Histo final until Lymphatic chapter.pdf

Topic #1: Epithelial Tissue (Chapter 4) Characteristic Features Cells brightly bond together. Presence of Basal Lamina Polarization Origin: Ectoderm Functions Protective: Cover tissues....

Topic #1: Epithelial Tissue (Chapter 4) Characteristic Features Cells brightly bond together. Presence of Basal Lamina Polarization Origin: Ectoderm Functions Protective: Cover tissues. Absorptive: Exchange of chemical substances. Transcellular Transport. Secretory: exocrine and endocrine glands. Sensory: detection of sensations. Polarization Apical domain: o Stereocilia. o Microvilli. o Cilia. Basolateral domain: o Lateral Surface (Cell to Cell Junctions) o Basal Surface (Cell to Extracellular Matrix) Morphological Forms Squamous: Flat cells, flat nuclei. Cuboidal: Spherical nucleus. Columnar: Tall cells, oval nuclei. Simple Epithelia Simple layer. All cells attached to basement membrane. Stratified Epithelia 2 or more layers. Basal layer attached to basement membrane. Pseudostratified Epithelia All cells attached to basement membrane. Not all cells reach apical surface. Glands Number of cells: o Unicellular glands (goblet cells) o Multicellular glands (pancreas) Destination of secretion: o Exocrine (secrete to surface of epithelium with ducts) o Endocrine (secrete to blood without ducts) Mode of secretion (exocrine glands) o Apocrine o Merocrine o Holocrine Target of secretion: o Autocrine o Paracrine o Endocrine Type of secreted product: o Mucous glands. o Serous glands. o Mixed glands. Morphology of exocrine glands: o Simple glands (tubular and acinar) o Compound Exocrine glands Merocrine glands: Secrete by exocytosis. (Sweat glands, salivary glands, goblet cells) Apocrine glands: Secrete by apical portion of cytoplasm into a duct. (Mammary gland, lipid vacuoles) Holocrine glands: Secrete by shedding entire cells from the lining of the duct. (Sebaceous Glands) Glands Classification Simple Glands: o Simple Tubular Gland (Interstitial glands of Lieberkühn) o Simple coiled tubular gland (sweat gland) o Simple tubular branched gland (glands of stomach and uterus) o Simple acinar/alveolar gland (sebaceus glands of skin) Compound Glands: o Compound tubular gland (glands of oral cavity) o Compound acinar / alveolar gland (exocrine pancreas) o Compound tubuloacinar gland (mammary gland) Basement membranes: Semipermeable filter formed of glycoproteins and other components. Two parts: o Basal lamina o Reticular lamina (III collagen) bound to basal lamina by type IV collagen. Include: Type IV collagen. o Laminin. o Nidogen and Perlecan. Cell Junctions: Tight Junctions: (Zonulae Occludens) o Present in apical part of cells. o Prevent free passage of substances between lumen of natural tract and basolateral intercellular space. o Proteins involved: ▪ Occludins and Claudins. ▪ JAMs (Junctional Adhesion Molecule) & Zonula Occludens proteins.  Anchoring Junctions (Adherens Junction) o Strong cellular adhesion and strength to tissues and strong cell to cell adhesion. o 3 forms: ▪ Zonula adherens: Contains E cadherins connected to actin filaments through catenin, vinculin and a-actinin. ▪ Desmosomes: provides points of strong intermediate filament between adjacent cells, strengthening the tissue. Contains cadherins. ▪ Hemidesmosomes: connects the cell with basement membrane. Anchors the intermediate filaments of the cytoskeleton into the basement membrane. o Common in epidermis, vagina, cervix, cardiac muscle tissue. Focal Adhesions: o Form structural link between actin cytoskeleton and FCM proteins. (Integrins, Talin, Vinculin, Focal Adhesion Kinase) o Responsible for attachment of actin filaments into basal lamina. Gap Junctions: o Formed by connexons. o Connects two cells and may be opened permanently or transitory. o Cells may be coupled both electronically and metabolically. o Localization: epithelia, cardiac muscle, hepatocytes, osteocytes, odontoblasts, granulosa cells. Apical Cell Surface: Microvilli: o Specialized for absorption. o Covered by glycocalyx. o Intestinal brush border Stereocilia: o Epithelial cell in male reproductive system. o Non-motile o Core with actin filaments. o Important for ear sensory cells. o Fimbrim, villin and espin o A-actin  Cilia: o Core of 9 microtubule doblets around two central microtubules (9+2) o Motile o Primary cilia are enriched in mechanoreceptors and signal transduction complexes for detection of light, odors, motion, and flow of liquids. o Localization: Respiratory epithelium, oviduct, uterine epithelium. o Opens calcium channels by deflection. These channels are formed by Polycystin 1 and 2. (initiates influx of calcium) o *Primary Cilia Dyskinesia=PCD, lack of dynein arms due to mutations, responsible for immotile cilia syndrome (Kartagener syndrome), which causes immotile spermatozoa, situs inversus, and chronic respiratory infections. Axoneme Consists of microtubule cytoskeleton (9 microtubule doublets and central pair) Main extracellular part of cilia and flagella. Microtubule pairs located at periphery, move against each other due to ATP hydrolysis catalysed by dynein. Cellular Adhesion Molecules (CAMs) Transmembrane proteins. Ca+2 dependent: o Cadherins: bind with similar proteins of same tissue and with cytoskeleton filaments. o Selectins: weak intercellular connections. ▪ Bind to specific oligosaccharide groups of glycoproteins and glycolipids. o Integrins: glycoproteins that function as membrane receptors for ECM macromolecules. ▪ Enable cells aggregation and migration (embryogenesis, organogenesis) ▪ Heterodimers: 2 subunits (A and B) ▪ EC domains bind directly to ECM components (fibronectin, laminin, tenascin) ▪ Cytoplasmatic tail of B subunit binds to actin filaments of cytoskeleton. Ca+2 independent: o These are immunoglobulins, like IgSF: ICAMs, NCAMs, E-CAMs, VCAMs, etc. o It also includes Nectins, which establishes weak both hemophilic and heterophilic interactions with related nectin family members. *Important: Pemphigus vulgaris. It involves the epidermis or stratified squamous epithelia of oral mucosa, due to abnormal desmosome and hemidesmosome function due to autoimmune reactions against specific desmoglein that reduce cell to cell adhesion. Pemphigus antibody binds to desmoglein 3, and as a result desmosomes are weakened.  Topic #2: Connective Tissue (Chapter 5 and 6) Cells are embedded in abundant ECM (Ground substance + Fibers) Functions: Support other tissues and organs. Act as medium for exchange of nutrients. Protect against infectious agents. Repair damaged tissues. Store fat (Adipose Tissue), Ca+2 (bone), water (loose connective tissue) Types of Connective Tissue 1) Embryonic Connective tissue 2) Connective Tissue Proper 3) Specialized connective tissue Extracellular Matrix (ECM): 1) Ground Substance: a. Components: i. Glycosaminoglycans (GAGs): Made of Uronic Acid + Hexosamine. 1. Are polysaccharides negatively charged. 2. Have capability of binding large quantities of water. 3. Resistant for compression. 4. Most of GAGs together form PGs. 5. Most ubiquitous GAG is hyaluronan, synthetized directly to ECM by hyaluronan synthase. 6. Major GAGs: Dermatan Sulfate (Type I collagen), Chondroitin sulfates (Type II), keratan sulfate, heparan sulfate. (Type III) ii. Proteoglycans (PGs): 90% GAGs + 10% Protein Core. 1. Macromolecules w/protein core and GAGs attached. 