Wound healing Flashcards
What are cytokines?
Cytokines are a broad and loose category of small proteins that are important in cell signaling. Their release has an effect on the behavior of cells around them.
Name a few cytokines.
Cytokines may include chemokines, interferons, interleukins, lymphokines, tumor necrosis factors. Growth factors are sometimes included as a cytokines but technically, they are not cytokines.
What are the growth factors?
Growth factors are proteins which are capable of stimulating cellular growth, proliferation, healing, and differentiation. They can also stimulate angiogenesis (fibroblast GF and vascular endothelial GF).
Who discovered growth factors?
Rita Levi Montalcini, Italian, winner of Nobel prize for physiology or medicine
Do cytokines only stimulate growth and proliferation?
No, some cytokines (for examples: Fas-ligand) are used as death signals, for programmed cell death called apoptosis.
Name some growth factors.
Platelet Derived Growth Factor (PDGF) Epidermal Growth Factor (EGF) Keratinocyte Growth Factor (KGF) Fibroblast Growth Factor (FGF) Transforming Growth Factor (TGF)
What cells secrete growth factors?
Growth factors are secreted by many different cells. In the platelets, growth factors are stored in the alpha granules.
Name the 4 different categories of cellular communication
Autocrine, Juxtacrine, Paracrine, Endocrine
How do growth factors work?
Growth factors (ligands) bind to the growth factor receptors on the cell membrane of the target cell. This initiates the process of signal transduction which stimulates a cellular response.
What are Cell Adhesion Molecules (CAMs)?
Cell Adhesion Molecules (CAMs) are proteins on the cell surface involved in binding with other cells or with the extracellular matrix in a process called cell adhesion. The CAMs help the cells stick to each other and to their surrounding. CAMs are crucial to maintaining tissue structure and function.
How are CAMs categorized?
There are 4 groups of CAMs: 1. Cadherins 2. Integrins 3. C type of lectin-like domains proteins (CTLDs) 4. Proteoglycans CAMs can also be subdivided into Calcium-independent CAMs and Calcium-dependent CAMS.
What are Calcium-independent CAMs?
Integrins
What are Calcium-dependent CAMs?
Cadherins and Selectins
What are Integrins?
Integrins are transmembrane receptors which facilitate cell-extracellular adhesion. Ligands for integrins include fibronectin, vitronectin, collagen, and laminin. The integrin receptor has 2 units: alpha and beta. The integrins enable the cells to detect and interact with components of the extracellular matrix.
What are selectins?
Selectins are CAMs found on endothelial cells. During an inflammatory response, the selectins are mobilized to the cell surface of the endothelial cells, bind to certain carbohydrate groups on the proteins of the leukocytes, slow these leukocytes down, and allow these leukocytes to leave the blood vessels and enter the infection site.
What is the immunoglobulin superfamily of CAMs? (IgSF of CAMS)
The immunoglobulin superfamily is a large:
- protein superfamily of cell surface proteins and soluble proteins
- important in cell recognition, binding, and adhesion of cells
- shared the same structural domain with immunoglobulin:
With regards to wound healing, when are Integrins used?
- Platelet interactions with collagen during hemostasis 2. Leukocyte extravasation during early inflammation 3. Endothelial cell budding and ingrowth during angiogenesis 4. Epithelial cell migration 5. Fibroblast movement through granulating tissue
What are the Matrix Metalloproteases?
The Matrix Metalloproteases (MMPs) are calcium-dependent, zinc-containing endopeptidases. They are capable of degrading extracellular matrix proteins.
Which cells secrete MMPs?
Many cells can secrete MMPs, including macrophages, neutrophils, monocytes, fibroblasts, keratinocytesWha.
Which MMPs degrade collagen and which degrade gelatin?
MMPs 1 and 8 are collagenases and MMPs 2 and 9 are gelatinases. 1 and 8 cause initial breakdown of vital structure, 2 and 9 further degrade already damaged ECM into even smaller components.
What are TIMPs?
Tissue Inhibitors of MMPs.
What cells secrete TIMPs?
All cells can secrete TIMPs.
What do TIMPs do?
TIMPs can reversibly bind MMPs in 1:1 ratio to inactivate the MMPs. There are only 4 TIMPs known.
What are some conditions resulted from excessive protease activity?
- Rheumatoid arthritis 2. Osteoarthritis 3. Aneurysm 4. Atherosclerosis 5. Tumor growth 6. Periodontal disease 7. Cystic fibrosis
What is the ECM?
ECM or extracellular matrix is a complex scaffold of biologically active molecules. These active molecules are secreted by the cells that are suspended in the extracellular matrix. The ECM supports the activity of the cells that it surrounds.
What is the composition of the ECM?
The extracellular matrix is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs)
What are the glycosaminoglycans?
