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This document summarizes key concepts related to growth, repair, and cellular regulation from a pathology course. It describes Menkes disease, which is caused by a deficiency in cuproenzymes leading to connective tissue weaknesses. The phases of the cell cycle are defined, as well as mechanisms of cellular growth control involving cyclins, checkpoints, and growth factors. Processes of regeneration and fibrosis in tissue repair are compared. Extracellular matrix components, adhesion molecules, angiogenesis, and fibrosis are also summarized.
This document summarizes key concepts related to growth, repair, and cellular regulation from a pathology course. It describes Menkes disease, which is caused by a deficiency in cuproenzymes leading to connective tissue weaknesses. The phases of the cell cycle are defined, as well as mechanisms of cellular growth control involving cyclins, checkpoints, and growth factors. Processes of regeneration and fibrosis in tissue repair are compared. Extracellular matrix components, adhesion molecules, angiogenesis, and fibrosis are also summarized.
This document summarizes key concepts related to growth, repair, and cellular regulation from a pathology course. It describes Menkes disease, which is caused by a deficiency in cuproenzymes leading to connective tissue weaknesses. The phases of the cell cycle are defined, as well as mechanisms of cellular growth control involving cyclins, checkpoints, and growth factors. Processes of regeneration and fibrosis in tissue repair are compared. Extracellular matrix components, adhesion molecules, angiogenesis, and fibrosis are also summarized.
Paul G. Koles, MD Asst. Prof. Pathology and Surgery Director of Pathology Education Boonshoft School of Medicine at Wright State University Described Menkes Kinky-hair syndrome in 1962: Males only, gross abnormalities in hair, deficiency of cupro-enzymes (e.g., lysyl oxidase which crosslinks collagen and elastin), leading to weakened connective tissue. Many untreated patients dies of aortic dissection Parameter Menkes Disease Wilson Disease Lab findings Increased serum copper Decreased liver copper Increased intestinal/kidney copper Decreased serum copper Increased liver copper Increased urinary copper excretion Pathogenesis Increased absorption of copper from intestine Decreased excretion of copper in bile Treatment Daily Cu-histidine injections Copper chelation therapy Gene location X chromosome /recessive Chromosome 13/recessive Overview Part 3 Control of normal cell growth and regeneration Extracellular matrix & cell-matrix interactions Repair by connective tissue (fibrosis) Wound healing Aaron 17 years later, with Naomi his wife, November, 2008 Repair following inflammation: two simultaneous processes : replacement of injured/necrotic cells by cells of same type, often leaving no evidence of previous injury : replacement of injured/necrotic cells by connective tissue, leaving a permanent scar (microscopic or macroscopic) Regeneration Fibrosis Control of cellular population Stem Cells Differentiation Proliferation Apoptosis Cell Cycle PHASES of Cell Cycle: G1: S: G2: M: G0: presynthetic DNA synthesis premitotic mitotic quiescent Correlation of Cell Cycle and Tissue Types Continuously dividing (labile) cells: Surface epithelium and excretory ducts of glands (skin, gi/gu mucosa, biliary tract, pancreas) Marrow hematopoietic cells Stem cells in multiple organs (immature, undifferentiated cells) Quiescent (stable) cells in G0: Organ parenchymal cells (liver, kidneys) Mesenchymal cells (fibroblasts, smooth muscle, endothelium, chondrocytes, osteocytes) Nondividing permanent cells (cant re-enter cell cycle) Neurons, skeletal & cardiac myocytes Control of Passage through Cell Cycle : group of proteins that control cascade of phosphorylation pathways at various points in cell cycle : surveillance mechanism for ensuring orderly completion of molecular events, sensing problems in DNA replication, DNA repair, and chromosome segregation. If problems identified, progression to next phase of cell cycle can be delayed or stopped. Cyclins Checkpoints Mechanism: control of cell cycle Cyclin E / cdk 2