2. Many PGs attach to hyaluronic acid particles and join aggregates. 3. They’re produced in the RER. 4. Major PGs: Perlecan in basal laminae. 5. Aggrecan is the largest, joined with chondroitin and keratan sulfates. 6. Cell Membrane PG: Syndecan. → Scar.  iii. Adhesive Glycoproteins: Protein 90% + Carbohydrates 10% 1. Bind to components of ECM and to receptors of cell surface. 2. Form Cell to ECM adhesions. 3. Fibronectin (ECM): synthetized by fibroblasts, with binding sites for collagen and GAGs. a. Fibroblasts + Fibroblasts = Focal Adhesions 4. Laminin (Basal Lamina): Binding sites for Integrins, Type IV collagen, giving adhesion for epithelial / other cells. 5. Chondronectin (Cartilage) 6. Osteonectin (Bone) 2) Fiber: a. Collagen and reticular fiber: i. Non elastic and has great tensile strength. ii. Major collagen types: 1. Type I: Connective Tissue, Dentin and Cementum. (Bones, tendons, organ capsules, dermis) 2. Type II: Hyaline and elastic cartilages. Resistant to pressure. 3. Type III: Reticular fibers. (Lymphatic system, lung, spleen, skin, cardiovascular system) 4. Type IV and VII: Basement Membranes. (Basal Lamina associated w/epithelial // Junction of epidermis and dermis) b. Elastic Fibers: Composed of fibrillin → forms network of microfibrils, layered over a mass of cross-linked elastin. i. Highly elastic. ii. The cross-linked elastin consists of desmosine. Cells of Connective Tissue Proper: 1) Fixed (resident) cells: a. Have developed and remain in place within connective tissue. b. Are stable and long lived. c. Fibroblasts, adipose cells, pericytes and macrophages. 2) Transient (free) cells: a. Originate mainly in bone marrow and circulate in the bloodstream. b. After stimuli/signal, they leave the bloodstream and migrate into connective tissue. c. Plasma cells, mast cells, lymphocytes, granulocytes, monocytes, and macrophages. Some macrophages are fixed, and some are transient. Fibroblasts Most common cell type in CT, only permanent resident cell, but able to move. It has abundant RER and well-developed actin cytoskeleton. Actively produces and secretes ground substance, fibers, and enzymes which degrade them. 1) Active Fibroblast: a. Basophilic. b. RER and GA (Golgi) well developed. c. Relaxed chromatin. d. Many cell projections. 2) Inactive Fibroblast (Fibrocyte) a. Acidophilic. b. Small amount of RER and GA. c. Condensed Chromatin. d. Only few projections. These two participate an important role in wound repair. ECM Glycoproteins 1) Fibronectin: a. Mediates cell adhesion to ECM by binding to integrins on cell surface via RGD sequence. (Arg-Gly-Asp) i. Matrix FN: forms fibrils in ECM. ii. Cell Surface FN: transiently attaches to surface of cells. iii. Plasma FN: circulating plasma protein that functions blood clotting, wound healing and phagocytosis. 2) Laminin: a. Mediates interaction between epithelia cells and ECM. b. Located in basal laminae and external laminae. c. Have binding sites for integrins, heparan sulfate, type IV collagen and entactin. 3) Entactin/Nidogen: a. Sulfated adhesive glycoprotein present in all basal laminae, binds laminin w/ collagen type IV in lamina densa. 4) Tenascin: a. Most abundant in embryonic tissues. Secreted by glial cells in developing nervous system. Promotes cell matrix adhesion. Macrophages (Histiocytes) Functions: Phagocytosis, antigen presentation to lymphocytes, secretion of cytokines (IL-1, TNF) Once made in bone marrow, they circulate for a short time in blood. This stage, they’re called monocytes. In various tissues, Macrophages are called differently: o Histiocytes: Connective Tissue Proper. o Kupffer cells: Liver. o Microglia: CNS. o Septal/Alveolar macrophages: Lung Alveoli’s Wall. o Dust cells: Inside the lumen of lung alveoli. Two types: o M1: Promotes inflammation, the destruction of ECM and apoptosis. ▪ Lots of M1: Langerhans cells. o M2: Anti-inflammatory promotes rebuilding of ECM, proliferation and angiogenesis. Mast Cells (Mastocytes/Labrocytes) Most numerous in loose CT. Basophilic granules rich in histamine, heparin, and neutral proteases. (tryptase, chymase) Secrete proinflammatory factors. Key role in allergy, anaphylaxis, wound healing. High affinity receptor for IgE. They secrete: o Histamine, heparin, serine proteases, eosinophil and neutrophil chemotactic factors, cytokines, and phospholipids. Connective tissue mast cells (CTMCs): o T-Cell independent. Mucosa Mast Cells (MMCs): o Predominantly in intestine and lungs, T cell Dependent. Plasma Cells Derived from B-Lymphocytes. Responsible for synthesis of antibodies. Cytoplasm very basophilic. Tendons Attach muscle to bone. Consist of parallel bundles of collagen fibers, between these bundles are situated tendinocytes. Ligaments Consists of fibers and fibroblasts. Less arranged than those in tendon. Join bone to bone, sometimes they require elasticity (spinal cord) Adipose Tissue Largest repository of energy. Energy is stored in form of triglycerides. Composed mainly of fat cells (adipocytes) Adipocytes Development: o Adipocytes arise from mesenchymal stem cells. o Precursor cell is converted into mature fat cell by accumulation and coalescence of lipid droplets. o Process is partly reversible. o Cells in early stages can divide, mature adipocytes cannot. o Adipocytes are surrounded by basal lamina. White Adipose Tissue: o Functions: Synthesis, storage, and release of triglycerides. o Release of hormones/cytokines. o Protection (cold, mechanical, physical) o Forms body shape of a given sex. Brown Adipose Tissue: Multilocular liquid droplets and mitochondria rich. o Functions: Heat production, due to uncoupling of oxidative phosphorylation in mitochondria by thermogenin.  Adipokines: o Biologically active molecules. (Hormones, cytokines, growth factors...) secreted by adipose tissue. o Act in autocrine, paracrine, and endocrine ways. o Immune cell migration via autocrine and paracrine signalling. o Endocrine/systemic effects on appetite and satiety control. o Functions: ▪ Regulates adipogenesis. ▪ Regulates the volume of adipose tissue within the body (obesity) ▪ Regulation of energy expenditure. ▪ Affects tissues sensitivity to insulin in liver, muscle and fat. ▪ Affects insulin secretion in pancreatic B cells. ▪ Regulates haematogenesis, osteogenesis, angiogenesis and blood clotting. o Types of Adipokines: ▪ Leptin: Satiety hormone inhibits hunger. Binds to hypothalamus. ▪ Adiponectin: anti-inflammatory, prevents atherosclerosis and insulin resistance. ▪ Resistin: decreases the cellular sensitivity to insulin (diabetes type II) ▪ TNF: induces the deficiency of insulin receptors, high concentration in obese individuals. ▪ IL-6: induces insulin resistance. ▪ ASP: Stimulates the acetylation. ▪ Adipsin: (Factor D of complement) stimulates glucose transport for triglyceride accumulation in adipocytes and inhibits lipolysis, role in immune responses. ▪ Plasminogen activator inhibitor: (Serpin) inhibitor of fibrinolysis, physiological process of blood clotting degradation. Obesity Hypertrophic obesity: accumulation and storage of fat in adipocytes. Size of adipocytes increases. Hypercellular obesity: increased number of adipocytes.  