3 tejido conectivo

Tejido conectivo

Tejidos del cuerpo

Epitelial

Conectivo

Muscular

Nervioso

74 CHAPTER 4 ■ Epithelial Tissue

Epithelial cells generally show polarity, with organelles and membrane proteins distributed unevenly within the cell. The region of the cell contacting the connective tissue is called the basal pole and the opposite end, usually facing a space, is the apical pole. The two poles of epithelial cells differ in both structure and function. Regions of cuboidal or columnar cells that adjoin the neighboring cells are the lateral surfaces; cell membranes here often have numerous infoldings to increase the area of that surface, increasing its functional capacity.

Basement MembranesAll epithelial cells in contact with subjacent connective tissue have at their basal surfaces a specialized, feltlike sheet of extra-cellular material referred to as the basement membrane (Figure 4–1). Glycoproteins and other components in this structure can be stained and make it visible beneath epithelia with the light microscope (Figure 4–2).

Cuboidal or pyramidal cells of epithelia generally have spheri-cal nuclei, while nuclei of squamous epithelial cells are flattened. An extracellular basement membrane (red) always lies at the interface of epithelial cells and connective tissue. Nutrients for epithelial cells must diffuse across the base-ment membrane. Nerve fibers normally penetrate this struc-ture, but small blood capillaries (being epithelial themselves) normally never enter epithelia.

With the transmission electron microscope (TEM) the basement membrane may be resolved into two structures. Nearest the epithelial basal poles is an electron-dense layer, 20-100 nm thick, consisting of a network of fine fibrils that comprise the basal lamina (Figure 4–3). Beneath this layer is often a more diffuse and fibrous reticular lamina.

FIGURE 4–2 Basement membranes.

This section of kidney shows the well-stained basement membranes (arrows) of epithelia forming structures within the large, round renal glomerulus and its surrounding tubules. In kidney glomeruli the basement membrane, besides having a supporting function, has a highly developed role as a filter that is key to renal function. X100. Picrosirius-hematoxylin (PSH).

FIGURE 4–1 Epithelia and adjacent connective tissue.

TABLE 4–1 Main characteristics of the four basic types of tissues.

Tissue Cells Extracellular Matrix Main Functions

Nervous Elongated cells with extremely fine processes Very small amount Transmission of nerve impulses

Epithelial Aggregated polyhedral cells Small amount Lining of surface or body cavities; glandular secretion

Muscle Elongated contractile cells Moderate amount Strong contraction; body movements

Connective Several types of fixed and wandering cells Abundant amount Support and protection of tissues/organs

100 CHAPTER 5 ■ Connective Tissue

FIGURE 5–2 Cellular and extracellular components of connective tissue.

Mesenchymal cell

Elastic fiber

Fibroblast

Collagen fiber

Reticular fiber

Macrophage

Extracellularmatrix

Blood vessel

Ground substance

Adipocyte

Protein fibers

Resident cells

Connective tissue is composed of fibroblasts and other cells and an extracellular matrix (ECM) of various protein fibers, all of which are surrounded by watery ground substance. In all

types of connective tissue the extracellular volume exceeds that of the cells.

Functions of cells in connective tissue proper.TABLE 5–1

Cell Type Major Product or Activity

Fibroblasts (fibrocytes) Extracellular fibers and ground substance

Plasma cells Antibodies

Lymphocytes (several types) Various immune/defense functions

Eosinophilic leukocytes Modulate allergic/vasoactive reactions and defense against parasites

Neutrophilic leukocytes Phagocytosis of bacteria

Macrophages Phagocytosis of ECM components and debris; antigen processing and presentation to immune cells; secretion of growth factors, cytokines, and other agents

Mast cells and basophilic leukocytes

Pharmacologically active molecules (eg, histamine)

Adipocytes Storage of neutral fats

❯❯ MEDICAL APPLICATION

Besides their function in turnover of ECM fibers, macrophages are key components of an organism’s innate immune defense system, removing cell debris, neoplastic cells, bacteria, and other invaders. Macrophages are also important antigen-presenting cells required for the activa-tion and specification of lymphocytes.

When macrophages are stimulated (by injection of foreign substances or by infection), they change their morphologic characteristics and properties, becoming activated macrophages. In addition to showing an increase in their capacity for phagocytosis and intracellular digestion, activated macrophages exhibit enhanced metabolic and lysosomal enzyme activity. Macrophages are also secretory cells producing an array of substances, including various enzymes for ECM breakdown and various growth factors or cytokines that help regulate immune cells and reparative functions.

When adequately stimulated, macrophages may increase in size and fuse to form multinuclear giant cells, usually found only in pathologic conditions.

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Nerve Tissue &

the Nervous System

■ Neurons

Postsynaptic neuron (or effector)

Synaptic cleft

Synapse

b

NucleusNucleolus

Cell body

Axon (beneathmyelin sheath)

Axon hillock

Neurofibril node

Neurolemmocyte

Axon collateral

Synaptic knobs

a

Telodendria

D

A

Synaptic vesiclescontaining neurotransmitter

Myelin sheath

Chromatophilic(Nissl) substance

Neurofibrils

AxoplasmAxolemma

DendritesPerikaryon

G

N

AH

NS

FIGURE 9–3 Structures of neuron.

(a) The diagram of a “typical” neuron shows the three major parts of every neuron. The cell body is large and has a large, euchromatic nucleus with a well-developed nucleolus. The perikaryon also contains basophilic Nissl substance or Nissl bodies, which are large masses of free polysomes and RER and indicate the cell’s high rate of protein synthesis. Numerous short dendrites extend from the perikaryon, receiving input from other neurons. A long axon carriesimpulses from the cell body and is covered by a myelin sheath composed of other cells. The ends of axons usually have many small branches (telodendria), each of which ends in a knob-like structure that forms part of a functional connection (synapse) with another neuron or other cell.(b) Micrograph of a large motor neuron showing the large cell body and nucleus (N), with a long axon (A) emerging from an axon hillock (AH) and several dendrites (D). Evenly dispersed Nissl substance (NS) can be seen throughout the cell body and cytoskeletal elements can be detected in the processes. Nuclei of scattered glial cells (G) are seen among the surrounding tissue. X100. H&E.