2 critical checkpoints to insure normal DNA, regulated by: Cyclins A B / cdk 1 2 G1 /S G2 / S Cell Growth: molecular overview Growth Factors or Cytokines Cell Surface Receptors Intracellular Activation of Transcription Factors Changes in Gene Expression (up and down regulation) Cell Proliferation or Inhibition Bind to Initiate Promote Resulting in Modes of Intercellular Signalling Autocrine Paracrine Endocrine Surface Receptors: 3 classes Receptors with intrinsic Tyrosine kinase activity Seven transmembrane (G protein-coupled) Receptors without intrinsic tyrosine kinase activity Consequences of Receptor Activation Intrinsic-kinase activity receptors: Irreversible commitment of cell to enter (proliferative response) Receptors without intrinsic kinase activity (cytokine superfamily): Activation cytosolic kinases to mediate functional response (not proliferative) G-protein coupled (seven spanning) receptors: Over 1500 receptors identified Bind various ligands, producing specific intracellular response Cell cycle Signal Transduction by Tyrosine Kinase Receptors Growth factors: coming soon! Clinical application: if mutant ras protein is permanently fixed in active GTP form, what pathologic process may result? Neoplasia Transcription Factors Definition: intracellular proteins that regulate gene expression, thereby controlling cell growth Specific domains in transcription factors:
: permits factor to bind specifically to short sequences of DNA
: allows factor to increase transcription of DNA
:allows factor to decrease transcription of DNA Transcription factors known to be operative in malignant neoplasms: Growth promoting: c-MYC and c-JUN Cell cycle inhibiting (tumor suppressor gene): p53 DNA-binding Activation Repression Growth Factors Definition: proteins that bind to cell surface receptors with generating cascade response that signals cell to enter S-phase (cell division). These factors can also modulate cell functions: locomotion, contractility, differentiation, etc. Intrinsic tyrosine kinase activity Major growth factors / effects FACTOR EGF = epidermal TGF-a = transforming VEGF=vascular endothelial PDGF= platelet-derived
FGF= fibroblast FGF-1=acidic FGF-2=basic
EFFECTS Mitogenic for epithelium & fibroblasts Mitogenic for hepatocytes Mitogenic for endothelial cells Mitogenic for monocytes, fibroblasts, smooth muscle cells; activates neutrophils
Angiogenesis, wound repair (mitogenic for both fibroblasts and keratinocytes)
Tissue Regeneration Liver from living donor before transplantation, outlining right lobe to be used for grafting into recipient Liver of donor one week post- partial hepatectomy, showing marked growth of left lobe (compensatory hyperplasia) without regrowth of right lobe. Why didnt right lobe regrow also? Extracellular matrix 1 Definition: macromolecules outside cells, formed by local secretion and assembled into network surrounding cells Functions: Sequester H2O for turgor; minerals for rigidity Reservoir for growth factors Scaffolding within which cells adhere, migrate, and proliferate Extracellular matrix (ECM) 2 Groups of macromolecules in ECM: Fibrous structural proteins: 2 major families are:
Adhesive glycoproteins Gel proteins in intercellular junctions and cell surfaces: proteoglycans & hylauronic acid Collagens Elastins Extracellular matrix (ECM) 3 Macromolecules of ECM assemble into two types of organizational structure: : fills spaces between cells
: closely associated with cell surfaces Interstitial matrix Basal membranes (basement membranes) Collagen: summary of major types Skin (80%), bone (90%), tendons Basal membranes Genetic deficiency of type IV in: Alport syndrome Collagen synthesis Nutrient required for hydroxylation of alpha chains: Deficiency of this nutrient causes poor wound healing in disease called: Inherited disorders of collagen synthesis, leading to defective fibers: Vitamin C Scurvy Ehlers-Danlos syndromes Elastic Fibers Definition: fibers capable of stretching and recoiling to original size Present in tissues requiring elasticity:
Structure: Central core protein: Peripheral microfibrillary network: Inherited defect in synthesis of peripheral microfibrillary network: abnormally weakened elastic fibers. Syndrome?
