Connective+Tissue+Part+1


 * 28 August 2006**
 * Connective Tissues Part 1**
 * Dr. Robert Crissman, Ph.D.**

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=**Definition**=


 * All connective tissue is composed of cells, extracellular fibers and ground substances
 * Group of interrelated tissues generally classified as “connective tissue”
 * Connects all the other cells of different tissues types both structurally and metabolically
 * Provides and maintains the form of body
 * Matrix that connects and binds cells tissues, and organs together
 * All connective tissues are derived from a common origin of **embryonic mesenchyme**

**Classification of Connective Tissues**

 * Embryonic
 * Mesenchyme – Embryo and Fetus
 * Mucoid Connective Tissue – Umbilical Cord
 * Connective Tissue “Proper”
 * Areolar Connective Tissue – Loose packing (few extracellular fibers) and surrounds blood vessels (BV)
 * **All blood vessels are surrounded by connective tissues**
 * Dense Connective Tissues – lots of extracellular fibers
 * Dense irregular connective tissue – Dermis, organ capsules, and periosteum
 * Fibers in all sorts of directs
 * Dense regular connective tissue – tendons, ligaments
 * Fibers all run parallel in sheets
 * Elastic connective tissue – ligamentum nuchae and fava
 * Instead of lots of collagen fibers, you have lots of elastin fibers
 * A type of regular connective tissue
 * Reticular tissue – lymphatic tissue and bone marrow
 * Can be classified as loose connective tissue
 * Adipose tissue – subcutaneous and omentum
 * Special Connective Tissue
 * Cartilage – trachea, pina, nose, joint cartilage
 * Bone -- skeleton
 * Blood – cardiovascular and hemopoietic tissue

=**Functions of Connective Tissue**=


 * Mechanical support
 * Structural support of organs
 * e.g. connective tissue surrounding gland to support gland
 * Connective tissue of any organ is called **stroma** and supports the parenchyma
 * **Parenchyma** is the functional part of an organ supported by the stroma
 * Packing material
 * “Mother nature’s mortar”
 * Fills in all that’s between
 * Rigid structural support
 * Mechanical Protection
 * Bony and cushioning
 * e.g. thoracic cage, skull, heel of foot
 * Energy storage and temperature regulation
 * Fat – stored energy and insulator
 * Metabolic support
 * e.g. blood vessel must go through stroma to get to parenchyma
 * stroma determine transportability of molecules and waste to parenchyma
 * Transportation of material
 * Protection against infection
 * e.g. immune system does most of its work in connective tissue
 * Inflammation is in connective tissue
 * Repair after injury

=**Composition of All Connective Tissues**=


 * **Cells**
 * Fixed
 * Responsible for synthesis and maintenance of extracellular matrix and particular connective tissue
 * Secretory cells secreting extracellular matrix and ground substances
 * e.g. fibrocytes, mesenchymal cells, reticular cells, adipocytes, osteocytes, and chondrocytes
 * Wandering
 * Transient cells that migrate in and out of extracellular matrix of connective tissue
 * e.g. macrophages, mast cells, plasma cells, leukocytes
 * Associated
 * Cells associated with blood vessels that are always within connective tissue
 * e.g. endothelial cells, smooth muscle cells, and pericytes
 * Relatively acellular with lots of extracellular space between cells filled by extracellular matrix
 * Extracellular matrix includes extracellular fibers and amorphous ground substances
 * **Extracellular Fibers**
 * Collagen fibers for strength
 * Reticular fibers for delicate support
 * Elastic fibers for stretch and flexibility
 * **Amorphous Ground Substances**
 * Interstitial fluid (water)
 * Proteoglycans
 * Complex macromolecules consisting of core protein with glycoaminoglycans (GAG) attached to it
 * Glycoproteins

=**Fixed Cells**=

**Fibrocytes**

 * Most common connective tissue proper
 * Vesicular nucleus with nucleolus – hard to identify cytoplasm
 * Probably mostly euchromatin visible on nucleus
 * Secretory cell
 * Fibroblast – “-blast” is still capable of division and capable of adding new matrix around it
 * Fibrocyte – “-cyte” terminally differentiated, incapable of dividing, and maintain existing matrix but can’t add new matrix
 * Can’t tell fibroblast from fibrocyte unless the fibroblast is dividing

**Mesenchymal Cell**

 * Looks and does the same thing as a fibroblast
 * Identify mesenchymal or fibrocyte by location
 * Only difference is that its location is pluripotential
 * Can differentiate to muscle, bone, cartilage, etc.