Matriz extracelular

Es el principal componente del tejido conectivo

Formado por:

Fibras proteinicas

Ground substance!!

Ground substance… matrix extrafibrilar

Proteoglucanos

Glucosaminoglucanos

Proteinas adhesivas

Laminina

Fibronectina

Mesenquima

Deriva del mesenquima embrionario

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onnective Tissue

FIGURE 5–1 Embryonic mesenchyme.

Mesenchyme consists of a population of undifferentiated cells, generally elongated but with many shapes, having large euchromatic nuclei and prominent nucleoli that indi-cate high levels of synthetic activity. These cells are called mesenchymal cells. Mesenchymal cells are surrounded by an ECM that they produced and that consists largely of a simple ground substance rich in hyaluronan (hyaluronic acid), but with very little collagen. X200. Mallory trichrome.

marrow and move to the connective tissue where they func-tion for a few days, then die by apoptosis.

FibroblastsFibroblasts (Figure 5–3), the most common cells in connective tissue, produce and maintain most of the tissue’s extracellular components. Fibroblasts synthesize and secrete collagen (the most abundant protein of the body) and elastin, which form large fibers, as well as the GAGs, proteoglycans, and multiadhesive glycoproteins that comprise the ground substance. As described later, most of the secreted ECM components undergo further modification outside the cell before assembling as a matrix.

Two levels of fibroblast activity can be observed histo-logically (Figure 5–3b). Cells with intense synthetic activity are morphologically distinct from the quiescent fibroblasts that are scattered within the matrix they have already syn-thesized. Some histologists reserve the term “fibroblast” to denote the active cell and “fibrocyte” to denote the quiescent cell. The active fibroblast has more abundant and irregularly branched cytoplasm. Its nucleus is large, ovoid, euchromatic, and has a prominent nucleolus. The cytoplasm has much rough endoplasmic reticulum (RER) and a well-developed Golgi apparatus. The quiescent cell is smaller than the active

fibroblast, is usually spindle-shaped with fewer processes and much less RER, and contains a darker, more heterochromatic nucleus.

Fibroblasts are targets of many families of proteins called growth factors that influence cell growth and differentiation. In adults, connective tissue fibroblasts rarely undergo division. However, stimulated by locally released growth factors, cell cycling and mitotic activity resume when the tissue requires additional fibroblasts, for example, to repair a damaged organ. Fibroblasts involved in wound healing, sometimes called myo-fibroblasts, have a well-developed contractile function and are enriched with a form of actin also found in smooth muscle cells.


The regenerative capacity of connective tissue is clearly observed in organs damaged by ischemia, inflammation, or traumatic injury. Spaces left after such injuries, especially in tissues whose cells divide poorly or not at all (eg, cardiac muscle), are filled by connective tissue, forming dense irreg-ular scar tissue. The healing of surgical incisions and other wounds depends on the reparative capacity of connective tissue, particularly on activity and growth of fibroblasts.

In some rapidly closing wounds, a cell called the myofi-broblast, with features of both fibroblasts and smooth muscle cells, is also observed. These cells have most of the mor-phologic characteristics of fibroblasts but contain increased amounts of actin microfilaments and myosin and behave much like smooth muscle cells. Their activity is important for the phase of tissue repair called wound contraction.

AdipocytesAdipocytes (L. adeps, fat + Gr. kytos, cell), or fat cells, are found in connective tissue of many organs. These large, mesenchymally derived cells are specialized for cytoplasmic storage of lipid as neutral fats, or less commonly for the pro-duction of heat. The large deposits of fat in the cells of adi-pose connective tissue also serve to cushion and insulate the skin and other organs. Adipocytes have major metabolic significance with medical importance and are described and discussed in Chapter 6.

Macrophages & the Mononuclear Phagocyte SystemMacrophages are characterized by their well-developed phagocytic ability and specialize in turnover of protein fibers and removal of dead cells, tissue debris, or other particulate material. They have a wide spectrum of morphologic features corresponding to their state of functional activity and to the tissue they inhabit. A typical macrophage measures between 10 and 30 μm in diameter and has an eccentrically located, oval or kidney-shaped nucleus. Macrophages are present in the connective tissue of most organs and are often referred to by pathologists as “histiocytes.”


FIGURE 5–2 Cellular and extracellular components of connective tissue.

Mesenchymal cell

Elastic fiber

Fibroblast

Collagen fiber

Reticular fiber

Macrophage

Extracellularmatrix

Blood vessel

Ground substance

Adipocyte

Protein fibers

Resident cells

Connective tissue is composed of fibroblasts and other cells and an extracellular matrix (ECM) of various protein fibers, all of which are surrounded by watery ground substance. In all

types of connective tissue the extracellular volume exceeds that of the cells.

Functions of cells in connective tissue proper.TABLE 5–1

Cell Type Major Product or Activity

Fibroblasts (fibrocytes) Extracellular fibers and ground substance

Plasma cells Antibodies

Lymphocytes (several types) Various immune/defense functions

Eosinophilic leukocytes Modulate allergic/vasoactive reactions and defense against parasites

Neutrophilic leukocytes Phagocytosis of bacteria

Macrophages Phagocytosis of ECM components and debris; antigen processing and presentation to immune cells; secretion of growth factors, cytokines, and other agents

Mast cells and basophilic leukocytes

Pharmacologically active molecules (eg, histamine)

Adipocytes Storage of neutral fats


Besides their function in turnover of ECM fibers, macrophages are key components of an organism’s innate immune defense system, removing cell debris, neoplastic cells, bacteria, and other invaders. Macrophages are also important antigen-presenting cells required for the activa-tion and specification of lymphocytes.