Topic #3: Bone and Cartilage (Chapter 7 and 8) Bone Specialized type of connective tissue with calcified matrix. Functions: o Protect vital organs. o Support fleshy structures. o Provide a calcium reserve. (99% of body’s calcium) o Dynamic tissue. Applied pressure → Bone resorption. Applied Tension → Bone formation. Woven Bone – Primary – Immature. Contains many osteocytes and fine fibers of type I collagen. Low mineral content First bone produced during fetal development and bone repair. Localization: o Prenatally and in rapidly growing child. o During fracture repair and remodelling. o Tooth sockets, insertions of some tendons, skull. Mechanically weak. Gradually replaced by mature bone or included within its fabric. Lamellar Bone – Secondary – Mature – In adults. Calcified matrix is arranged in regular layers = lamellae. Contains osteocytes in lacunae. Most bones are mixtures of compact outer surface and spongy interior. o Compact Bone (cortical bone): ▪ No trabeculae or bone marrow cavity. It builds diaphysis of long bones. ▪ Composed of many haversian systems (osteons) Composed of lamellae surrounding harversian canal, which contains blood vessels, nerves, and loose CT. Are interconnected by Volkmann’s canals, also to periosteum and endosteum. ▪ Bordered by circumferential lamellae. / 75-80% bone mass  o Spongy Bone (cancellous bone): ▪ Consists of twin trabeculae of bone tissue. ▪ Interconnected trabeculae surround cavities filled with bone marrow. ▪ Trabeculae, made of bone lamellae contain osteocytes, lined by a single layer of endosteum. (comprised of osteogenic progenitor and osteocytes) ▪ Localization: epiphysis of long bones / vertebral bodies, flat bones. ▪ Reduces skeletal weight without reducing strength. ▪ Multiple surfaces are important sites of bone remodelling. Bone Surfaces Periosteum: Noncalcified CT covering bone on its external surfaces. o Layers: Outer and Inner. o Sharpey’s Fibers (Collagen Type I): attaches tendons to bone surface. o Function: Distribution of blood vessels to bone. Endosteum: Layer of flat osteoprogenitor cells. o Very small amount of CT. o Lines up: ▪ Haversian canals. ▪ Marrow cavities in bone. Osteoprogenitor/Osteogenic cells Derived from embryonic mesenchyme. Located in periosteum and endosteum. They differentiate into osteoblasts. At low oxygen tensions, may change into chondrogenic cells. Inorganic part of bone matrix Composed of calcium, phosphate, magnesium. Consists of hydroxyapatite crystals. Organic part of bone matrix Contains mainly type I collagen. Ground substance contains: o PG o Osteocalcin o Growth Factor o Other Glycoproteins. Other components: o Osteopontin: mediates formation sealing zone adjacent to osteoclast. o Osteonectin: binding of hydroxyapatite crystals to type I collagen. o Bone sialoprotein: adherence of osteoblasts to bone matrix o Bone Morphogenic Proteins (BMP): binding of osteoblasts to ECM, w/integrins. o Bone matrix contains growth factors: FGF, TFG-B Osteoblasts Derived from osteogenic stem cells. BMP-6 and TGF-B induce osteoprogenitor cells to differentiate into osteoblasts. Synthetizes and secretes organic matrix, osteoid (uncalcified bone matrix) Located on bony surfaces. In active state → cuboidal and basophilic. While secreting, they become entrapped in lacunae (transforms into osteocytes) Maintain contact with osteoblasts and osteocytes via gap junctions. Matrix calcifies and becomes acidophilic. Marker Enzyme: o ALP: ▪ Its activity is necessary for the initial phase of bone mineralization. ▪ Its activity disappears when a cell becomes osteocyte. ▪ The activity of a bone isoform of ALP in blood increases in active bone synthesis and in some bone cancers. Osteocytes Mature bone cells housed in their own lacunae. Contact each other via gap junctions. Secrete sclerostin in low Ca+2 levels, which inhibits bone formation. They secrete IGF-1 (insulin growth factor 1) and osteocalcin. They’re nourished and maintained by nutrients that diffuses from Loose CT that fills up Haversian canal. Osteoclast Derived from bone marrow cells that are also precursors of monocytes. Localized How ship’s Lacunae. Specialized macrophages. They do not have receptors for parathormone (parathyroid gland hormone, increases bone resorption) They have receptors for calcitonin (hormone for thyroid c cells which inhibits bone reabsorption) o Performs bone resorption: ▪ Creates acidic environment (H+) necessary for decalcification of bone’s surface. ▪ Secretes proteolytic enzymes that degrade organic part of bone. ▪ Resorbs organic and inorganic matrix components and release them into capillaries. Ruffled border is a site of secretion of acids (to dissolve bone minerals) and hydrolases. (to digest organic components of bone matrix) Osteoblasts and osteoclasts cooperation Osteoblasts have receptors that control Ca+2 economy (PTH, Vitamin D3, IL-1, Prostaglandins, IGF-1) Osteoblasts produce: o M-CSF and RANKL, cytokines that induce differentiation of osteoclasts. o Osteoprotegerin (OPG), cytokines that inhibits differentiation of osteoclasts. o Osteoclast-Stimulating Factor (OSTF) that induces osteoclast formation and bone resorption. M-CSF and RANKL secreted by osteoblasts are necessary for differentiation of osteoclasts (OCL) Bone development Two processes (Intramembranous / Endochondral) bone formation. o Both result in histologically identical bone. Bone synthesis is accompanied by bone resorption. Bone remodelling: Bone formation + bone resorption. Occurs more often and faster in primary bone, and slower in secondary bone. Intramembranous ossification Formation of twin bones (parietal bones of skull) Mesenchymal cells differentiate into osteoblasts, which begin secreting osteoid. As calcification occurs, osteoblasts are trapped in their own matrix and become osteocytes. Centres of developing bone: Trabeculae. Endochondral ossification Proceeds in first in diaphysis (primary centre of ossification) and then at epiphyses (secondary centres of ossification) of hyaline model. Formation of primary center of ossification Vascularization of perichondrium → Transformation of chondrogenic cells to osteoprogenitor cells, which differentiate into osteoblasts. Perichondrium → Periosteum. Osteoblasts secrete matrix deep to periosteum, via intramembranous ossification, from subperiosteal bone collar. Chondrocytes undergo hypertrophy and degenerate and form large cavities. (marrow spaces) Osteoclasts create perforations in bone collar that permit periosteal bud (blood vessels, osteoprogenitor cells, and mesenchymal cells) to enter in cartilaginous model. o Cartilage that makes walls → Calcified. Newly developed osteoblasts elaborate bone matrix → calcified on surface of calcified cartilage, forming calcified cartilage-calcified bone complex. Subperiosteal bone collar → Thicker and elongates towards epiphysis. Osteoclasts resorb calcified cartilage-calcified bone complex, enlarging primitive primary marrow cavity → fills up with multicellular hemopoietic bone marrow tissue. Repetition of this sequence of events → results in bone formation spreading towards epiphyses. Formation of secondary center of ossification: develop out of epiphyses similarly to primary center, except that bone collar is not formed. Zones of Epiphyseal Plate Reserve or Resting Cartilage: Located at epiphyseal side of plate and possess inactive chondrocytes. Cell proliferation (of chondrocytes): Presence of isogenous cell groups. IGF-1 Cell maturation and hypertrophy: Cells produce collagen and ground substance, and VEGF. Cartilage Calcification: Chondrocytes die, and cartilage becomes