**Reticular cells**

 * Similar morphology to fibrocyte
 * Can identify reticular fibers around them
 * Secretory
 * Glycoproteins
 * Forms cell-covered fiber framework

**White adipocytes**

 * Diagnostic characteristic – lipid droplet is all one lipid droplet (unilocular)
 * Large cells with signet ring appearance with nucleus pushed to one side
 * Adipose tissue is called **subcutaneous fascia**
 * Function – lipid storage
 * Hypercellular obesity – increased number of fat cells
 * Worse type to have and thought to be caused by overfeeding during the first year of life
 * Hardest one to treat
 * Hypertrophic obesity – increased size of fat cells
 * Most common condition

**Lipid Storage**

 * **Lipoprotein Lipase**
 * Put fatty acids into adipose cell
 * **Hormone Sensitive Lipase**
 * Breakdown triglycerides to glycerol and fatty acids
 * Takes fatty acids out of adipose cell
 * Leptin
 * Protein produced by adipocyte
 * Targets hypothalamus to decrease food intake and increase energy consumption
 * Insulin
 * Stimulates insulin receptors on fat cells to synthesize and store lipids
 * Epinepherine and norepinepherine
 * Stimulate fat cells to break down lipids and release glycerol and free fatty acids

**Brown fat cells**

 * Smaller than white fat cell
 * Multilocular – several small lipid lakes in cytoplasm
 * Numerous mitochondria on EM level
 * Function is to produce heat
 * Free fatty acid uncouples oxidation process from ATP production
 * Thermogenin on mitochondrial membrane protein that permits back flow of H+ protons instead of using for ATP formation
 * “Parasite Eve”
 * Found in newborns that is thought to gradually be converted to white fat in the first year
 * Newborn mediastinum, aorta, axilla between scapula
 * Also found in hibernating animals

=**Wandering cells**=

**Marcophage**

 * “Big Eater”
 * Antigen presenting cell
 * Have lots of phagosomes, lysosomes, and phagolysosomes
 * Mono-nuclear phagocyte system
 * Derived from granulocytic-monocyte stem cell
 * Transported as monocytes in blood stream
 * When a monocyte leaves the blood and enters connective cell, it becomes a macrophages
 * Name dependent on location where monocyte leaves blood stream
 * Identify with vital dye ingestion such as Indian ink, trypan blue, carbon black
 * Can’t see cytoplasm
 * Foreign-body giant cell – in an inflammation situation, several macrophages fuse to surround and encapsulate foreign-body

**Mast Cell**

 * Full of granules
 * contain mediators of inflammatory response such as histamine, heparin, neutral protease, leukotrienes (C4 and D4), Eosinophilic chemotaxtic factor, neutrophilic chemotaxtic factor
 * Associated with small blood vessels
 * Antibody attaches to IgE receptor which interacts with antigen
 * Secondary signal via cAMP and phosophylation is activated that leads to activation of phospholipases and Ca2+ release which triggers release of granules
 * Important because of anaphylactic shock
 * Fluid leaking out of blood and entering connective tissue
 * Resulting swelling and dilation of blood vessels on a large scale
 * Blood pressure drops and patient goes into anaphylactic shock
 * Histamine also constricts smooth muscle in bronchia
 * Also releases cytokines such as TNFγ
 * Paracrine secretion – localized secretion that isn’t distributed throughout the body

**Plasma cells**

 * Morphologically eccentrically located nucleus (nucleus not in center)
 * Has cart wheel appearance
 * Packed with rough ER (visible on EM level)
 * Produces immunoglobulins (antibodies) and needs lots of rough ER
 * Terminally differentiated from B-lymphocytes
 * If shows up on a blood smear, patient has a massive infection somewhere

=**Extracellular Fibers**=

**Collagen Fibers**

 * Strength
 * Most common protein of the body
 * Lots of collagen fiber diseases
 * 20% of all proteins
 * 30% of dry weight of body
 * High tensile strength, inelastic yet flexible
 * Use as model of fiber organization and formation
 * Collagen can be organized into fibrils which are organized into fibers
 * Fibers are organized into bundles or fascicle
 * Fibers are barely visible on light microscope
 * Fibrils are made of trophocollagen molecules which are made of alpha chains
 * Each alpha chain is 1,000 amino acids containing lots of glycine, hydroxyproline, and hydroxylysine
 * Glycine is used as a diagnostic test for collagen wasting diseases
 * H+ bonding between hydroxyproline holds alpha chains together
 * Covalent bonds between lydroxylysine of adjacent tropocollagen molecules hold fibrils together
 * Gap is offset by a quarter of their length, hence “quarter stagger theory”