When macrophages are stimulated (by injection of foreign substances or by infection), they change their morphologic characteristics and properties, becoming activated macrophages. In addition to showing an increase in their capacity for phagocytosis and intracellular digestion, activated macrophages exhibit enhanced metabolic and lysosomal enzyme activity. Macrophages are also secretory cells producing an array of substances, including various enzymes for ECM breakdown and various growth factors or cytokines that help regulate immune cells and reparative functions.

When adequately stimulated, macrophages may increase in size and fuse to form multinuclear giant cells, usually found only in pathologic conditions.

Fibroblastos

Son celulas del tejido conectivo que se originan de diferenciacion del mesenquima in situ…

Producen y mantienen la matriz extracelular de la mayoría de los tejidos

Fibroblastos

Producen:

Colageno

Elastina

Proteinas adhesivas

Glucosaminoglucanos

Proteoglucanos

Fibroblastos

Son blanco de factores de crecimiento, bajo estimulo entran en reproducción

Rara vez se multiplican en adultos

Tienen papel en la cicatrización

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onnective Tissue

FIGURE 5–3 Fibroblasts.

a

C

b

(a) Fibroblasts typically have large active nuclei and eosino-philic cytoplasm that tapers off in both directions along the axis of the nucleus, a morphology often referred to as “spindle-shaped.” Nuclei (arrows) are clearly seen, but the eosinophilic cytoplasmic processes resemble the collagen bundles (C) that fill the ECM and are difficult to distinguish in H&E-stained sections.

(b) Both active and quiescent fibroblasts may sometimes be distinguished, as in this section of dermis. Active fibroblasts have large, euchromatic nuclei and basophilic cytoplasm, while inactive fibroblasts (or fibrocytes) are smaller with more het-erochromatic nuclei (arrows). The round, very basophilic round cells are in leukocytes. Both X400. H&E.

In the TEM, macrophages are shown to have a charac-teristic irregular surface with pleats, protrusions, and inden-tations, a morphologic expression of their active pinocytotic and phagocytic activities (Figure 5–4). They generally have a well-developed Golgi apparatus and many lysosomes.

Macrophages derive from bone marrow precursor cells that divide, producing monocytes that circulate in the blood. These cells cross the epithelial wall of venules to penetrate con-nective tissue, where they differentiate further, mature, and acquire the morphologic features of phagocytic cells. There-fore, monocytes and macrophages are the same cell at different stages of maturation. Macrophages play an important role in the early stages of repair after tissue damage, and under such conditions of inflammation these cells accumulate in connec-tive tissue by local proliferation of macrophages in addition to monocyte recruitment from the blood. Macrophages are dis-tributed throughout the body and are present in most organs. Along with other monocyte-derived cells, they comprise a family of cells called the mononuclear phagocyte system

(Table 5–2). The macrophage-like cells have been given differ-ent names in different organs, for example Kupffer cells in the liver, microglial cells in the central nervous system, Langer-hans cells in the skin, and osteoclasts in bone tissue. However, all are derived from monocytes. All are long-living cells and may survive for months in the tissues. In addition to debris removal, these cells are highly important for the uptake, pro-cessing, and presentation of antigens for lymphocyte activa-tion, a function discussed later with the immune system. The transformation from monocytes to macrophages in connec-tive tissue involves increases in cell size, increased protein syn-thesis, and increases in the number of Golgi complexes and lysosomes.

Mast CellsMast cells are oval or irregularly shaped connective tissue cells, between 7 and 20 μm in diameter, whose cytoplasm is filled with basophilic secretory granules. The nucleus is centrally situated

QuiescentesActivos

Adipocitos

Celulas con citoplasma especializado en el almacenamiento de lipidos

Algunas se especializan en produccion de calor

Funciona para proteger y dar aislamiento termico

Funcion metabolica: ENERGIA!!!

Transformacion de hormonas

Macrofagos (histiocitos) y el sistema fagocitico mononuclear

Gran actividad Fagocitica

Son celulas especializadas en el recambio y remocion de celulas muertas

Gran espectro de caracteristicas morfológicas

Actividad

Tejido en el que habitan


FIGURE 5–4 Macrophage ultrastructure.

NuNu

LL

LL

LL

NN

Characteristic features of macrophages seen in this TEM of one such cell are the prominent nucleus (N) and the nucleolus (Nu) and the numerous secondary lysosomes (L). The arrows

indicate phagocytic vacuoles near the protrusions and indenta-tions of the cell surface. X10,000.

and often obscured by abundant secretory granules (Figure 5–5). These granules are electron-dense and heterogeneous (ranging from 0.3 to 2.0 μm in diameter.) Because of their high content of acidic radicals in their sulfated GAGs, mast cell granules display

metachromasia, which means that they can change the color of some basic dyes (eg, toluidine blue) from blue to purple or red. The granules are poorly preserved by common fixatives, so that mast cells are frequently difficult to identify.

Distribution and main functions of the cells of the mononuclear phagocyte system.TABLE 5–2

Cell Type Major Locations Main Function

Monocyte Blood Precursor of macrophages

Macrophage Connective tissue, lymphoid organs, lungs, bone marrow, pleural and peritoneal cavities

Production of cytokines, chemotactic factors, and several other molecules that participate in inflammation (defense), antigen processing, and presentation

Kupffer cell Liver (perisinusoidal) Same as macrophages

Microglial cell Central nervous system Same as macrophages

Langerhans cell Epidermis of skin Antigen processing and presentation

Dendritic cell Lymph nodes, spleen Antigen processing and presentation

Osteoclast (from fusion of several macrophages)

Bone Localized digestion of bone matrix

Multinuclear giant cell (several fused macrophages)

In connective tissue under various pathological conditions

Segregation and digestion of foreign bodies

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FIGURE 5–5 Mast cells.

a

E

M

N

GG

C

E

MBV

NC

b

Mast cells are components of loose connective tissues, often located near small blood vessels (BV). (a) They are typically oval shaped, with cytoplasm filled with strongly basophilic granules. X400. PT.(b) Ultrastructurally mast cells show little else around the nucleus (N) besides these cytoplasmic granules (G), except

for occasional mitochondria (M). The granule staining in the TEM is heterogeneous and variable in mast cells from different tissues; at higher magnifications some granules may show a characteristic scroll-like substructure (inset) that contains pre-formed mediators such as histamine and proteoglycans. The ECM near this mast cell includes elastic fibers (E) and bundles of collagen fibers (C).

