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Lymphocyte precursor
Undifferentiated mesenchymal cell
Chondroblast
Chondrocytes Adipocyte
Fibroblast Mesothelial cell
Endothelial
cell Osteoblast
Osteocyte
Hematopoietic stem cell
Monocyte
Mast cell
Neutrophil
Eosinophil
Basophil Macrophage
Megakaryocyte Osteoclast
Plasma cell
Red blood cell
B lymphocyte T lymphocyte
Figure 6.1 origins of connective tissue cells. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Phila- delphia, Saunders, 2007, p 112.)
Collagen
Endothelial cell
Elastic fiber
Fat cells
Pericyte
Macrophages
Mast cell
Plasma cells Fibroblast
Figure 6.2 cell types and fiber types in loose connective tissue. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 113.)
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66 Storage and Release of Fat by adipose cells
During digestion, fats in the lumen of the small intes- tine are catabolized by pancreatic lipase into fatty acids and glycerol, substances that are absorbed by surface absorptive cells of the epithelial lining. When in the cytoplasm of these cells, the fatty acids and glycerol enter the smooth endoplasmic reticulum, where they are re-esterified and conveyed to the golgi apparatus, where they are invested with a pro- tein coat. these proteinated triglycerides, called chy- lomicrons, are released into the lamina propria of the small intestine to enter lymph channels, known as lacteals, and eventually are released into the blood- stream.
capillaries that vascularize adipose tissue have an enzyme, lipoprotein lipase, manufactured by adipo- cytes, on the luminal surface of their endothelial cells (Fig. 6.3). this enzyme catabolizes chylomicrons and other blood-borne lipids, such as very-low-density lipoproteins (VlDl), into glycerol and fatty acids.
the fatty acids leave the capillaries; penetrate the adipocyte plasmalemma; and within the cytoplasm of fat cells are formed into triglycerides, which are stored in the pool of lipid droplets, an efficient and low weight method of energy storage. When norepi- nephrine and epinephrine bind to their respective receptor sites on the fat cell membrane, the adipo- cyte’s adenylate cyclase system is activated to form cyclic adenosine monophosphate (AMP), which induces the cytoplasmic enzyme hormone-sensitive lipase to degrade triglycerides of the lipid droplet.
the fatty acids and glycerol leave the adipocyte to enter the surrounding capillaries (see Fig. 6.3).
Mast cells
Mast cells (20 to 30 µm in diameter) are derived from precursors in the bone marrow and enter the connective tissue compartment where they mature, live for a few months, and only seldom enter the cell cycle. these ovoid cells with a centrally placed nucleus have membrane bound granules (Fig. 6.4 and table 6.3) that are responsible for their meta- chromasia. Mast cells store some pharmacologic agents, known as primary or preformed mediators, in granules and synthesize others, known as second- ary mediators, as they are required.
• Primary mediators are histamine and heparin (in connective tissue mast cells) or histamine and chondroitin sulfate (in mucosal mast cells of the mucosa of the respiratory tract and
alimentary canal), neutral proteases (tryptase, chymase, and carboxypeptidases), aryl sulfatase, β-glucuronidase, kininogenase, peroxidase, superoxide dismutase, eosinophil chemotactic factor, and neutrophil chemotactic factor.
• Secondary mediators, synthesized from membrane arachidonic acid precursors, include leukotrienes (c4, D4, and e4), thromboxanes (thromboxane A2 and thromboxane B2), and prostaglandins (prostaglandin D2).
• Secondary mediators that are not derived from arachidonic acid precursors include platelet- activating factor, bradykinins, interleukins (il-4, il-5, and il-6), and tumor necrosis factor-α. (see table 6.3 for a list of the major primary and secondary mediators released by mast cells.) Mast cell activation and Degranulation
the plasma membranes of mast cells possess high- affinity cell surface Fc receptors (FcεRi) for ige mol- ecules that project into the extracellular space. these cells have the ability to release pharmacologic agents that set off a localized response known as immedi- ate hypersensitivity reaction or, in extreme cases, a wide spread, possibly fatal response known as an ana- phylactic reaction. certain drugs, venoms of some insects, various pollens, and other antigens may elicit these responses in the following manner (see Fig.
6.4):
1. Mast cells become sensitized when they bind ige antibodies against a particular antigen to their FcεRi receptors, but the mast cells do not respond to the first exposure to the antigen.
2. if the same antigens enter the connective tissue for a second time, the antigens bind to the ige on the mast cell surface, causing the
immunoglobulin molecules to be linked to each other and the receptors to be crowded together, stimulating receptor coupling factors to activate adenylate cyclase and phospholipase A2. 3. Adenylate cyclase is responsible for the
formation and increased concentration of cyclic AMP within the plasma cell cytosol, inducing the release of Ca++ ions from sequestered storage compartments, which induces the exocytosis of preformed mediators by degranulation.