calcified. Ossification: Osteoblasts elaborate bone matrix on calcified cartilage forming a calcified cartilage/calcified bone complex, cartilage is resorbed. Calcification begins with deposition of calcium phosphate and is stimulated by PGs and osteocalcin. (Ca+2 binding glycoprotein) Repair of Bone Fracture Damages bone matrix, bone cells and blood vessels. o Proliferation of osteoprogenitor cells occurs in periosteum and endosteum in vicinity of fracture. Cellular tissue surrounds fracture and penetrates between ends of bone. Formation of bony callus occurs internally and externally at fracture site. o Fibrous CT and hyaline cartilage are formed. Endochondral bone formation replaces cartilage with primary bone. Intramembranous bone formation also produces primary bone. o Primary bone joins the ends of fractured bone, forming bony callus. Primary bone is resorbed and replaced with secondary bone as fracture heals. Cartilage Model Long bones developed from miniature cartilage model. Cartilage is not converted to bone but is gradually replaced by it. Ossification begins in embryo and is not completed until the end of puberty. Joints Where adjacent bones are capped and held together by connective tissues. Type of joint determines the degree of movement. o Synostoses: ▪ No movement. ▪ Adults: Skull bones. ▪ Children and young adults held together by sutures. o Syndesmoses: ▪ Joins bones by dense connective tissue. ▪ Ex. Interosseous Ligament. o Symphyses: ▪ Thick pad of fibrocartilage. ▪ All symphyses occur in midline of body. ▪ Ex. Intervertebral discs and Pubic Symphysis. ▪ Each Intervertebral Disc has anulus fibrosus (fibrocartilage) At center of anulus fibrosus, there is nucleus pulposus. (shock absorber) o Diarthroses: ▪ Free bone movement. ▪ Elbow and Knee. ▪ Long bones. ▪ Capsule encloses a joint cavity. Contains viscous liquid → Synovial fluid. Lines up by synovial membrane. (produces synovial fluid) o Macrophage-like synovial cells → Type A cells. o Fibroblastic synovial cells → Type B cells. *Achondroplasia: Dwarfism. Produced by mutation in amino acid 380, in FGF receptor 3. Interferes with the growth of Cartilage in developing long bones. Cartilages: Cartilage is an avascular specialized fibrous CT. It has firmer ECM than that of CT proper. Has chondrocytes embedded in matrix. Functions: o Supports soft tissues. o Development and growth of long bones. Hyaline, Elastic and Fibro cartilages vary in certain matrix components. o Hyaline Cartilage → Type II collagen. o Elastic Cartilage → Type II collagen and elastic fibers. o Fibrocartilage → Type I and II collagen Hyaline cartilage has ground substance with PG aggregates and Chondronectin w/Type 2 collagen. Chondronectin mediates binding of cells w/ECM. Chondrocytes: Mature cartilage cells that are embedded within lacunae. Former chondroblasts that derived by: mesenchymal chondrogenic cells and chondrogenic cells within inner layer of perichondrium. o Once these cells are enveloped by matrix, they’re chondrocytes. Isogeneous group → group of chondrocytes derived from 1 progenitor cell. Perichondrium Layer of dense irregular CT that surrounds hyaline cartilage except at articular surfaces. Composed of: o Outer fibrous layer → Type I collagen, fibroblasts and blood vessels. o Inner cellular layer → has chondrogenic cells. Elastic Cartilage: Has perichondrium Similar to Hyaline Cartilage but has network of elastic fibers. Type II collagen. Localization: Eustachian tube, epiglottis, cuneiform cartilage in larynx. Fibrocartilage: Lacks perichondrium. Rows of fibroblast-derived-chondrocytes surrounded by scant matrix. Has Type I collagen fibers, some w/type II Dermatan and chondroitin sulfate prevail in GAGs. Located in: intervertebral discs, articular disks of the knee, mandible, sternoclavicular joints, public symphysis.  Topic #4: Nervous Tissue (Chapter 9) Composed of two main cell types: Neurons: o Transmit messages between cells by synapses. o Specialized long processes called axons transmit signals over long distances. o Short processes -> dendrites allow neurons to receive information. o Synapses allow to communicate with other neurons. o They cannot divide. They’re postmitotic cells. o Ex of Multipolar neurons: Purkinje cells of cerebellum, Pyramidal cells of cerebrum, interneurons of CNS and Motoneurons of spinal cord. o They possess a cell body = perikaryon, rich in organelles, nucleus, Golgi, mitochondria, RER + free ribosomes (Nissl bodies) o Axon hillock has no ribosomes but many microtubules and neurofilaments. It is the spike trigger zone of the neuron. o Axon and dendrites contain flattened cisternae of SER called hypolemmal cisternae. They contain Ca+2 and some proteins. o Neurotransmitters: Inhibitory neurons: GABA, Glycin Stimulatory/Excitory neurons: A, NA, DOPA, Ach, Serotonin, Glutaminic acid and histamine.  Glial Cells: o Represent CT of the nervous system. o Neuroglia processes are in direct contact with neurons. o They do not make synapses. o Functions: Provide nutrients for neurons Give nervous tissue structural support Can regenerate if injured: replace destroyed neurons by a process called gliosis. Control the chemical environment of neurons. o Types of Glia In CNS: Oligodendrocytes Astrocyte Ependymal cells Microglial cells. In PNS: Neurolemmocyte/Schwann Cells Satellite Cells Alzheimer's Disease: Neurofibrillary tangles, accumulations of tau protein and neuritic plaques. (these plaques are dense aggregates of B-amyloid protein that form outside of these neuronal regions) Types of Nerve Fibers: Unmyelinated → Axons of small diameter. Myelinated → myelin sheath is produced by the action of: o Schwann cells in PNS, Oligodendrocytes in CNS. There is almost no ECM in the CNS - 93% of the brain’s volume is occupied by neurons and glia cells, their processes and blood vessels. Distribution of glial cells in the brain (CNS) Astrocytes interacts with blood vessels as well with axons and dendrites. Astrocytes send their processes into the brain surface, contacting pia mater, forming glia limitans. They also extend towards fluid filled spaces in CNS, contacting ependymal cells. Oligodendrocytes myelinate nerve fibers in CNS. Microglia exhibit phagocytotic functions. Microglial cells are the monocyte-derived antigen presenting cells (APC) of the CNS. They’re evenly distributed between Gray and White matter. o They remove dead cells and cellular material and bacteria from CNS. Ependymal cells Epithelial-like cells → forms single layer lining the fluid filled ventricles of cerebrum and central canal of spinal cord. Lack basal lamina. Specialized subset of ependymal cells that make choroid plexus, secrete CSF. (Cerebro-spinal fluid) Blood brain barrier In the CNS, capillaries are lined by continuous endothelial cells linked by tight junctions (zonulae occludens) Main components of BBB (Blood-brain-barrier) o Tight junctions between endothelial cells. o Basal lamina of endothelial capillaries. o Perivascular astrocyte end-feet. Astrocytes w/extended foot processes called vascular end feet or glia limitants contact brain capillaries and induce and maintain BBB. Many drugs and peptide hormones may be transferred through the BBB by specific transport systems of endothelial cells. Central Nervous System Consists of: o Sensory division (afferent) ▪ Somatic: conscious input, skin, musculoskeletal structures, eyes, ears. ▪ Visceral: sensory input not conscious. Internal organs and cardiovascular structures. o Motor division (efferent) ▪ Somatic: motor output controlled consciously or voluntarily. Skeletal muscle effectors. ▪ Autonomic: motor output not controlled consciously. Ex. Heart Gray and white matter o Brain Gray matter is located at the cortex (periphery) of the cerebrum and cerebellum. ▪ Composed of neuronal cell bodies with dendrites, many unmyelinated fibers, some myelinated fibers, and neuroglial cells. o White matter lies beneath the gray matter. ▪ Composed of myelinated nerve fibers, some unmyelinated and neuroglial cells. o Gray matter forms the basal ganglia, located deep within the cerebrum. Cerebellar cortex: It has three layers. o Inner granular layer: densely packed with nuclei of small neurons. Receives mayor input to the cerebellum. (Mossy fiber input) o Purkinje cell layer: single row of large flask-shaped neurons. Dendrites arborize richly in the molecular layer. Axons exit in the medullary core. PCs are the only cerebellar neurons with efferent axons. o Molecular Layer: composed of dendrites of Purkinje, axons of granule cells, and axons and dendrites of stellate, golgi and basket cells. o Nuclei belong mostly to glial cells.  Topic #5: Muscle Tissue (Chapter 10) Myogenesis of skeletal muscles Mesodermal cells of the myotome → Premyoblasts. Filaments and microtubules appear in the cytoplasm of the myoblasts. Filaments aggregate into myofibrils near the sarcolemma, going to the myotube stage. Structure of skeletal muscle Endomysium: thin layer of CT surrounding individual nerve fibers. Perimysium: dense CT surrounding fascicles of nerve fibres. Epimysium: Dense CT surrounding the whole muscle, continuous w/fascia and tendon. Limited potential for regeneration due to presence of satellite cells. Presence of triads. Types of skeletal muscle cells Slow oxidative (type I, red) Fast oxidative-glycolytic (type II a, red, intermediate) Fast glycolytic. (type II b, white) o Type 2A or white fibers contain small amount of myoglobin. o Type 1 or red fibers contain much more myoglobin. They’re slow. o There is an intermediary type of muscle fibers: 2B. Thin Filament Composed of F-actin, tropomyosin, troponin, and associated proteins. F-actin is a polymer of G-actin monomers arranged in a double helix. Each monomer possesses an active site that can interact with myosin head. F-actin is present as filaments that present polarity. Actin F-actin G-actin Tropomyosin In the absence of Ca+2, tropomyosin troponin complex blocks the binding of myosin to actin. Binding of Ca+2 to TnC shifts the complex, relieves the tropomyosin blockage of the interaction between actin and the myosin head. As a result Ca+2 binding allows contraction to proceed. Troponin Associated with each tropomyosin molecule and is composed of: o Troponin T: forms tail of molecule and functions in binding troponin complex to tropomyosin. o Troponin C: has 4 binding sites for Ca+2 ions. o Troponin I: binds to actin inhibiting interaction of myosin and actin. Myosin ATP hydrolysis enables its binding to actin. Myosin → 2 heavy chains + 2 pairs of light chains. Thick filaments have myomesin, titin and C protein Sarcomere Z discs – border sarcomeres o Composed of a-actinin. A band – beginning of myosin to end of adjacent myosin held together at M line. o Contains actin and myosin filaments. H zone/band – end of one actin filament to the beginning of the next actin filament in the same sarcomere. o Contains only myosin filaments. M line – bisects sarcomere, anchors two adjacent myosin myofilaments together (center of H zone), contains myomesin and creatine kinase. (this transfers a phosphate group of phosphocreatine to ADP and regenerates ATP molecule) I band – area in two adjacent sarcomeres that only contain actin myofilaments and is halved by Z disc. o Contains only thin ligaments. Proteins: *Nebulin is a long protein. Two nebulin molecules wrap around each thin filament and assist it in anchoring it to Z disc. *Titin is a large linear protein. It forms an elastic lattice that parallels thick and thin filaments. It binds in the M line to the protein Myomesin. Cap Z protein and tropomodulin inhibit dissociation of G-actin monomers from F- actin. Myomesin is a protein at the M line that crosslinks adjacent thick filaments to one another to maintain their spatial relations. Desmin (IF) encircles the Z disk and extends from one myofibril to the other binding their Z disks. Desmin inserts in costameres. o Plectin links desmin filaments to each other. o A,B-crystallin a heat shock protein, protects desmin from stress induced damage. A-actinin anchors ends of actin filaments to Z disk. Z disks contain a-actinin. Dystrophin-Glycoprotein complex: Dystroglycans are glycoproteins composed of transmembrane B-dystroglycan and extracellular a-dystroglycan. o A-dystroglycan binds to merosin, which makes a complex with the intracellular part of B-dystroglycan that binds to dystrophin. (actin-binding protein) o Dystrophin connects F-actin through the dystroglycan complex to endomysium. The sarcoglycan complex of 4 glycoproteins are associated with the dystroglycan complex. *Myasthenia gravis: antibodies are produced against acetylcholine receptors, leading to progressive muscle weakness. *Duchenne muscular dystrophy (DMD) → mutation of dystrophin gene at locus xp21. Absence of dystrophin permits excess calcium to penetrate the sarcolemma. Triad Two membrane systems that relay the signal to contract from muscle cell plasma to all myofibrils in the cell. o Composed of central T tubule with each side with a terminal cisternae of SER. ▪ T tubules are made by the invaginations of the myofiber’s plasma membrane. o Located at the A-I junction. o Help providing uniform contraction throughout the muscle fiber. Release and recovery of Ca+2 ions by the SER: 1. Deporalization of a muscle cell 2. Release of Ca+2 ions in SER via CA+2 channel proteins. 3. Ca2+ ATPases in SER membrane pump CA2+ ions from the cytosol back to the SER, restoring the concentration to its resting level. 4. Inside SER cisternae CA++ is bound to protein calsequestrin. Motor Unit Single motor neuron and all of the muscle fibers it innervates by branches of it’s axon. The larger motor unit, the lower precision of muscle movement. ACH is released from motor neuron ending at the motor plate = neuromuscular junction. Structure of the intercalated disks Intercalated disks have transverse portions, where fascia adherents and desmosomes abound, as well as lateral portions w/ gap junctions. On the cytoplasmic aspect of sarcolemma, thin (actin) myofilaments attach to fasciae adherents. Analogous to Z disks. Gap junctions form where cells are lying side by side. Differences between cardiac and striated muscle cells: 1. T tubules are larger. They invaginate at Z disks, and are accompanied by 1 Ser sacculae. Dyads are responsible for Ca+2 release from SER. 2. Mitochondria are more abundant than in skeletal muscle. 