**Types of Collagen**

 * Type I
 * Strength
 * Most common type
 * Dermis, tendon, organ capsules, bone, dentin
 * Type II
 * Resists pressure
 * Hyaline and elastic cartilage
 * Type III
 * Delicate support meshwork
 * Lymphatic system, spleen, liver, lung, cardiovascular system
 * Make reticular fibers
 * Type IV
 * Attachment, filtration
 * Basal lamina

**Collagen Formation**

 * Transcription in nucleus
 * Translation to form alpha chains in Rough ER
 * Hydroxylate and glycosylated in Rough ER
 * Formation of procollagen in Rough ER
 * Has a tag at the end of them to prevent procollagen from self-aggregating inside the cell
 * Packaged and secreted via golgi through merocrine secretion
 * Cleavage to form tropocollagen by procollagen peptidase
 * Tropocollagen self-aggregates and lines up quarter-staggared to form fibrils
 * Self-assembly to form collagen fiber via lysyl oxidase

**Defects in Collagen Formation**

 * Scurvy
 * Vitamin C needed to hydroxylate proline
 * No hydroxylation means no hydrogen bonds and instabilitly
 * Collagen literally melts in body temperature
 * Capillary collagen collapse and cause little bleeds
 * Teeth held in sockets by ligaments; collapse of collagen and teeth falls out
 * Bruise very easily
 * Ehler-Danlos VII
 * Mutation in procollagen peptidase
 * No cleavage to form tropocollagen
 * Weaken stability
 * Tend to dislocate very easily and be super-flexible
 * Collagen wasting disease
 * Mutations in collagenase increase collagen turn over rate
 * High amounts of glycine in urine
 * Normally, collagen is turned over at a certain rate and needs to be replaced

**Reticular Fibers**

 * Branched network
 * Diagnostic: intersect at right angles
 * Argyophilic – silver loving
 * Taken up by polysaccharides
 * For delicate support
 * Contains lots of wandering cells
 * Needs space for wandering cell but support to keep spaces open
 * EM level shows that each fiber contains bundles of **type III collagen fibrils** surrounded by a sugar coat
 * Cross striations visible from **type III collagen fibrils**
 * Located in areolar connective tissue, liver, reticular, lymphatic and hemopoietic tissue
 * Ehlers-Danlos Type IV
 * Deficiency in Type III Collagen
 * Apparent in aorta which form aneurisms with form easily

**Elastic fibers**

 * Continuous network of “Y” branching fibers
 * Intersect at acute angles
 * “Chicken-wire” networks
 * Function is to stretch, up to 150x its original shape, reversibly
 * Location: blood vessels, lungs (forcing air back out of alveoli)
 * Secreted like collagen – have trophoelastin and proelastin precursors, etc.
 * EM morphology:
 * Amorphous elastin
 * Desmosine
 * Isodesmosine
 * Microfibrils

**Disease of Elastin fibers**

 * Marfan’s Syndome
 * Microfibrils not produced
 * G.I. problems
 * Tendency to rupture aorta and other blood vessels
 * Emphysema
 * Elastin fibers are damaged and regrow incorrectly
 * No longer able to force air out of alveoli
 * Become barrel cavity

=**Amorphous Ground Substances**=


 * Whats left after you remove all cells and fibers
 * No visible structure

**Proteoglycans**

 * Slippery and viscous
 * Protein core with sulfated glycoaminocylcans (GAGs) attached
 * In 3-D, they look like a bottle brush
 * 6 types of GAG’s with different GAG’s or protein core to get a different proteoglycan
 * Common Proteoglycans:
 * Free
 * Aggrecan – most common
 * In collagen, Aggrecan links to chondroitin sulfate to form aggregates
 * Perlecan – has heprin sulfate
 * Transmembrane
 * Syndecan – has heparin sulfate and chondroitin sulfate
 * Fibroglycan

**GAGs**

 * Hyaluronic Acid
 * Non-sulfated
 * Long Chain of repeated disaccharides
 * Will swell up and takes up all the space it can
 * Negatively charged and attracts cations like Ca2+ and Na+ which in turn **pulls in water**
 * Slippery and resilient gel-like consistency that can resists compression
 * Forms physical barrier – bacteria produce hyaluronidases to break down barriers
 * Inhibits cell adhesion and facilitate cell migration
 * Sulfated GAGs
 * Keratin Sulfate in cartilage
 * Heparan Sulfate in basement membranes
 * Condroitin-6-Sulfate in cartilage, skin and bone
 * Condroitin-4-Sulfate in cartilage, skin and bone
 * Dermatan sulfate in dermis

**Interstitial Fluid**

 * Diffusion of nutrients and waste

**Glycoproteins**

 * Adhesion molecules