4. Phospholipase A2 induces the synthesis of arachidonic acid, which is transformed into secondary mediators that are immediately released into the extracellular space.
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Figure 6.3 transport of lipid between a capillary and an adipocyte. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed.
Philadelphia, Saunders, 2007, p 119.) FAT CELL
Cleavage of triglycerides to glycerol and fatty acids by hormone- sensitive lipase
Breakdown by lipoprotein lipase to free fatty acids within the capillary
Glycerol Fatty acids
Albumin Transport in blood Glucose Glycerol
phosphate Free
fatty acids Triglyceride stored in droplet
Chylomicrons VLDL particles CAPILLARY
Figure 6.4 Binding of antigens and cross-linking of ige receptor complexes on the mast cell plasma membrane. ecF, eosinophil chemotactic factor; ncF, neutrophil chemotactic factor. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed.
Philadelphia, Saunders, 2007, p 120.) 1 Binding of antigen to IgE-receptor
complex causes cross-linking of IgE and consequent clustering of receptors
2 Activation of adenylate cyclase
3 Activation of protein kinase
4 Phosphorylation of protein
5 Release of Ca2+
6 Fusion of granules 7 Release of
granules' contents 5a Activation of
phospholipases
6a Conversion of arachidonic acid in membrane
7a Secretion of:
Leukotrienes Thromboxanes Prostaglandins
Chondroitin sulfate Histamine Heparin ECF NCF Aryl sulfatase Antigen
Receptor coupling factor IgE
Fc receptor
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68 Mast cells and the inflammatory Response
the release of mediators (both primary and second- ary) by mast cells (see table 6.3) in response to the binding of antigens to their surface ige results in the following sequence of events:
1. Histamine is a vasodilator, and its effects are to increase vascular permeability; it also is a bronchoconstrictor, and it not only reduces the luminal diameter of bronchioles, but also causes an increase in mucus production.
2. the leakage of plasma from the blood vessels brings complement into the connective tissue spaces, which is catabolized by neutral proteases into macromolecules that contribute to the inflammatory process.
3. Neutrophil and eosinophil chemotactic factors recruit neutrophils and eosinophils to the site of inflammation; neutrophils kill microorganisms, and eosinophils phagocytose antigen-antibody complexes and kill parasites.
4. Bradykinins also increase vascular permeability and elicit pain in the area of inflammation.
5. Leukotrienes C4, D4, and E4 have similar functions as histamine, but are much more potent in their action; they do not affect mucus production, however.
6. Prostaglandin D2 causes contraction of bronchiolar smooth muscles and increases mucus production.
7. Platelet-activating factor attracts neutrophils and eosinophils to the site of inflammation, increases the permeability of blood vessels, and is a bronchoconstrictor.
8. Thromboxane A2, although it is rapidly inactivated by being converted into thromboxane B2, is a vasoconstrictor and induces aggregation of platelets.
Macrophages
Macrophages, irregularly shaped cells about 10 to 30 µm in diameter, are phagocytes, belonging to the mononuclear phagocyte system, all of whose mem- bers are derived from common bone marrow pre- cursor cells. they travel in the bloodstream as mono cytes, but when they enter connective tissue, they mature and become macrophages. some macro- phages remain in the area of the body that they enter and are known as resident (fixed) macrophages
(e.g., Kupffer cells, langerhans cells, dust cells, microglia), whereas others are transient (free, elic- ited) macrophages that perform their function and then either die or migrate from the area of their activity.
some macrophages that have to eliminate larger substances fuse with each other to be able to perform their duties; examples of such cells are osteoclasts and foreign body giant cells. the macrophage cell membranes have a smooth outline, unless they are actively moving or phagocytosing foreign substances or cellular debris, and then they develop folds and pleats on their plasmalemma. to be able to perform their functions, some macrophages have to be acti- vated by signaling molecules released by lympho- cytes that are participating in an immune response (see chapter 12). As macrophages mature, their cyto- plasm possesses numerous vacuoles, a prominent golgi apparatus, a copious amount of lysosomes, many microtubules, and numerous profiles of ReR.
their nuclei are dense and characteristically kidney shaped. the principal functions of macrophages, other than phagocytosis of invading microorganisms and cellular and extracellular debris, are to synthesize and release signaling molecules, such as tumor necro- sis factor-a and IL-1, and to act as antigen presenting cells that display antigenic fragments on their mem- brane bound receptors to lymphocytes inducing them to initiate an immune response.
