged area
- Capillary formation and fibroblast migration form a loose connective tissue framework; this is called granulation tissue
Process of new vessel formation
- Proteolysis of parent vessel basement membrane; allows sprouting
- Migration of endothelial cells toward stimulus
- Proliferation of endothelial cells behind migrating edge
- Maturation of endothelial cells behind migrating edge
- Recruitment- pericytes for small vessels (capillaries), smooth muscle cells for large vessels- needed to support new vessels
*NOTE* All above steps depend on vascular cells, growth factors and extracellular matrix interactions
Growth factors regulating the repair process
- VEGF
*receptors are confined to endothelial cells
*induced by hypoxia
*promotes angiogenesis, endothelial cell migration and proliferation, increased vascular permeability
- TGF-beta
*induced by hypoxia
- PDGF
*induced by hypoxia
- EGF
- FGF
- Other regulators; Cytokines
*TNFa and IL-1 are fibrogenic cytokines- promote migration and proliferation of fibroblasts in granulation tissue
VEGF-C
- Selectively induces hyperplasia of lymphatic vessels
Transforming growth factor-beta (TGF-B) Functions
- Most widespread in mammals
- Promotoes monocyte chemotaxis, fibroblast migration, collagen synthesis; inhibits collagenase secretion
Platelet-derived Growth Factor (PDGF) Functions
- Dimers A and B
- Stored in platelets alpha granules, released upon activation
- Promotes monocyte chemotaxis, fibroblast migration and proliferation, collagen synthesis and collagenase secretion
*making collagen and breaking it down b/c the early collagen thats layed down is an immature collagen that is not forming a super-structure, its forming the initial ECM that needs to be digested away and put down in a more organized fashion
Epidermal Growth Factor (EGF) Functions
- Binds to cERB1 receptor (has tyrosine kinase activity)
- Distributed in tissue secretions (sweat, saliva, urine, intestinal contents)
- Promotes fibroblast migration and proliferation
Fibroblast Growth Factor (FGF) Functions
- Acidic FGF (FGF1) and basic FGF (FGF2) are two best characterized forms
- Made constitutively; binds onto ECM proteins; hanging around waiting to release and bind to FGF receptors
- Associates/binds to heparan sulfate proteoglycans in ECM- serves as a reservoir for local cell proliferation
- Bound receptors have intrinsic tyrosine kinase activity
- Promotes monocyte chemotaxis, fibroblast migration and proliferation, angiogenesis and collagenase secretion
*NOTE* Important in new blood vessel formation, wound repair, development and hematopoiesis
ECM Proteins
- Proteoglycans- heparan sulfate, condroitin sulfate, dermatan sulfate
*Syndecan; a cell surface proteoglycan example
- AlphavBeta3 integreins- critical for maintaining new blood vessels
Fibrosis
A. Fibroblast proliferation; collagen for the most part that is being layed down in response to damage and repair
*provisional stroma for fibroblast in-growth; granulation tissue
*growth factors promote migration and proliferation to site of injury of the fibroblasts
*TGFB most important- being made by the fibroblasts and other cells to turn on fibroblast to now lead to this massive production of collage to repair
*Expressed in chronic fibrotic diseases*
B. Extracellular matrix deposition
*more fibrillar collagen (Types I, II, III) made at this time; important for wound strength
*net collagen accumulation; a function of collagen synthesis + collagen degradation
C. Tissue remodeling
*replacing granulation tissue w/a scar; replacing immature w/mature
*Net result of ECM synthesis versus degradation
*degradation of collagen and other ECM proteins; matrix metalloproteinases (Zn++ dependent); e.g., interstitial collagenases, gelatinases, stromelysins
*MMPs are rapidly inhibited by tissue inhibitors of metalloproteinase (TIMPs)
Wound Healing Summary of processes
- Induction of inflammation by injury
- Regeneration of parenchymal cells
- Migration and proliferation of parenchymal cells + connective tissue cells
- Synthesis of ECM
- Remodeling
- Collagenization and increased wound strength
Healing by first intention (surgical incision example)
A. Incision- death of epithelial and connective tissue cells- basement membrane disruption- blood clot filled w/fibrin and blood cells- scab upon dehydration
B. 24hrs- PMNs at margins- migrate to clot- epidermis thickens at cut edge- mitotic activity of basal cells increased
C. 24-48hrs- epithelial spurs migrate and grow along margins of dermis- basement membrane laid down- epithelial cells fuse at midline
D. Day 3- PMNs replace by macs- granulation tissue invades incision space- vertically oriented collagen fibers apear at margins- epithelial cell layer thickens
E. Day 5- space filled w/granulation tissue- max. neovas.- more abundant collagen fibrils begin to bridge incision- epidermis obtains normal thickness- surface differentiates (normal architecture and keratinization)
F. Second week- collagen continues to accumulate- fibroblast also continue to proliferate- leukocyte infiltrate, edema, increased vessels have disappeared- blanching begins
G. End of first month- scar makes up cellular connective tissue- no inflammatory cells- wound covered by intact epidermis- dermal appendages in incision line permanently lost- tensile strength increases
*NOTE* maximal strength may take months to achieve
Healing by second intention (wounds w/opposed edges)
- Represents a large tissue defect that must be filled- as parenchymal cells cannot completely fill, abundant granulation tissue grows in from margins
-
Differences b/w this and first intention healing:
i. inflammatory reaction more intense- more necrotic debris and exudates to be removed
ii. larger amounts of granulation tissue formed
iii. wound contraction- occurs in lg surface wounds- presence of myofibroblasts
*NOTE* Primary and secondary intention wound healing is determined by the nature of the wound, not by the healing process itself
Wound Strength timeframe
- Upon removal of sutures at end of first week- 10% strength of unwounded skin
- Increases rapidly over next 4wks- 20% by 3rd wk
- At third month rate slows, 60% by 4th month
*plateau reached at 70-80% of original tensile strength
- Mature scare at 6-12 months (80% of original- defined now as maximal strength)
Factors influencing wound healing
- Local:
a. persistent infection or foreign material
b. inadequate blood supply
c. excessive movement
d. irradiation
e. locally applied drugs, e.g., corticosteroids - Systemic:
a. age- healing slower and less effective w/increasing age
b. nutritional deficiencies, e.g., vit. C, Zinc, protein
c. metabolic disease, e.g., renal failure, diabetes mellitus
d. catabolic state assoc. w/malignancy
e. systemic drugs, e.g., corticosteroids