Mast cells function in the localized release of many bioac-tive substances with roles in the local inflammatory response, innate immunity, and tissue repair. A partial list of impor-tant molecules released from these cells’ secretory granules includes the following:

■ Heparin, a sulfated GAG that acts locally as an anticoagulant ■ Histamine, which promotes increased vascular perme-

ability and smooth muscle contraction ■ Serine proteases, which activate various mediators of

inflammation ■ Eosinophil and neutrophil chemotactic factors,

which attract those leukocytes ■ Cytokines, polypeptides directing activities of leuko-

cytes and other cells of the immune system ■ Phospholipid precursors for conversion to prostaglan-

dins, leukotrienes, and other important lipid mediators of the inflammatory response.

Occurring in connective tissue of many organs, mast cells are especially numerous near small blood vessels in skin and mesenteries (perivascular mast cells) and in the tissue that lines digestive and respiratory tracts (mucosal mast cells); the granule content of the two populations differs somewhat. These major locations suggest that mast cells place themselves strategically to function as sentinels detecting invasion by microorganisms.

Mast cells originate from progenitor cells in the bone marrow. The progenitor cells circulate in the blood, cross the wall of venules and capillaries, and penetrate connective tissues, where they differentiate. Although they are in many respects similar to basophilic leukocytes, they appear to have a different lineage at least in humans.

Release of certain chemical mediators stored in mast cells also promotes the allergic reactions, also known as immedi-ate hypersensitivity reactions because they occur within a few minutes after the appearance of an antigen in an individ-ual previously sensitized to the same or a very similar antigen. There are many examples of immediate hypersensitivity reaction; a dramatic one is anaphylactic shock, a potentially fatal condition. The process of anaphylaxis consists of the following sequential events. The first exposure to an antigen (allergen), such as bee venom, results in production of the immunoglobulin E (IgE) class of immunoglobulins (antibodies) by plasma cells. IgE is avidly bound to the surface of mast cells. A second exposure to the antigen results in binding of the antigen to IgE on the mast cells. This event triggers release of the mast cell granules, liberating histamine, leukotrienes, chemokines, and heparin (Figure 5–6). Degranulation of mast cells also occurs as a result of the action of the comple-ment molecules that participate in the immunologic reactions described in Chapter 14.

Se encuentra en tejidos conectivos blandosTiene granulos de secresion activa…

Cercanos a los vasos sanguineosSe originan de celulas progenitoras de la medula osea

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FIGURE 5–5 Mast cells.

a

E

M

N

GG

C

E

MBV

NC

b

Mast cells are components of loose connective tissues, often located near small blood vessels (BV). (a) They are typically oval shaped, with cytoplasm filled with strongly basophilic granules. X400. PT.(b) Ultrastructurally mast cells show little else around the nucleus (N) besides these cytoplasmic granules (G), except

for occasional mitochondria (M). The granule staining in the TEM is heterogeneous and variable in mast cells from different tissues; at higher magnifications some granules may show a characteristic scroll-like substructure (inset) that contains pre-formed mediators such as histamine and proteoglycans. The ECM near this mast cell includes elastic fibers (E) and bundles of collagen fibers (C).

Mast cells function in the localized release of many bioac-tive substances with roles in the local inflammatory response, innate immunity, and tissue repair. A partial list of impor-tant molecules released from these cells’ secretory granules includes the following:

■ Heparin, a sulfated GAG that acts locally as an anticoagulant ■ Histamine, which promotes increased vascular perme-

ability and smooth muscle contraction ■ Serine proteases, which activate various mediators of

inflammation ■ Eosinophil and neutrophil chemotactic factors,

which attract those leukocytes ■ Cytokines, polypeptides directing activities of leuko-

cytes and other cells of the immune system ■ Phospholipid precursors for conversion to prostaglan-

dins, leukotrienes, and other important lipid mediators of the inflammatory response.

Occurring in connective tissue of many organs, mast cells are especially numerous near small blood vessels in skin and mesenteries (perivascular mast cells) and in the tissue that lines digestive and respiratory tracts (mucosal mast cells); the granule content of the two populations differs somewhat. These major locations suggest that mast cells place themselves strategically to function as sentinels detecting invasion by microorganisms.

Mast cells originate from progenitor cells in the bone marrow. The progenitor cells circulate in the blood, cross the wall of venules and capillaries, and penetrate connective tissues, where they differentiate. Although they are in many respects similar to basophilic leukocytes, they appear to have a different lineage at least in humans.

Release of certain chemical mediators stored in mast cells also promotes the allergic reactions, also known as immedi-ate hypersensitivity reactions because they occur within a few minutes after the appearance of an antigen in an individ-ual previously sensitized to the same or a very similar antigen. There are many examples of immediate hypersensitivity reaction; a dramatic one is anaphylactic shock, a potentially fatal condition. The process of anaphylaxis consists of the following sequential events. The first exposure to an antigen (allergen), such as bee venom, results in production of the immunoglobulin E (IgE) class of immunoglobulins (antibodies) by plasma cells. IgE is avidly bound to the surface of mast cells. A second exposure to the antigen results in binding of the antigen to IgE on the mast cells. This event triggers release of the mast cell granules, liberating histamine, leukotrienes, chemokines, and heparin (Figure 5–6). Degranulation of mast cells also occurs as a result of the action of the comple-ment molecules that participate in the immunologic reactions described in Chapter 14.

