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Pathology chapter 03


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Describe the cell cycle and define the single-lettered abbreviations (M, G0, G1, S, G2).
The cell cycle consists of G1 (presynthetic), S (DNA synthesis), G2 (premitotic), and M (mitotic) phases. Quiescent cells are in a plhysiologic state called G0. Therefore the cell cycle is G1(<>G0)<>S<>G2<>M<>G1
Describe the term labile cells
Labile is continuously dividing tissues in which cells proliferate throughout life, replacing those that are destroyed. Cells/tissues that fall into this category are: hematopoietic, epithelial.
Describe the term Stable cells
Stable (or quiescent) tissues normally have a low level of replication, however, cells from these tissues can undergo rapid division in response to stimuli and are thus capable of reconstituting the tissue of origin. Cells/tissues in this category are: smooth muscle, glandular parenchymal, glial, osseous and chondroid, connective
Describe the term Permanent cells
Permanent (nondividing) tissues containing cells that have left the cell cycle and cannot undergo mitotic division in postnatal life. Cells/tissues in this category are: skeletal and cardiac muscle, neuronal
What stimulates collagen synthesis
PDGF, FGF, IL-1, and TNF
Discuss the basic aspects of collagen synthesis
Procollagen is hydroxylated (requiring Vitamin C) and, subsequently, three procollagen chains align in phase to form the triple helix. Procollagen is secreted from the cell and cleaved by proteases to form the basic unit of fibrils. Collagen fibril formation is associated with the oxidation of specific lysine and hydroxylysine residues by extracellular enzyme (lysyl oxidase), thus stabilizing the array that is characteristic of collagen
Discuss the basic aspects of collage degradation
Degradation of collagen and other ECM proteins is achieved by a family of matrix metalloproteinases (MMPs), which are dependent on zinc ions for their activity
Discuss the basic aspects of collagen function
Fibrillar collagens form a major portion of the connective tissue in repair sites and are important for the development of strength in healing wounds. Types I, II, and III are interstitial, or fibrillar, collage; Type IV collagen is nonfibrillar (it forms sheets instead of fibrils) and is the main component of the basement membrane. Type I is found in connective tissue of skin, bone, tendons, and ligaments; Type II is found in cartilage; Type III is found in connective tissue of organs, smooth muscle, and blood vessels.
Discuss the basement membranes with regard to morphology, composition, and function
BMs are produced by epithelial and mesenchymal cells and are closely associated with the cell surface. They consist of a network of amorphous nonfibrillar collagen (Type IV), laminin, heparan sulfate, proteoglycan, and other glycoproteins. They function to anchor the cells/tissues in place and regulate what passes out of (and into the cells).
What is resolution
the arrest of an inflammatory process without suppuration; the absorption or breaking down and removal of the products of inflammation or of a new growth
What is regeneration
the growth of cells and tissues to replace lost structures. One example would be the process that occurs in the liver after partial hepatectomy. Can occur as quickly as within one week and occurs via hepatocyte proliferation (as well as replication of Kupffer cells, endothelial cells, and stellate cells). The ultimate outcome is the replacement of lost structures.
What is repair
a process that restores tissue to its original state; it contains the damage, eliminates the damaging stimulus, removes injured tissue, and initiates the deposition of ECM components in the area of injury. It begins as early as 24 hours after injury (if resolution has not occurred)-fibroblasts and endothelial cells begin proliferating forming granulation tissue
What is organization
In parenchymal organs, the replacement of inflammatory infiltrates by granulation tissue and ultimately fibrosis. Occurs in cirrhosis of the liver and in some forms of coal-induced lung disease. Ultimately the outcome is the replacement of functioning tissue with fibrosis.
State the role of collagen in the ECM
Provides the extracellular framework for all multicellular organisms. Important in forming the basement membrane and also in meshworks and as anchors in epidermal-dermal junctions, cartilage, and blood vessel walls
State the role of laminin in the ECM
most abundant glycoprotein in the basement membrane and has binding domains for both ECM and cell-surface receptors
State the role of elastin in the ECM
Provides the ability of tissue to recoil. Fibers can stretch several times their length and then return to their original size after the release of tension. Found in the walls of large blood vessels, skin, and ligaments
State the role of integrin in the ECM
Bind both to matrix proteins and laminin, mediating adhesiveness b/t cells and ECM as well as to adhesive proteins in other cells, establishing cell-cell contacts
State the role of fibrillin in the ECM
glycoprotein that associates with itself or other components of the ECM to form the scaffolding for the deposition of elastin and the assembly of elastic fibers
State the role of Fibronectin in the ICM
large protein that binds many molecules, such as collagen, fibrin, proteoglycans, and cell-surface receptors. Tissue fibronectin forms fibrillar aggregates at wound healing sites. Plasma fibronectin forms the provisional blood clots that fills the space created by a wound.