Skin, lung, uterus, ligaments, large blood vessels Elastin Fibrillin Marfan syndrome Cystic medial degeneration--aortic dissection Associated Vascular disease? Adhesion molecules 1 Function: attach cells to ECM matrices; 2 glycoprotein chains held together by disulfide bonds; produced by fibroblasts, endothelial cells, & monocytes Fibronectin Adhesion molecules 2 Most abundant glycoprotein in basement membranes; it spans basal lamina and binds to both cell surfaces and ECM components: Laminin Adhesion molecules 3 Transmembrane glycoproteins with alpha and beta chains that bind to fibronectin, laminin, & collagen. This family of surface receptors mediate attachment of cell membranes to ECM: integrins These also mediate adhesion of which cell type to endothelium? neutrophils Summary: interactions cell-ECM laminin Major EC structural protein: fibronectin integrins Fig. 3-16, Pathologic Basis of Disease, 7th ed, Elsevier 2005 Collagen Overview: Repair after injury ACUTE AND CHRONIC INFLAMMATION Damage to parenchymal cells and interstitial framework Regeneration of parenchymal cells whenever possible Replacement of non-regenerated damaged tissue by what? Fibrosis Fibrosis (fibroplasia) Four components: : formation new blood vessels of fibroblasts into damaged tissue of extracellular matrix Organization fibrous tissue = angiogenesis Migration and proliferation synthesis remodeling Sequence of events in repair 24 hrs: proliferation of fibroblasts & endothelial cells Within 3-5 days: Granulation tissue New capillaries Proliferation of young fibroblasts Little mature collagen blue-staining collagen (trichrome stain) Permanent result: Mature scar Angiogenesis Definition: pre-existing vessels send out capillary sprouts to form new vessels cf. vasculogenesis: the primitive vascular network established during embryogenesis Clinical importance: Repair post-inflammation Formation collateral circulation (post-MI) Support growth of neoplasms (therapeutic implications) Angiogenesis: 2 mechanisms ECM proteins affecting angiogenesis Integrins: formation and maintenance new vv. Matrix proteins which destabilize cell-matrix interactions, promoting angiogenesis: Thrombospondin SPARC Tenascin C Proteases that remodel matrix Plasminogen activators Matrix metalloproteinases Fragment of collagen that inhibits endothelial proliferation and angiogenesis, with therapeutic application in neoplasia?
endostatin Fibrosis (fibroplasia) Emigration and proliferation of fibroblasts at injury site, triggered by multiple growth factors produced by cells in granulation tissue, most important of which is: ECM deposition by fibroblasts: fibrillar collagen synthesis enhanced by growth factors and cytokines, thus converting Granulation tissue Into a Fibrous scar TGF-beta Tissue remodeling Conversion granulation tissue into scar involves changes in composition of ECM. : enzymes which degrade ECM components for remodeling. These enzymes are dependent on ions for activity. Matrix metalloproteinases zinc Wound Healing Healing by first intention Healing by second intention Summary: phases of wound healing Wound tensile strength: 10% of normal at 7 days; 70-80% of normal at 3 months Factors influencing wound healing Local Factors : most important single cause of delay Mechanical: too early motion can delay Foreign bodies: may impede or cause abscess Location: speed of healing proportional to richness of blood supply: face > trunk > extremities Type of wound: primary intention heals faster than secondary intention Infection Factors influencing wound healing Systemic factors: : first of two most important factors. Most important deficiencies (2):
: second of two most important factors. Arterial or venous insufficiency commonly delays healing. : iatrogenic delay of healing by blunting the normal inflammatory/repair response Nutritional deficiency Protein and vitamin C Inadequate blood supply Steroid therapy Pathologic complications of healing : exaggeration normal contraction of wound, resulting in deformity (palms, soles, anterior thorax). Common after burns. Deficient granulation tissue/ scar formation: : rupture of wound, usually due to increased mechanical pressure or inappropriate movement : usually due to arterial insufficiency caused by atherosclerosis; venous stasis also can contribute. Dehiscence Ulceration/poor healing Contracture Pathologic complications 2 Excessive formation of repair components:
Excessive granulation tissue Desmoid tumor (aggressive fibromatosis) Best viewed as low grade neoplasm with stubborn tendency for recurrences Keloid (hypertrophic scar) Fibrosis: Summary Overview: inflammation & repair Conclusion Physicians stand in wonder at the amazing capacity of the body to restore itself after injury, usually without loss of normal function. This represents an advanced kind of engineering and self-regulated maintenance function that humbles human technology.