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Derivan de los linfocitos B

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Connective Tissue ■ Fibers

LeukocytesBesides macrophages and plasma cells, connective tissue nor-mally contains other leukocytes derived from cells circulat-ing in the blood. Leukocytes, or white blood cells, make up a population of wandering cells in connective tissue. They leave blood by migrating between the endothelial cells lining venules to enter connective tissue by a process called diape-desis. This process increases greatly during inflammation, which is a vascular and cellular defensive response to injury or foreign substances, including pathogenic bacteria or irritating chemical substances.

Classically, the major signs of inflamed tissues include “redness and swelling with heat and pain” (rubor et tumor cum calore et dolore). Inflammation begins with the local release of chemical mediators from various cells, the ECM, and blood plasma proteins. These substances act on the local microvascu-lature, mast cells, macrophages, and other cells to induce events characteristic of inflammation, for example increased blood flow and vascular permeability, diapedesis and migration of leukocytes, and activation of macrophages for phagocytosis.

Most leukocytes function for a few hours or days in con-nective tissue and then die. However, as discussed with the immune system, some lymphocytes and phagocytic antigen-presenting cells normally leave the interstitial fluid of con-nective tissue, enter blood or lymph, and move to selected lymphoid organs.

FIGURE 5–7 Plasma cells.

a b

Antibody-secreting plasma cells are present in variable numbers in the connective tissue of many organs.(a) Plasma cells are large, ovoid cells, with basophilic cytoplasm. The round nuclei frequently show peripheral clumps of heterochromatin, giving the structure a “clock-face” appearance. X640. H&E.(b) Plasma are often more abundant in infected tissues, as in the inflamed lamina propria shown here. A large pale

Golgi apparatus (arrows) at a juxtanuclear site in each cell is actively involved in the terminal glycosylation of the antibodies (glycoproteins). Plasma cells leave their sites of origin in lymphoid tissues, move to connective tissue, and produce antibodies that mediate immunity. X400 PT.


Increased vascular permeability is caused by the action of vasoactive substances such as histamine released from mast cells during inflammation. Increased blood flow and vascular permeability produce local swelling (edema), redness, and heat. Pain is due mainly to the action of the chemical mediators on nerve endings. All these activities help protect and repair the inflamed tissue. Chemotaxis (Gr. chemeia, alchemy + taxis, orderly arrangement), the phenomenon by which specific cell types are attracted by specific molecules, draws much larger numbers of leuko-cytes into inflamed tissues.

❯ FIBERSThe fibrous components of connective tissue are elongated structures formed from proteins that polymerize after secre-tion from fibroblasts (Figure 5–2). The three main types of fibers include collagen, reticular, and elastic fibers. Collagen and reticular fibers are both formed by proteins of the collagen family, and elastic fibers are composed mainly of the protein elastin. These fibers are distributed unequally among the different types of connective tissue, with the predominant fiber type usually responsible for conferring specific tissue properties.

Leucocitos

Fibras

Colageno

Es una familia de proteínas

Es la proteina mas abundante en en cuerpo humano

Constituye 30% de su peso seco

Da origen a muchas estructuras extracelulares


CollagenThe collagens constitute a family of proteins selected dur-ing evolution for their ability to form a variety of extracellu-lar structures. The various fibers, sheets, and networks made of collagens are all extremely strong and resistant to normal shearing and tearing forces. Collagen is a key element of all connective tissues, as well as epithelial basement membranes and the external laminae of muscle and nerve cells.

Collagen is the most abundant protein in the human body, representing 30% of its dry weight. A major product of fibro-blasts, collagens are secreted by several other cell types and are distinguishable by their molecular compositions, morphologic characteristics, distribution, functions, and pathologies. A family of 28 collagens exists in vertebrates, the most impor-tant of which are listed in Table 5–3. They can be grouped into the following categories according to the structures formed by their interacting subunits:

■ Fibrillar collagens, notably collagen types I, II, and III, have subunits that aggregate to form large fibrils clearly visible in the electron or light microscope (Figure 5–8). Collagen type I, the most abundant and widely distributed collagen, forms large, eosinophilic bundles usually called collagen fibers. These often densely fill the connective tissue, forming structures such as tendons, organ capsules, and dermis.

■ Sheet-forming collagens such as type IV collagen have subunits produced by epithelial cells and are the major structural proteins of external laminae and the basal lamina in all epithelia.

■ Linking/anchoring collagens are short collagens that link fibrillar collagens to one another (forming larger fibers) and to other components of the ECM. Type VII collagen binds type IV collagen and anchors the basal lamina to the underlying reticular lamina in basement membranes (see Figure 4–3).

TABLE 5–3 Collagen types.

TypeMolecule Composition Structure Optical Microscopy Major Locations Main Function

Fibril-Forming Collagens

I [α1 (I)]2[α2 (I)] 300-nm molecule, 67-nm banded fibrils

Thick, highly picrosirius birefringent, fibers

Skin, tendon, bone, dentin

Resistance to tension

II [α1 (II)]3300-nm molecule, 67-nm banded fibrils

Loose aggregates of fibrils, birefringent

Cartilage, vitreous body Resistance to pressure

III [α1 (III)]367-nm banded fibrils Thin, weakly birefringent,

argyrophilic (silver-binding) fibers

Skin, muscle, blood vessels, frequently together with type I

Structural maintenance in expansible organs

V [α1 (V)]3390-nm molecule, N-terminal globular domain

Frequently forms fiber together with type I

Fetal tissues, skin, bone, placenta, most interstitial tissues

Participates in type I collagen function

XI [α1 (XI)] [α2 (XI)] [α3 (XI)]

