(From Path First Week, Sept 2000, by Brian Buschman)
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When cellular injury results there are two important mechanisms for replacing dead cells:
1) Regeneration of the original cell type.
2) Replacement by C.T. to form a scar.
Cell growth can be speed up by either speeding up the cell cycle or by recruiting cells of the Go phase to renter the cycle. The later is the most important. Cells fall into three types:
1) Labile (continuously dividing) cells
2) Stable (quiescent) cells
3) Permanent (non-dividing) cells. These cells do not divide after birth like neurons and cardiac muscle.
These events are primarily controlled by proto-oncogenes. They are controlled by three mechanisms:
1) Autocrine (hepatic regeneration, neoplasm)
2) Paracrine (C.T. repair stimulated by macrophages)
3) Endocrine (GF stimulated cells)
There are three types of receptors for growth mediators:
1) Receptors with kinase activity which turn on src and ras genes. Ras then activates Raf-1 which activates a cascade of “mitogen-activated protein kinases.”
2) Receptors which activate a cytosolic protein kinase.
3) G-proteins
There are five important pathways for signal transduction:
1) Mitogen-Activated Protein Kinase pathway (MAPK) involves the use of GRB2 and SOS to activate ras which activates the MAPK activating myc and such.
2) Phosphoinositide-3-kinase
3) IP3
4) CAMP
5) JAK/STAT pathway. JAK is Janus kinase and STAT signal transducers and activators or transcription. They work to activate other protein kinases.
Growth is inhibited by polypeptide factors such as transforming growth factor-b (TGF-b), TNF, b-interferon. TGF-b diminishes phosphorylation of retinoblastoma protein and keeping the cell in the S phase.
Major growth factors include:
1) Epidermal growth factor (EGF)/TGF-a which are widely distributed in tissue secretions. The two are interrelated.
2) PDGF comes from platelets and causes proliferation of other cells.
3) Fibroblast growth factor (FGF) works with tyrosine kinase activity and is related to angiogenesis, wound repair, hematopoiesis and development of the skeletal muscle and lungs.
4) Vascular endothelial growth factor (VEGF) is related to cancer, chronic inflammation and wound healing.
5) TGF-b is made by platelets, endothelial cells, macrophages and functions as both a stimulator and inhibitor. In low concentrations it leads to the production of PDGF but in high concentration it is inhibitory.
6) Cytokines mediate growth.
Matrix proteins include fibrous structures, adhesive molecules and proteoglycans. The most important molecules are:
1) Collagen of various types.
2) Elastin, fibrillin and elastic fibers that binds cells to the ECM in the skin, uterus and lungs.
3) Adhesive glycoproteins and integrins that bind components to the ECM. They play a role in holding down cancer cells.
4) Matricellular proteins that interact with the ECM and can block cells from sticking to the ECM.
5) Proteoglycans function as a basic structural feature.
Necrotic areas are repaired by the following sequence:
1) Angiogenesis which is begun by VEGF and cytokines. bFGF is another antigenic factor. The process of angiogenesis is regulated by the ECM.
2) Fibrosis (fibroplasia) which includes:
a. Fibroblast proliferation by all sorts of growth factors and cytokines.
b. ECM formation by fibroblasts because of GFs.
3) Tissue remodeling is carried out by metalloproteinases and are blocked by TIMP.
Would healing is carried out in two phases. In the first the epidermis proliferated and collagen accumulates to form a scar within the first four weeks in wounds with two edges still next to each other. The second method is for wounds with a chunk missing. It has a greater level of inflammation and the area must be filled.
10% of the wound is healed at the end of one week but at the end of three months it’s 70-80% healed.
Healing is affected by nutrition, metabolic issues (diabetes), circulatory status, hormones, infection and mechanical bodies.
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