Glycosaminoglycans are:
- polysaccharides
- signaling molecules
- important in cytokine production
- Proteoglycans: core protein with 2 chains of glycosaminoglycans
What are the adhesive glycoproteins?
Fibronectin, laminin, tenascin and nidogen.
What is the function of the adhesive glycoproteins?
The adhesive glycoproteins connect the cells to the matrix, organize the cells and the ECM structures and facilitate movement of the cells into the wound site.
What are the key cells in wound healing?
The key cells in wound healing are: 1. Platelets 2. Erythrocytes 3. Neutrophils 4. Monocytes 5. Macrophages 6. Fibroblasts 7. Myofibroblasts 8. Granulocytes 9. Endothelial cells 10.Keratinocytes
What are the phases of wound healing?
- hemostasis and coagulation 2. inflammation 3. proliferation (angiogenesis, granulation, epithelialization 4. maturation and remodling
What happens in the inflammatory phase of wound healing?
- Endothelial cells lining the capillaries in the vicinity of the wound develop gaps. This increased vascular permeability results in migration of leukocytes into extracellular space. 2. Vasoconstriction transition to vasodilatation (effects of endothelial products and mast cell derived factors such as histamine) 3. Elastase and collagenase are released into the ECM at the site of the wound 4. Leukocytes weakly adhere to selectin molecules causing them to decelerate and ahhere to endothelial cells lining the capillaries (margination). Chemotactic signals outside the venule induce leukocytes to squeeze between the endothelial cells. 5. Integrin on the neutrophil surface facilitates transmigration through the endothelium (diapedesis). 6. Migrating monocytes transform into macrophages in the extravascular space. 7. Neutrophils and macrophages initiate cellular wound debridement by phagocytosing bacteria and foreign material. 8. MMPs start to breakdown collagen 9. Neutrophils usually depleted after 2-3 days by apoptosis. 10. Macrophages later in inflammation, mediate transition into proliferative phase of healing.
What are the main cells in the proliferation phase of wound healing?
Fibroblast and endothelial cells: fibroblasts for granulation tissue proliferation and endothelial cells for angiogenesis.
What type of collagen is predominant in granulation tissue?
Type 3
When does angiogenesis become active in a wound?
from day 2 after wounding
What stimulate angiogenesis?
vascular endothelial GF, fibroblast GF
What type of cells is predominantly responsible for wound contraction?
Myofibroblasts.
When do myofibroblasts appear in the wound?
The myofibroblasts appear 4-6 days after initial injury and commonly seen in the wound during the following 2-3 weeks.
What is the rate of contraction of wounds?
Averages 0.6 to 0.7 mm per days.
When does epithelialization start?
Reconstruction of injured epithelium begins almost immediately after wounding. Cells migrate as a monolayer, begin to proliferate approximately 24 hours after initiation.
When does remodeling occur?
Usually 21 days after injury. MMPs involved with the breakdown of collagen. Immature scar contains disorganized fine collagen fibers. These are replaced by type 1 collagen arranged in an orientation paralleling skin stresses.
The timing of wound strength
1 week after the closure of wound: 3% of the normal tissue wound strength 3 weeks after the closure of wound: 20% 3 months after the closure of wound: 80%
When is a wound chronic?
Most consider wound not healed or healing well by 4 weeks to be chronic.
What is a prognostic indicator of venous leg ulcers?
If there is <40% reduction in wound size by week 4, it is unlikely to have complete wound closure at 24 weeks.
What is a prognostic indicator of diabetic foot ulcers?
If there is < 50% reduction in wound size by week 4, it is unlikely to have complete closure at 12 weeks.
Factors affecting wound chronicity
- Disease or conditions competing for metabolic resources, oxygen and or resulting in abnormal blood or tissue function; 2. Effects of medication such as steroids or immunosuppressive agents. 3. Increased bacterial load 4 Excessive proteases 5. Senescent cells
What is the composition of blood?
Plasma: 55%, Buffy Coat (leukocytes and platelets <1%), Erythrocytes: 45%
What are the three kinds of granulocytes?
Neutrophils, eosinophils, basophils
What are the two kinds of leukocytes without granules?
Lymphocytes and monocytes
What are some proteoglycans?
Glycosaminoglycans (GAGs) are carbohydrate polymers, attached to extracellular matrix proteins to form proteoglycans. Some types of proteoglycans are: heparan sulfate, chondroitin sulfate, keratan sulfate.
What are some proteins in the ECM?
Collagen, Elastin
What are fibronectins?
Fibronectins are glycoproteins that connect cells with collagen fibers in the ECM, allowing cells to move through the ECM. Fibronectins beind collagen and cell-surface integrins, causing a reorganization of the cell’s cytoskeleton to facilitate cell movement.