3. Intercalated disks are complex step like junctions between adjacent cardiac muscle cells. Smooth muscles: No T tubules. Presence of caveolae and dense bodies as well as gap junctions. Dense bodies correspond to Z disks. They form a homogenous bundle of myocytes. Smooth muscles cells are connected by gap junctions. Present in walls of blood vessels, digestive tract and conductive part of respiratory system and other organs. No striations, no sarcomeres. Dense bodies (focal densities) are made of a-actinin, serve as filament attachment site like Z line. When localized at the plasma membrane, they’re called attachment plaques. Intermediate Filaments (IF) (desmin and in vascular myocytes, vimentin) bind dense bodies to hold the filaments together.  Topic #6: Blood (Chapter 12 and 13) Functions of Blood Delivery of nutrients and oxygen to cells. Transport of wastes and CO2 away from cells. Delivery of hormones to and from cells and tissues. Maintenance of homeostasis by acting as a buffer and participating in coagulation and thermoregulation. Transport of humoral agents and cells of immune system that protects the body from pathogenic agents, foreign proteins and transformed cells. Composition of Blood Plasma: o Water 92% o Proteins 7%: ▪ Albumins ▪ Globulins ▪ Fibrinogen ▪ Regulatory proteins o Other 1% Buffy Coat: o Platelets o Leukocytes ▪ Neutrophils. ▪ Lymphocytes ▪ Monocytes ▪ Eosinophils ▪ Basophils Erythrocytes: Anucleated and practically contains any organelles Anemia Concentration of erythrocytes or Hb below normal range (unable to receive adequate O2) May result from iron deficiency or from blood loss. Sickle Cell Anemia → Substution of HbA by HbS, by point mutation. Erythrocytosis Increased concentration of erythrocytes in blood. Elevated haematocrit increased blood viscosity. Neutrophils Function: to destroy invading microorganisms by phagocytosis and by secreting proteases and mediators of inflammation. (cytokines) Cytoplasmatic granules. Nucleus: lobulated (2-6 lobes) Unspecific: Primary granules are modified lysosomes (azurophilic granules) o Contains: ▪ Myeloperoxidase (Neutrophil’s marker enzyme) ▪ Defensins (function similar to antibodies) ▪ Cathelicidin Specific: Secondary granules Contains: o Proteases (collagenase Type IV, gelatinase, phospholipase A) o Lactoferrin: (A protein which competes with bacteria for iron ions) o Lysozyme (small protein that destroys any wall of bacteria) o Vitamin B12 (binding protein) Tertiary granules: o Two types: ▪ Containing phosphatases ▪ Containing metalloproteinases. Compartments of neutrophils in the body: o Granulopoietic compartment → Bone marrow o Storage (reserve) compartment → red marrow o Circulating compartment → blood o Marginating Compartment → surface of endothelium in venules and small veins. Phagocytosis of bacteria by neutrophils 1. Neutrophils engulf bacteria by pseudopodia and internalize them in phagosomes. 2. Specific granules fuse with and discharge their content into phagosomes. 3. Phagosomes are acidified by proton pumps. 4. Azurophilic granules discharge their enzymes into this acidified vesicle killing and digesting the engulfed microorganisms. Eosinophils Associated with allergic reactions, parasitic infections and chronic inflammation. They can phagocytose antigen-antibody complexes. Eosinophilia: increased number of eosinophils in blood. Contents: o Eosinophil peroxidase: it binds to microorganisms and facilitates their killing by macrophages. o Major Basic Protein (MBP): ▪ Predominant component of eosinophil granules. ▪ Binds to and disrupts the membrane of parasites (Fc receptor) ▪ Causes basophils to release histamine by a Ca2+ dependent mechanism. o Eosinophilic cationic protein: ▪ it neutralizes heparin. ▪ With MBP, causes the fragmentation of parasites. Basophils Involved in allergic reactions. They do not phagocytose. They mediate hypersensitivity and anaphylactic reaction. Bind IgE via high affinity FCER1 receptors. Function: o Unspecific granules: azurophilic granules ▪ Hydrolytic enzymes or lysosomes. o Specific granules: secondary granules ▪ Like mast cells, they do not contain tryptase or chymase. ▪ GAGs: heparin, heparan sulfate, chondroitin sulfate. ▪ Histamine, leukotrienes, ▪ IL-4 and IL-13 (promotes synthesis of IgE by B lymphocytes) ▪ ECF-A, NCF (eosinophil and neutrophil chemotactic factor) ▪ Peroxidase Lymphocytes Agranulocytes Some large lymphocytes which have granules → NK cells 2 categories: o B lymphocytes (Bone marrow) CD4, helper o T lymphocytes (bone marrow → thymus) CD8, cytotoxic Primary lymphoid organs: bone marrow and thymus Secondary lymphoid organs: lymph nodes, spleen, and lymphoid aggregates of Gi and RT. Monocytes (Macrophages) Contain azurophilic granules. Very high capacity to phagocytosis. Belong to APCs (Antigen Presenting Cells) After 1-3 days leave blood and become tissue macrophages After activation secretes tens of cytokines and biologically active compounds involved in the inflammatory reaction. Largest Leukocytes Platelets (Thrombocytes) Fragments of megakaryocytes cytoplasm. Important role in stopping leaks in vessels (haemostasis) Alpha granules contain: o PDGF, PF4, Fibrinogen, Plasminogen Delta granules contain: o ADP, ATP, Serotonin, Histamine. Lambda granules contain: o Lysosomes. Structure: o 2 regions: ▪ Hyalomere (clear, peripheral) ▪ Granulomere (central, with purple granules) o Plasma membrane: rich in glycocalyx and many adhesion molecules. o Calcium ions and ADP increase the stickiness of glycocalyx and enhance platelet adherence. Function: o Blood coagulation, they aggregate at lesions in vessel walls, and produce factors that aid in clot formation. o Clot retraction and clot removal. Fibrin Clot Formation 1. Platelets make contact with collagen, and they aggregate, swell and release factors that trigger formation of fibrin meshwork that traps erythrocytes. 2. A clot grows with blood loss from the vasculature stops. 3. After repair of vessel wall, fibrin clots are removed by proteolysis (plasmin) Haematopoiesis Aka “Hemopoiesis” Formation of new blood cells in red bone marrow. Location during development: o Prenatal Hemopoiesis: ▪ Yolk sac ▪ Liver ▪ Spleen ▪ Bone Marrow (Starts at 6 month of gestation) o Postnatal Hemopoiesis: ▪ Stem: Capable of self-renewal. Differentiate into multiple cell lineages. Present in bone marrow and small numbers in circulation. Multipotent progenitors: o Lymphoid or myeloid cell lineage. o Give rise to multipotential hematopoietic progenitors. ▪ CFU-S (Myeloid) gives rise to: Erythrocytes Granulocytes Myeloid dendritic cells Platelets Basophils Mast cells ▪ CFU-Ly (Lymphoid) gives rise to: T, B, and NK cells. Lymphoid dendritic cells. Unipotential progenitors: reduced self-renewal capacity. o Precursor cells: All cells in each lineage that show specific morphologic characteristics. ▪ First cell of particular cell line. Not Self-renewal capacity Hematopoietic cytokines (CSF, Interleukins, Inhibitory factors) Nearly all of them act on: o Progenitor stem cells o Lineage-restricted progenitor cells o Committed cells, maturing and mature cells. Erythropoiesis Begins with 2 types of progenitor’s cells. o BFU-E (Derived from CFU-S) o CFU-E (Derived from BFU-E) Forms about 1 million RBCs daily in adults. EPO (erythropoietin) induces common myeloid progenitor (CFU-GEMM/CFU-S) in presence of IL-3,4 and SCF to differentiate into BFU-E which divides to form CFU-E. BFU-E: increased rate of mitotic activity o Responds to high levels of EPO. CFU-E: responds to low concentrations of EPO and gives rise to proerythroblast. Erythrocyte precursor cells include the erythroid series that differentiates sequentially to form mature erythrocytes. o Proerythroblast: basophilic cytoplasm. o Basophilic erythroblast: basophilic cytoplasm, chromatin more condensed than before. o Polychromatophilic erythroblast: both basophilic and acidophilic (Hb), more condensed chromatin. o Ortho chromatophilic erythroblast (normoblast): condensed heterochromatin, acidophilic. o Reticulocyte: more acidophilic than basophilic, anucleated. o Mature Erythrocyte: acidophilic. Granulopoiesis Sequence of cytoplasmatic events in maturation of granulocytes from myeloblasts. Begins with production of 3 Unipotential or bipotential cells (descendants of CFU- S/CFU-GMM) Granulocyte progenitor gives rise to: o CFU-Eo: Eosinophil Lineage o CFU-Ba: Basophil Lineage o CFU-NM or CFU-GM: Common progenitor of neutrophils and monocytes, which gives rise to: ▪ CFU-N (G): Neutrophil ▪ CFU-M (Monocyte) They developed characteristic granules unique to each type during myelocyte stage and a distinctive nuclear shape during band stage. 