300-nm molecule Small fibers Cartilage Participates in type II collagen function

Sheet-Forming Collagens

IV [α1 (VII)]2 [α1 (IV)] 2-dimensional cross-linked network

Detected by immunocytochemistry

All basal and external laminae

Support of epithelial cells; filtration

Linking/Anchoring Collagens

VII [α1 (VII)]3450 nm, globular domain at each end


Epithelial basement membranes

Anchors basal laminae to underlying reticular lamina

IX [α1 (IX)] [α2 (IX)] [α3 (IX)]

200-nm molecule Detected by immunocytochemistry

Cartilage, vitreous body Binds various proteoglycans; associated with type II collagen

XII [α1 (XII)]3Large N-terminal domain


Placenta, skin, tendons Interacts with type I collagen

XIV [α1 (XIV)]3Large N-terminal domain; cross-shaped molecule


Placenta, bone Binds type I collagen fibrils, with types V and XII, strengthening fiber formation

Fibers 107C

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PT

ER

5Connective Tissue ■ Fibers

FIGURE 5–8 Type I collagen.

a

b

CC

C

Subunits of type I collagen, the most abundant collagen, assemble to form extremely strong fibrils, which are then bundled together further by other collagens into much larger structures called collagen fibers.(a) TEM shows fibrils cut longitudinally and transversely. In longitudinal sections fibrils display alternating dark and light bands; in cross section the cut ends of individual collagen molecules appear as dots. Ground substance completely sur-rounds the fibrils. X100,000.(b) The large bundles of type I collagen fibrils (C) appear as acidophilic collagen fibers in connective tissues, where they

Collagen synthesis occurs in many cell types but is a specialty of cells that produce the various kinds of connective tissue. The initial procollagen α chains are made in the cells’ abundant RER. The collagen gene family is very large, and many different α chains have been identified, varying in length and sequence. In the ER three α chains are selected, aligned, and stabilized by disulfide bonds at their carboxyl terminals, and folded as a triple helix, which is the defining feature of

FIGURE 5–9 The collagen subunit.

8.6 nm

In the most abundant form of collagen, type I, each procollagen molecule or subunit has two α1- and one α2-peptide chains, each with a molecular mass of approximately 100 kDa, inter-twined in a right-handed helix and held together by hydrogen

bonds and hydrophobic interactions. The length of each molecule (sometimes called tropocollagen) is 300 nm, and its width is 1.5 nm. Each complete turn of the helix spans a distance of 8.6 nm.

may fill the extracellular space. Subunits for these fibers were secreted by the fibroblasts (arrows) associated with them. X400. H&E.

collagens. The triple helix undergoes exocytosis and is cleaved to a rodlike procollagen molecule (Figure 5–9) that is the basic subunit from which the fibers or sheets are assembled. These subunits may be homotrimeric, with all three chains identical, or heterotrimeric, with two or all three chains hav-ing different sequences. Different combinations of procollagen α chains produce the various types of collagen with different structures and functional properties.

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FIGURE 5–8 Type I collagen.

a

b

CC

C

Subunits of type I collagen, the most abundant collagen, assemble to form extremely strong fibrils, which are then bundled together further by other collagens into much larger structures called collagen fibers.(a) TEM shows fibrils cut longitudinally and transversely. In longitudinal sections fibrils display alternating dark and light bands; in cross section the cut ends of individual collagen molecules appear as dots. Ground substance completely sur-rounds the fibrils. X100,000.(b) The large bundles of type I collagen fibrils (C) appear as acidophilic collagen fibers in connective tissues, where they

Collagen synthesis occurs in many cell types but is a specialty of cells that produce the various kinds of connective tissue. The initial procollagen α chains are made in the cells’ abundant RER. The collagen gene family is very large, and many different α chains have been identified, varying in length and sequence. In the ER three α chains are selected, aligned, and stabilized by disulfide bonds at their carboxyl terminals, and folded as a triple helix, which is the defining feature of

FIGURE 5–9 The collagen subunit.

8.6 nm

In the most abundant form of collagen, type I, each procollagen molecule or subunit has two α1- and one α2-peptide chains, each with a molecular mass of approximately 100 kDa, inter-twined in a right-handed helix and held together by hydrogen

bonds and hydrophobic interactions. The length of each molecule (sometimes called tropocollagen) is 300 nm, and its width is 1.5 nm. Each complete turn of the helix spans a distance of 8.6 nm.

may fill the extracellular space. Subunits for these fibers were secreted by the fibroblasts (arrows) associated with them. X400. H&E.

collagens. The triple helix undergoes exocytosis and is cleaved to a rodlike procollagen molecule (Figure 5–9) that is the basic subunit from which the fibers or sheets are assembled. These subunits may be homotrimeric, with all three chains identical, or heterotrimeric, with two or all three chains hav-ing different sequences. Different combinations of procollagen α chains produce the various types of collagen with different structures and functional properties.


TABLE 5–4 Examples of clinical disorders resulting from defects in collagen synthesis.

Disorder Defect Symptoms

Ehlers-Danlos type IV Faulty transcription or translation of collagen type III Aortic and/or intestinal rupture

Ehlers-Danlos type VI Faulty lysine hydroxylation Increased skin elasticity, rupture of eyeball

Ehlers-Danlos type VII Decrease in procollagen peptidase activity Increased articular mobility, frequent luxation

Scurvy Lack of vitamin C, a required cofactor for prolyl hydroxylase Ulceration of gums, hemorrhages

Osteogenesis imperfecta Change of 1 nucleotide in genes for collagen type I Spontaneous fractures, cardiac insufficiency

FIGURE 5–11 Assembly of type I collagen.

4

5Collagen fiber

Bundle ofcollagen fibers

Gap region

300 nm

Procollagen subunit

Overlapping region

1

2

3

300 nm

Gapregion

Collagen fibril

Overlapping region (about 10%of tropocollagen length)

67 nm

Shown here are the relationships among type I collagen molecules, fibrils, fibers, and bundles.