TRANSIENT coNNEcTIvE TISSuE cELLS Plasma cells
Plasma cells, derived from a subcategory of lympho- cytes (B cells) that have been activated by contact with an antigen, are large (approximately 20 µm in diameter), oval cells, the heterochromatin of whose acentric, dense nucleus displays a characteristic clock- face or cartwheel configuration (Fig. 6.5). the cyto- plasm of these cells is richly endowed with golgi apparatus and ReR because they are responsible for the manufacture of antibodies in response to anti- genic challenges. these cells live for approximately 2 to 3 weeks. they are present throughout the connec- tive tissue compartment of the body, but they are especially numerous in regions of chronic inflamma- tion and areas that are susceptible to antigenic or microbial invasions, such as the lamina propria of the alimentary canal and respiratory tract.
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Table 6.3 PRINCIPAL PRIMARY AND SECONDARY MEDIATORS RELEASED BY MAST CELLS
Substance Type of
Mediator Source Action
histamine Primary granule increases vascular permeability, vasodilation, smooth muscle contraction of bronchi, mucus production
heparin Primary granule Anticoagulant binds and inactivates histamine
chondroitin sulfate Primary granule Binds to and inactivates histamine
Aryl sulfatase Primary granule inactivates leukotriene c4, limiting inflammatory response neutral proteases Primary granule Protein cleavage to activate complement (especially c3a);
increases inflammatory response eosinophil chemotactic
factor Primary granule Attracts eosinophils to site of inflammation
neutrophil chemotactic
factor Primary granule Attracts neutrophils to site of inflammation
leukotrienes c4, D4, and e4
secondary Membrane lipid Vasodilator; increases vascular permeability; causes contraction of bronchial smooth muscle
Prostaglandin D2 secondary Membrane lipid causes contraction of bronchial smooth muscle; increases mucus secretion; vasoconstriction
thromboxane A2 secondary Membrane lipid causes platelet aggregation, vasoconstriction Bradykinins secondary Formed by activity of
enzymes located in granules
causes vascular permeability and is responsible for pain sensation
Platelet-activating factor secondary Activated by phospholipase A2
Attracts neutrophils and eosinophils; causes vascular permeability and contraction of bronchial smooth muscle
From gartner lP, hiatt Jl: color textbook of histology, 3rd ed. Philadelphia, saunders, 2007, p 121.
Figure 6.5 Drawing of a plasma cell as observed on an electron micrograph. (From Lentz TL: Cell Fine Structure: An Atlas of Drawings of Whole-Cell Structure. Philadelphia, Saunders, 1971.)
Golgi apparatus
Mitochondrion
Rough endoplasmic reticulum Heterochromatin
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cLINIcAL coNSIDERATIoNS
Hay fever victims experience localized edema and swelling of the nasal mucosa, which hinders breathing and results in the stuffed up feeling.
These symptoms result from histamine being released by the mast cells of the nasal mucosa, increasing permeability of the small blood vessels and localized edema. Difficulty in breathing also accompanies patients with asthma resulting from leukotrienes being released in the lungs that brings about bronchospasm.
Mast cell degranulation is normally a localized condition bringing on a typical mild inflammatory response. Hyperallergic individuals are at risk, however, because they may experience systemic anaphylaxis after a second exposure to the allergen (e.g., bee sting). This exposure,
characterized by systemic and severe immediate hypersensitivity reaction, is called anaphylactic shock. The symptoms occur almost immediately to within a few minutes, and if they are left
untreated, death may occur within a few hours.
Symptoms include sudden decrease in blood pressure and shortness of breath. Wearing a medical emergency bracelet is suggested for hyperallergic individuals because it informs an emergency health provider of the need for immediate medical attention.
Normally, the extracellular fluid within the tissues is returned to capillaries directly or to lymph vessels and then to the bloodstream. During an inflammatory response, there is an accumulation of extracellular fluid within loose connective tissue that prevents the return of extracellular fluid to the bloodstream. This condition results in edema (gross swelling), which may be due to the excessive release of histamine and leukotrienes C4 and D4, products of mast cells that increase capillary permeability. Edema can also be caused by venous or lymphatic vessel obstructions.
Leukocytes
Leukocytes, or white blood cells, circulate in the blood and enter the connective tissue compartments to which they are recruited by cytokines or that they recognize by their own homing receptors (see Fig.
6.4). these cells are discussed in detail in chapters 10 and 12.
• Monocytes are discussed in the previous section on Macrophages.
• Neutrophils respond to neutrophil chemotactic factor released by mast cells to act in acute inflammation, where they phagocytose and digest bacteria. After they degranulate and destroy the bacteria, they die and become a component of pus.
• Eosinophils are recruited to the site by eosinophil chemotactic factor released by mast cells to act in acute inflammation. they kill parasites and phagocytose antibody-antigen complexes.
• Basophils are similar to mast cells and perform the same function as mast cells.
• Lymphocytes are most numerous at sites of chronic inflammation.