1) Myeloblast: No cytoplasmatic granules 2) Promyelocyte: Chromatin condensed, some azurophilic granules (primary granules) 3) Myelocyte: moderate number of azurophilic granules and initial production of specific granules. 4) Metamyelocyte: Specific granules fill cytoplasm, dispersed azurophilic granules. 5) Band stage: specific granules fill cytoplasm. Megakaryocytopoiesis Megakaryoblasts: Large cells with fine chromatin o Basophilic, non-granular cytoplasm. o Large mitochondria, many polysomes, some RER and large Golgi complex. Transition to Megakaryocyte: Biggest cell in bone marrow. o Cytoplasm with patchy basophilia and numerous azurophilic granules.  Topic #7: Cardiovascular and Respiratory (Chapter 11 and 17) Cardiovascular General Structure of Vessel’s wall o Tunica intima: Has Endothelium – Connective Tissue – Internal Elastic Lamina. o Tunica media: Alternating layers of smooth muscle and collagen or elastic lamellae. o Tunica adventitia (externa): Connective tissue, small vessels, and nerves. Blood Vessel Formation 1) Vasculogenesis: Process initiated by coalescence of free and migratory endothelial progenitors, or angioblasts during embryogenesis. a. Angioblasts proliferate and form endothelial capillary tubes. b. Proliferation is regulated by interaction of vascular endothelia growth factor. (VEGF) secreted by mesenchymal cells with vascular endothelial growth factor receptor (VEGF-R2) c. Formation of primitive vascular network in yolk sac and trunk axial vessels. Dependent on interaction of VEGF with VEGF-R2 d. Essential for embryonic survival. 2) Maturation: a. Angiopoietin (Ang1) interacts with endothelial receptor Tie2 to recruit perioendothelial myocytes to organize mature blood vessels. b. Ang2 interacts with Tie2 to induce loss of contact of endothelial cells with ECM. c. This results in absence of growth or death of EC. The role of ANG2 in tumor angiogenesis is emerging as a target for cancer treatment.  3) Angiogenesis a. A new blood capillary forms by the spouting of an endothelial cell from the wall of an existing small vessel. b. This process is strongly dependent on nature of ECM in environment of cells. The formation is promoted by basal lamina components (laminin) c. In the adult occurs during: i. Uterine menstrual cycle ii. Placental growth. iii. Wound healing iv. Inflammatory responses. 1) Degradation of basal lamina by lateral podosomes of parental endothelial cell in presence of integrin a6b1, induced by VEGF (enables formation lateral sprouts) 2) Migration and proliferation of endothelial cells, guided by a gradient of angiogenic factors (VEGF, Ang1) 3) Maturation of endothelia cells into endothelial capillary tube 4) Assembly of basal lamina and recruitment of perioendothelial cells (smooth muscle cells) Control of blood vessel growth Depends on a tissue’s requirements for O2. Lack of O2 → Secretion of VEGF (stimulates angiogenesis) 1) Cells produce proteases to digest their way through the basal lamina of the parent capillary of venule. 2) Endothelial cells migrate towards the source of the signal. 3) Cells proliferate. 4) Cells form tubes and differentiate. VEGF acts on endothelial cells selectively to stimulate this entire set of effects. Endothelium Specialized endothelium (simple squamous) that acts as a semipermeable barrier between 2 major internal compartments: o Blood and its components o Interstitial tissue fluid With its basal lamina is highly differentiated to mediate and actively monitor the bidirectional exchange of molecules by: o Simple and active diffusion o Receptor mediated endocytosis o Transcytosis o These are all trans endothelial transport function. Endotheliocytes (ECs) regulate ECM degradation and remodelling. ECs actively produce numerous factors that: o Prevent blood clotting. o Cause adjacent smooth muscle cells to contract or relax. o Secrete components of underlying basal lamina o Actors that initiate inflammation at sites of damage or infection by: ▪ Diapedesis of leukocytes ▪ Secreting proinflammatory cytokines Endothelial Cells (ECs) Flat, polygonal cells with small amount of cytoplasm. Plasma membrane often forms caveolae. Cytoplasm contains abundant pinocytotic vesicles. Major role: transcytosis: transport of substances from apical to basal cell membrane where they, unchanged, are released to ECM. ECs contain IF of either desmin, vimentin or both in perinuclear zone Joined by tight junctions, desmosomes, and gap junctions. They contain Weibel-Palade bodies: o Membrane bound granules that in EM present a dense matrix with tubular elements containing vWF, tissue factor and P-selectin. o vWF synthetized by all ECs but stored only in ECs of arteries. ECs modulate smooth muscle activity in various ways: 1. Release prostacyclin and nitric oxide (NO), potent vasodilators. 2. Secrete angiotensin converting enzyme (ACE) which hydrolyses inactive ang I to active angiotensin II (specially in lung) a. Ang II: powerful vasoconstrictor i. Stimulates secretion of aldosterone (hormone that promotes water retention by its reabsorption in kidney collecting tubules) 3. Synthetize and release endothelin 1 (constricts smooth muscles in wall of arteries and arterioles increasing blood pressure) a. Under pathological conditions, ECs secrete other vasoconstricting factors such as: i. Prostaglandin H2 (PGH2) ii. Thromboxane A2 iii. Prostaglandin F2A iv. Prostaglandin E2 Control blood coagulation by synthesis and release of: o Antithrombotic (anti-coagulation) molecules: ▪ Prostacyclin. ▪ Thrombomodulin and antithrombin 3 ▪ Tissue plasminogen activator (tPA) o Prothrombotic molecules: Von Willebrand factor (vWF) makes a complex with inactive factor VIII. ▪ Factor VIII ▪ Synthesis of tissue factor ▪ Synthesis of plasminogen-activator inhibitor (PAI) Other functions: o Synthesis of basal lamina components (Collagen IV, laminin) o Synthesis of ECM components (collagen, elastin, GAGs, fibronectin) o Synthesis of growth factors (PDGF, GM-CSF, TGF-B, heparans) o Regulation of the traffic of inflammatory cells (Selectin, ICAM-1 in diapedesis) o Deactivation of active substances (serotonin, thrombin, bradykinin, norepinephrine, prostaglandins) o Involvement in lipoprotein and cholesterol metabolism: ▪ Bind lipoprotein lipase. ▪ Oxidize lipoproteins that are endocytosed by macrophages. Transcytosis Main pathway of molecule’s transport through endothelial barrier. Fast, selective, regulated process. Important compounds which undergo endocytosis