1. Rodlike triple-helix collagen molecules, each 300 nm long, self-assemble in a highly organized, lengthwise arrange-ment of overlapping regions.

2. The regular, overlapping arrangement of subunits contin-ues as large collagen fibrils are assembled.

3. This structure causes fibrils to have characteristic cross striations with alternating dark and light bands when observed in the EM.

4. Fibrils assemble further and are linked together in larger collagen fibers visible by light microscopy.

5. Type I fibers often form into still larger aggregates bundled and linked together by other collagens.

The photo shows an SEM view of type I collagen fibrils closely aggregated as part of a collagen fiber. Striations are visible on the surface of the fibrils.

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in glycine, proline, and lysine, giving much of the protein a random-coil conformation (like that of natural rubber). Many lysines are present as pairs. During deposition on microfibrils the enzyme lysyl oxidase converts the paired lysines’ amino groups to aldehydes. Oxidized lysines on two different elastin molecules then condense as a desmosine ring that acts as a covalent cross-link between the polypeptides, which main-tain their rubberlike properties (Figure 5–15). Elastin resists digestion by most proteases, but it is hydrolyzed by pancreatic elastase.


Fibrillins comprise a family of proteins involved in making the scaffolding necessary for the deposition of elastin. Mutations in the fibrillin genes result in Marfan syndrome, a disease characterized by a lack of resistance in tissues rich in elastic fibers. Because the walls of large arteries are rich in elastic components and because the blood pressure is high in the aorta, patients with this disease often experience aortic swellings called aneurysms, which are life-threatening conditions.

❯ GROUND SUBSTANCEThe ground substance of the ECM is a highly hydrated (with much bound water), transparent, complex mixture of macro-molecules, principally of three classes: glycosaminoglycans (GAGs), proteoglycans, and multiadhesive glycopro-teins. It fills the space between cells and fibers in connective tissue and, because it is viscous, acts as both a lubricant and a barrier to the penetration of invaders. Many macromolecules and physical properties of ground substance profoundly influ-ence a variety of cellular activities. When adequately fixed for histologic analysis, its components aggregate and pre-cipitate in the tissues as granular material that is observed in TEM preparations as electron-dense filaments or granules (Figure 5–16).

GAGs (also called mucopolysaccharides) are long polysaccharides consisting of repeating disaccharide units, usually a uronic acid and a hexosamine. The hexosamine can be glucosamine or galactosamine, and the uronic acid can be glucuronic or iduronic acid. The largest, almost unique, and most ubiquitous GAG is hyaluronic acid (HA or hyal-uronan). With a molecular weight from 100s to 1000s kDa, hyaluronic acid is a long polymer of the disaccharide glucos-amine-glucuronate. It is synthesized directly into the ECM by an enzyme complex, hyaluronate synthase, located in the cell membrane of many cells. Hyaluronic acid forms a dense, viscous network of polymers, which binds a considerable amount of water, giving it an important role in allowing diffu-sion of molecules in connective tissue and in lubricating vari-ous organs and joints.

All other GAGs are much smaller (10-40 kDa), sulfated, covalently attached to proteins (as parts of proteoglycans), and are synthesized in Golgi complexes. The four major GAGs found in proteoglycans are dermatan sulfate, chondroitin sulfates, keratan sulfate, and heparan sulfate, all of which have different disaccharide units and tissue distributions (Table 5–5). Like hyaluronic acid, these GAGs are intensely hydrophilic, contributing to the viscosity of ground substance, and are polyanions, binding a great number of cations (usually sodium) by electrostatic (ionic) bonds.

Proteoglycans are composed of a core protein to which are covalently attached various numbers and combinations of the sulfated GAGs. Like glycoproteins, they are synthesized on RER, mature in the Golgi, where the GAG side chains are added, and secreted from cells by exocytosis. Unlike gly-coproteins, some proteoglycans, such as the major cartilage constituent aggrecan, contain a greater mass of polysaccharide chains than polypeptide. These structural differences between a typical glycoprotein and aggrecan are shown in Figure 5–17.

Proteoglycans are distinguished by their diversity, which is generated in part by enzymatic differences in the Golgi com-plexes. A region of ECM may contain several different core proteins, each with one or many GAGs of different lengths and composition. A small proteoglycan, decorin, has few GAG side chains and binds fibrils of type I collagen. Cell surface proteoglycans such as syndecan have transmembrane core

FIGURE 5–15 Molecular basis of elastic fiber elasticity.

Single elastinmoleculeCross-link

Stretched

Relaxed

The diagram shows a small piece of an elastic fiber, in two conformations. Elastin polypeptides, the major components of elastic fibers, have multiple random-coil domains that straighten or stretch under force, and then relax. Most of the cross-links between elastin subunits consist of the cova-lent, cyclic structure desmosine, each of which involves four converted lysines in two elastin molecules. This unusual type of protein cross-link holds the aggregate together with little steric hindrance to elastin movements. These properties give the entire network its elastic quality.

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onnective Tissue

cords that hold together components of the musculoskeletal system. Consisting almost entirely of densely packed collagen fibers, they are white in the fresh state and almost inextensible. The parallel, closely packed bundles of collagen are separated by very little ground substance (Figure 5–22a). The fibrocytes have elongated nuclei lying parallel to the fibers and sparse cytoplasmic folds that envelop portions of the collagen bun-dles (Figure 5–22b). The cytoplasm of these “tendinocytes” is rarely revealed in H&E stains, not only because it is sparse but also because it stains the same color as the fibers. Some ligaments, such as the yellow ligaments of the vertebral col-umn, also contain abundant parallel elastic fiber bundles.