State the role of adhesive glycoproteins
located in the cell membrane and function as receptors
State the role of fibrous structural proteins
help contribute to fibrosis that takes place after some injuries
State the role of proteoglycans
Regulate CT structure and permeability and also act as integral membrane proteins (acting as modulators of cell growth and differentiation).
State the role of hyaluronic acid
Helps provide resilience and lubrication to many types of CT, notably for the cartilage in joints.
Describe how cells are attached to the extracellular matrix, and how these attachments may alter cell and gene expression
Focal adhesion complexes attached to integrins with laminin fibers anchor with fibronectin and collagen in the ECM. The focal adhesion molecules in the cell are attached to the nucleus through an actin cytoskeleton and via cytoskeleton-mediated signals, thus affecting cell growth, motility, and protein synthesis. Basically changes in fibronectin and laminin (of the ECM) are transmitted through integrins>>focal adhesion molecules>>actin cytoskeleton>>nucleus in order to elicit changes in the cell
Describe the first step of tissue repair
Inflammatory response with redness and swelling, with the invasion of neutrophils, clot formation, and the development of a scab. Platelet derived growth factor is present during this process as well as fibronectin which stabilizes the clot, which occurs within 24 hours
Describe the second step of tissue repair
By day 3, neutrophils have been replaced with macrophages and granulation tissue progressively invades the incision space. Collagen fibers are present in the margins of the incision, but are vertical and do not bridge the incision. Epithelial cell proliferation thickens the epidermal layer. Here we would probably see transforming growth factor as well as epidermal growth factor, fibroblast growth factor, and vascular endothelial growth factor (small capillary angiogenesis)
Describe the third step of tissue repair
By day 5 the incisional space is filled with granulation tissue. Neovascularization is maximal and collagen fibrils become more abundant-bridging the incision. The epidermis recovers its normal thickness. We would probably see the same growth factors as in step 2
Describe the fourth step of tissue repair
During the second week there is continued accumulation of collagen and proliferation of fibroblasts-leukocyte infiltration, edema, and increased vascularity have largely disappeared. The long process of blanching begins, accomplished by the increased accumulation of collagen within the incisional scar, accompanied by regression of vascular channels. We would see the same growth factors as before with the exception of the vascular endothelial growth factor
Describe angiogenesis with regard to the time course and biochemical factors (growth factors and enzymes).
Vasodilation in response to nitric oxide and VEGF induce increased permeability of the pre-existing vessel>>proteolytic degradation of the BM of the parent vessel by metalloproteinases and disruption of cell-to-cell contact b/t endothelial cells of the vessel by plasminogen activator>>migration of endothelial cells toward the angiogenic stimulus>>proliferation of endothelial cells, just behind the leading front of migrating cells>>maturation of endothelial cells, which includes inhibition of growth and remodeling into capillary tubes>>recruitment of periendothelial cells to support the endothelial tubes and form the new vessel.