and transcytosis in ECs: o Albumin o LDL o Transferin and ceruloplasmin o Insulin, growth factors and other hormones o Non-enzymatically glycosylated proteins (glycosylated Hb in diabetics) Elastic Artery (Aorta) Helps to reduce changes in blood pressure. They have small vessels (vasa vasorum) and nerves in tunica adventitia and media. Elastic membranes/Fenestrated membranes are in tunica media. Tunica intima: o Endothelium with basal lamina o Subendothelial connective tissues + smooth muscle o Internal elastic membrane (collagen + elastic fibers) Tunica media (thickest layer): o Multiple layers of fenestrated elastic lamellae. o Fenestrations in lamellae facilitate diffusion of substance within arterial wall. o Elastic lamellae alternate with layers of smooth muscles fibers. Tunica adventitia: o Connective Tissue o Vasa vasorum + nerves Muscular Artery Tunica intima: o Endothelium + basal lamina o Thin layer of subendothelial connective tissue. o Internal elastic membrane. Tunica media (thickest layer): o Many smooth muscle layers, much less elastic material. o External elastic lamina is present only in larger muscular arteries. Tunica adventitia: o Connective tissue, thinner than media o Vasa vasorum, maybe present. Arterioles Subendothelial layer is very thin. Elastic laminae are absent. Tunica media: circularly arranged in 1-3 layers of smooth muscle cells. Thickest layer. Tunica adventitia: very thin. Almost always branches to form networks of capillaries. Typically forms metarterioles. Venules Have pericytes. Primary site at which diapedesis (leukocyte extravasation) occurs. Muscular venules: Increased size venules with surrounding tunica media with two or three smooth muscle layers. Large diameter of venule compared to overall thinness of the wall. Involved in exchange of metabolites. Capillaries Metarterioles (Precapillaries): gives rise to capillaries. o Surrounded by incomplete rings of smooth muscle cells that surrounds capillaries at their origin. ▪ Precapillary sphincter: individual smooth muscle cells. Control the entry of blood into the capillaries. Constriction prevents blood from entering the capillary bed ▪ Arterioles supplying → capillary bed → form branches → metarterioles. ▪ Distal portion lacks smooth muscle cells and merges with postcapillary venule. ▪ Branching from the metarteriole and distal portion are the true capillaries. True capillaries: o Smallest vessels o Lack of smooth muscle cells o Pericytes may be present. o Types: ▪ Continuous capillaries: Prevents the passage of many molecules. Found in muscle, nervous and connective tissues, lungs and exocrine glands. ▪ Fenestrated capillaries: found in organs where molecular exchange with blood is important. Such as endocrine organs, intestinal walls, kidney glomeruli, pancreas, and choroid plexus. ▪ Sinusoids: found in organs where the exchange of macromolecules and cells occur readily between tissue and blood. Bone marrow, liver, lymphoid organs, and spleen. Veins Venules (exchange of metabolites) Postcapillary venules. (Leukocytes migrate here by diapedesis) o They form muscular venules → that form into collecting venules. Small and medium sized veins (external jugular vein) Large veins: o Includes vena cava and pulmonary veins. o Tunica media: thin layer of circumferentially arranged smooth muscles. ▪ Has collagen and elastic fibers. o Tunica adventitia: has cardiac muscle cells for a short distance as they enter the heart. ▪ Has vasa vasorum + nerves. ▪ Thickest layer ▪ Collagen and elastic fibers network ▪ Contains smooth muscle cells separated from each other by connective tissues. Has valves Arteriovenous shunt: wide direct communication between artery and vein. Portal system: 2 capillary beds are connected by a vein. Lymphatic Vessels Functions: Conduct immune cells and lymph to lymph nodes. o Remove excess fluid accumulated in interstitial spaces. o Transport chylomicrons, lipid-containing particles, through lateral lymphatic vessels inside intestinal villi. Flow of lymph is under low pressure and unidirectional. Not found in CNS, cartilage nor bone. Heart Valves: flaps of connective tissue anchored in heart’s dense fibrous skeleton (chorda tendineae) Layers of heart’s wall: o Endocardium: ▪ Endothelium + areolar tissue. ▪ Fibroelastic connective tissue + fibers of smooth muscle. ▪ Purkinje fibers (comprises heart’s impulse conducting system) o Myocardium: muscular wall consisting of cardiac muscle cells. o Pericardium: ▪ visceral layer (epicardium): areolar tissue + mesothelium ▪ Parietal layer: dense fibrous tissue Mesothelium + areolar tissue. Mesothelium is simple squamous. Fibrous network: serves for attachment of cardiac muscle and cuspid and semilunar valves. Impulse-conducting system: o generated in sinoatrial node → atrioventricular node → AV bundle to Purkinje fibers. Endocardiomyocytes: They produce: o Atrial natriuretic factor (ANF) – Atrial o Brain natriuretic peptide (BNF) – Ventricular  Topic #7: Respiratory Function of Respiratory System Provides oxygen to the blood. Secondary function of sound production in the larynx. Respiratory system consists of: Air conducting region (Nasal cavity, Pharynx, Larynx, Trachea, Bronchi & Bronchioles) Respiratory region (Respiratory bronchioles, alveolar ducts and alveoli) Nasal Cavities Nasal cavities have: o Vestibules where air enters. o Three projections called conchae from medial walls which create turbulence in inspired air. Moist vibrissae (hairs) in the vestibular openings, the nares (nostrils) filter some material from air. Deeper areas of the vestibules and the floor, lateral walls and most of the conchae of the nasal cavities themselves are lined by a respiratory epithelium (pseudostratified ciliated columnar) Respiratory epithelium includes: o Goblet cells: ▪ numerous, basal nuclei and apical domains filled with granules of mucin glycoproteins, secretes mucin. o Brush cells: ▪ Much less numerous, columnar cell type, blunt microvilli are chemosensory receptors with signal transduction components and synaptic contact with afferent nerve endings on their basal surfaces. o Small granule cells: ▪ They are part of the diffuse enteroendocrine system (DNES) o Basal cells: ▪ Mitotically active stem and progenitor cells that give rise to the other epithelial cell types. o Ciliated columnar cells ▪ Sweeping the mucus along the surface. The mucosa of the nasal cavities and nasopharynx also contains a rich vasculature and many seromucous glands, which help warm, humidify and clean inspired air. Larynx, trachea, and bronchial tree: Larynx: Rigid wall (thyroid, cricoid, arytenoid cartilages): hyaline cartilage Epiglottis: Prevent swallowed food or fluid from entering into the respiratory canal. o Vestibular folds: ▪ respiratory epithelium, seromucous glands, lymphoid nodules. o Vocal folds: ▪ nonkeratinized stratified squamous → protects from abrasion and desiccation. ▪ Vocalis muscles. Trachea: Respiratory epithelium. Supported by C-shaped rings of hyaline cartilage with smooth trachealis muscles. Submucosa of trachea: mast cell Bronchial tree: Left and right primary bronchi enter the two lungs and bifurcate into secondary, tertiary, and smaller segmental bronchi. Bronchi and their branches are lined by respiratory mucosa with spiralling bands of smooth muscle and smaller pieces of hyaline cartilage. Bronchioles: branch with diameter