The collagen bundles of tendons vary in size and are enveloped by small amounts of irregular connective tissue containing small blood vessels and nerves. Overall, however, tendons are poorly vascularized and repair of damaged ten-dons is very slow. In some tendons, the dense irregular con-nective tissue sheath is covered by flattened synovial cells of mesenchymal origin, which produce lubricant fluid (similar to the fluid of synovial joints, Chapter 8) containing water, pro-teins, hyaluronate, and other GAGs.


Overuse of tendon-muscle units can result in tendonitis, characterized by inflammation of the tendons and their attachments to muscle. Common locations are the elbow, the Achilles tendon of the heel, and the shoulder rotator cuff. The swelling and pain produced by the localized inflammation restricts the affected area’s normal range of motion and can be relieved by injections of anti- inflammatory agents such as cortisone. Fibroblasts even-tually repair damaged collagen bundles of the area.

Reticular TissueIn reticular tissue fibers of type III collagen (see Figure 5–12) form a delicate 3D network that supports various types of cells. The fibrous network of this specialized connective tissue is produced by modified fibroblasts called reticular cells that remain associated with and partially covering the fibers (Figure 5–23). The loose disposition of glycosylated reticular

TABLE 5–6 Classification of connective or supporting tissues.

General Organization Major Functions Examples

Connective Tissue Proper

Loose (areolar) connective tissue

Much ground substance; many cells and little collagen, randomly distributed

Supports microvasculature, nerves, and immune defense cells

Lamina propria beneath epithelial lining of digestive tract

Dense irregular connective tissue

Little ground substance; few cells (mostly fibroblasts); much collagen in randomly arranged fibers

Protects and supports organs; resists tearing

Dermis of skin, organ capsules, submucosa layer of digestive tract

Dense regular connective tissue

Almost completely filled with parallel bundles of collagen; few fibroblasts, aligned with collagen

Provide strong connections within musculoskeletal system; strong resistance to force

Ligaments, tendons, aponeuroses, corneal stroma

Embryonic Connective Tissues

Mesenchyme Sparse, undifferentiated cells, uniformly distributed in matrix with sparse collagen fibers

Contains stem/progenitor cells for all adult connective tissue cells

Mesodermal layer of early embryo

Mucoid (mucous) connective tissue

Random fibroblasts and collagen fibers in viscous matrix

Supports and cushions large blood vessels

Matrix of the fetal umbilical cord

Specialized Connective Tissues

Reticular connective tissue (see Chapter 14)

Delicate network of reticulin/collagen III with attached fibroblasts (reticular cells)

Supports blood-forming cells, many secretory cells, and lymphocytes in most lymphoid organs

Bone marrow, liver, pancreas, adrenal glands, all lymphoid organs except the thymus

Adipose Tissue (Chapter 6)

Cartilage (Chapter 7)

Bone (Chapter 8)

Blood (Chapter 12)


consequent accumulation of these macromolecules in tis-sues. The lack of specific hydrolases in the lysosomes has been found to be the cause of several disorders, including the Hurler, Hunter, Sanfilippo, and Morquio syndromes.

Because of their high viscosity, HA and proteoglycans tend to form a barrier against bacterial penetration of tissues. Bacteria that produce hyaluronidase, an enzyme that hydrolyzes hyaluronic acid and disassembles proteo-glycans complexes, reduce the viscosity of the connective tissue ground substance and have greater invasive power.

The third class of ground substance components, the multiadhesive glycoproteins, all have multiple binding sites for cell surface receptors (integrins) and for other matrix macromolecules. The adhesive glycoproteins are very large molecules with branched oligosaccharide chains and have important roles in the adhesion of cells to their substrate. The large (200-400 kDa), trimeric, cross-shaped glycoprotein laminin provides adhesion for epithelial and other cells, with binding sites for integrins, type IV collagen, and specific pro-teoglycans. As shown in Figure 5–18a, all basal and external laminae are rich in laminin, which is essential for the assembly and maintenance of these structures.

Fibronectin (L. fibra, fiber + nexus, interconnection), synthesized largely by fibroblasts, is a 235-270 kDa dimeric molecule, has binding sites for collagens and certain GAGs, and forms insoluble fibrillar networks throughout connective tissue (Figure 5–18b). The fibronectin substrate provides spe-cific binding sites for integrins and is important both for cell adhesion and cellular migration through the ECM.

The integrin family of integral membrane proteins act as matrix receptors for specific sequences on laminin, fibronectin, some collagens, and certain other ECM proteins (Figure 5–19). Integrins bind their ligands in the ECM with relatively low affin-ity, allowing cells to explore their environment without losing attachment to it or becoming glued to it. They are heterodimers of two transmembrane polypeptides: the α and β chains. Great diversity in the subsets of integrin α and β chain cells express allows the cells to have different specific ligands preferentially.

Cytoplasmic portions of integrins associate with the peripheral membrane proteins talin and vinculin, which together bind actin filaments (Figure 5–19). In this way integ-rins mediate physical connections between ECM components and the cytoskeleton of cells in connective tissue, which allows the cells to monitor many physical aspects of their microenvi-ronment. These connections between cells and the ECM exert effects in both directions and are important for the physical orientation of both cells and fibers.

Integrins and other proteins associated with intermediate filaments form the hemidesmosomes of epithelia (see Chapter 4); clustered integrin-microfilament complexes in fibroblasts form structures called focal adhesions that can be local-ized by TEM or immunocytochemistry. This type of adhesive junction is typically present at the ends of actin filaments bun-dled by α-actinin as cytoplasmic stress fibers. Focal adhesion

FIGURE 5–18 Laminin and fibronectin localization by immunohistochemistry.

a

b

Both of these glycoproteins (and other similar glycoproteins) are multiadhesive, with binding sites for ECM components and for integrins at cell surfaces, and have important roles in cell migration and maintaining tissue structure.(a) Laminin is concentrated in the basal lamina of the stratified epithelium (top) and in the external laminae surrounding cross-sectioned nerves and muscle fibers. X200.(b) A fine network of fibronectin is localized more diffusely throughout the ECM. X400.

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