Vascular endothelial growth factor is important, but endothelial cell proliferation, differentiation, and migration can also be enhanced by fibroblast growth factor-2. Angiopoietins 1 and 2, platelet derived growth factor, and transforming growth factor participate in the vessel stabilization process
Discuss the role of cell migration in the repair reaction
necessary for the initial inflammation (ie-neutrophils and then macrophages) and initiation of healing (ie-proliferation and migration of parenchymal and CT cells)
Discuss the role of integrins in the repair reaction
help with cell signaling via the changes that occur in laminin and fibronectin that are then transmitted to the cell nucleus and can lead to changes in proliferation, differentiation, protein synthesis, attachment, migration, and shape change. They are also critical for the formation and maintenance of newly formed blood vessels
Discuss the role of growth factors in the repair reaction
signals may be autocrine, paracrine, or endocrine, but no matter what they are critical to affecting the cellular and tissue changes that are necessary for the repair process. They serve to promote wound contraction and epithelial migration (fibronectin), act as growth factor for fibroblasts and chemotactic for fibroblasts and macrophages (PDGF), inhibit cell growth and promote differentiation of fibroblasts and epithelium (TGF), and give rise to marked increase in CT and endothelial growth
Describe the role of myofibroblasts in the process of wound healing
Altered fibroblasts that have the ultrastructural characteristics of smooth muscle cells that aid in permanent wound contraction (important in healing with second intention)
Describe the role of endothelial cells in the process of wound healing
migration, proliferation, and maturation help to establish (or re-establish) blood supply to a damaged area. Also, in the initial inflammatory response, selectins help with rolling, ICAM-1 helps with adhesion, and the formation of gaps allows for diapedesis of leukocytes
Describe the role of fibroblasts in the process of wound healing
make collagens, deposit other extracellular matrix elements including elastin, proteoglycans, and hyaluronic acid; also give rise to contracting myofibroblast cells
Describe the role of macrophages in the process of wound healing
serve to clean up debris and also synthesize PDGF and TGF
Describe the role of collagen in the process of wound healing
wound strength is proportional to collagen accumulation, also helps to form the scar.
Compare healing by first intention (primary union) and second intention (secondary union) in terms of time, sequence of events, morphologic changes, and final outcome
With secondary intention the inflammatory reaction is more intense because the large tissue defects generate a larger fibrin clot that fills the defect and more necrotic debris and exudates that must be removed. Also, much larger amounts of granulation tissue are formed, which actually grows in from the margin to complete the repair. The biggest difference is that, after a few weeks, first intention ceases with fibrous union whereas second intention ceases with wound contraction (with the help of myofibroblasts). With second intention there is substantial scar formation and thinning of the epidermis
Describe how nutrition influences wound healing
Systemic effects. Protein deficiency and vitamin C deficiency inhibit collagen synthesis and retard healing
Desribe how metabolic status influences wound healing
Systemic effects. Can change wound healing. For example, diabetes mellitus is associated with delayed healing as a consequence of the microangiopathy that is a frequent feature of this disease
Describe how circulatory status influences wound healing
Systemic effects. Can modulate wound healing. Inadequate blood supply, due to arteriosclerosis or venous abnormalities that retard venous drainage, also impairs healing
Describe how hormones influence wound healing
Systemic effects. Glucocorticoids have anti-inflammatory effects that influence carious components of inflammation as well as inhibit collagen synthesis
Describe how infection influences wound healing
Local effects. Single most important cause of delay in healing because it results in persisten tissue injury and inflammation
Describe how mechanical factor influence wound healing
Local effects. Like early motion of wounds, can delay healing by compressiong blood vessels and separating the edges of the wound
Describe how foreign bodies can influence wound healing
Local effects. Things such as unnecessary sutures or fragments of steel, glass, or even bone constitute impediments to healing
Describe how size, location and type of wounds influences healing
Local effects. Smaller wounds may heal faster than larger ones, while wounds in richly vascularized areas will heal faster than poorly vascularized areas. Also, incisional injuries heal faster with less scar formation than blunt injuries
Describe the basic ways injured tissue might repair itself
1. Regeneration-reconstitution of normal structure. Example are liver regeneration after partial hepatectomy
2. Healing-scar formation; organization of exudates. Example includes deep excision wounds or myocardial infarction
3. Fibrosis-tissue scar. Cirrhosis and pulmonary fibrosis
What are the two basic types of cellular regeneration
Compensatory hyperplasia and hypertrophy. Stem cell differentiation or transdifferentiation could possible be included as well
List the major constituents of granulation tissue
Fibroblasts and vascular endothelial cells that have begun proliferating
Describe the sequence of events in skin wound healing
Inflammation, followed by formatio of granulatio tissue and subsequent tissue remodeling and scarring.
What are the four major growth factors in wound healing
1. Fibronecting. Glue that binds, promotes wound contraction and epithelial migration
2. PDGF. Chemotactic for fibroblasts and macros, growht factor for fibros
3. TGF. Inhibits cell growth, but promotes differentiation of fibroblasts and epithelium and promotes synthesis of collagen and fibronectin by fibroblasts
4. Epidermal growth factor-gives rise to marked increase in connective tissue and endothelial growth
What are three possible complications of wound healing
Deficient scar formation, leading to rupture or ulceration; Excessive formation of the repair components, leading to hypertrophic scar or a keloid; Formation of contractures, and exageration of wound contraction

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