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•The endothelium is located at the interface between the blood and the
vessel wall.
•The cells are in close contact and form a slick layer that prevents
blood cell interaction with the vessel wall as blood moves through the
vessel lumen.
•The endothelium consists of simple squamous epithelium that lines
the lumen of all blood vessels.
•It plays a critical role in the mechanics of blood flow, the regulation of
coagulation, leukocyte adhesion, and vascular smooth muscle cell
growth, and also serves as a barrier to the transvascular diffusion of
liquids and solutes.
•For years the endothelium was thought of as an inert single layer of
cells that passively allowing the passage of water and other small
molecules across the vessel wall.
• However, this dynamic tissue performs many other active functions,
such as the secretion and modification of vasoactive substances and
the contraction and relaxation of vascular smooth muscle.
Leukocytes
The cellular components of blood include erythrocytes (red blood cells), leukocytes
(white blood cells), and platelets. Normal human blood contains 4.8 - 5.2 million
erythrocytes/ml and 4000 - 10,000 leukocytes/ml. Leukocytes are divided into five
classes based on morphological and tinctorial characteristics when stained. The
five classes of leukocytes are:
Eosinophils
Eosinophils migrate from the marrow through the blood into the
extravascular tissue, and they survive there for weeks. Again,
chemoattractants direct the movement of eosinophils, and like
neutrophils, eosinophils are phagocytic. They do not ingest organisms,
but they do exert cytotoxic effects on them.
Basophils
Basophils are morphologically similar to mast cells, and along with other
granulocytes, basophils are motile cells with phagocytic properties. They
may migrate into extravascular tissues where they may be stimulated by
complexes of antigens that are bound to IgE.
Monocytes
Monocytes are larger than other leukocytes, and they mature into
macrophages once they are released into the bloodstream. Monocytes then
migrate to tissues, particularly the liver, lymph nodes, and lungs, where they
may stay for days or years. Here, the monocytes are actively phagocytic, and
they ingest particulate matter. Monocytes are also important to the immune
response. They ingest and process antigens and are involved in antigen
presentation, by B- and T-lymphocytes.
Lymphocytes
Two main types of lymphocytes are B-cells and T-cells. B-cells are
characterized by the presence of immunoglobulins on their surface, and upon
stimulation with antigen, they are transformed into plasma cells. Plasma cells
are then able to secrete antibodies specific to the antigen. T-cells take part in
cell mediated immune response, which does not depend on the presence of
circulating antibodies.
Selectins
Selectins are a family of transmembrane molecules, expressed on the surface of leukocytes and
activated endothelial cells. Selectins contain an N-terminal extracellular domain with structural homology
to calcium-dependent lectins, followed by a domain homologous to epidermal growth factor, and two to
nine consensus repeats (CR) similiar to sequences found in complement regulatory proteins. Each of
these adhesion receptors is inserted via a hydrophobic transmembrane domain and possesses a short
cytoplasmic tail. The initial attachment of leukocytes, during inflammation, from the blood stream is
afforded by the selectin family, and causes a slow downstream movement of leukocytes along the
endothelium via transient, reversible, adhesive interactions called leukocyte rolling. Each of the three
selectins can mediate leukocyte rolling given the appropriate conditions.
L-selectin is the smallest of the vascular selectins, and can be found on most leukocytes. P-selectin, the
largest selectin, is expressed on activated platelets and endothelial cells primarily. E-selectin is
expressed on activated endothelium with chemically or cytokine-induced inflammation.
L-Selectin
P-Selectin
E-Selectin
Slow Rolling
•After induction of inflammation by injection of a pro-inflammatory cytokine like
TNF- , leukocyte rolling velocity drops dramatically to an average between 5
and 10 µm/s
•This rolling requires the expression of E-selectin on endothelial cells and
CD18 integrins on the rolling leukocytes and has been termed "slow rolling" to
distinguish it from the much faster rolling without cytokine stimulation.
•Slow rolling can be reproduced in vitro on substrates of E-selectin and, at
equivalent site densities, P-selectin.
•This suggests that slow rolling is not based on a unique property of E-selectin,
but the expression of E-selectin and/or its ligands appears to be sufficiently
high in vivo to support slow rolling..
This slide shows the muscle coats and peritoneum of a
normal appendix. The peritoneal surface runs diagonally
across the upper right hand corner. It is covered by a layer
of mesothelial cells (not apparent in this picture) underlying
which is a layer of pale staining fibrous tissue in which are
a few small blood vessels. The outer longitudinal and inner
circular muscle coats consist of smooth muscle with a few
small blood vessels.
Pseudomembranous inflammation
The term 'pseudomembranous' describes superficial mucosal ulceration with an
overlying slough of disrupted mucosa, fibrin, mucus and inflammatory cells. This
is seen in pseudomembranous colitis due to Clostridium difficile colonisation of
the bowel, usually following broad-spectrum antibiotic treatment.
The neutrophil is the main cell to mediate the effects of acute inflammation. If
tissue damage is slight, an adequate supply is derived from normal numbers
circulating in blood. If tissue damage is extensive, stores of neutrophils,
including some immature forms, are released from bone marrow to increase the
absolute count of neutrophils in the blood. To maintain the supply of neutrophils,
growth factors derived from the inflammatory process stimulate division of
myeloid precursors in the bone marrow, thereby increasing the number of
developing neutrophils.
Chemical mediators released from cells
•Histamine. This is the best-known chemical mediator in acute inflammation. It causes
vascular dilatation and the immediate transient phase of increased vascular
permeability. It is stored in mast cells, basophil and eosinophil leukocytes, and
platelets. Histamine release from those sites (for example, mast cell degranulation) is
stimulated by complement components C3a and C5a, and by Iysosomal proteins
released from neutrophils.
•Lysosomal compounds. These are released from neutrophils and include cationic
proteins, which may increase vascular permeability, and neutral proteases, which may
activate complement.
•Prostaglandins. These are a group of long-chain fatty acids derived from arachidonic
acid and synthesised by many cell types. Some prostaglandins potentiate the increase
in vascular permeability caused by other compounds. Others include platelet
aggregation (prostaglandin 1. is inhibitory while prostaglandin A2 is stimulatory). Part of
the anti-inflammatory activity of drugs such as aspirin and the non-steroidal anti-
inflammatory drugs is attributable to inhibition of one of the enzymes involved in
prostaglandin synthesis.
•Leukotrienes. These arc also synthesised from arachidonic acid, especially in
neutrophils, and appear to have vasoactive properties. SRS-A (slow reacting substance
of anaphylaxis), involved in type I hypersensitivity, is a mixture of leukotrienes.
•5-hydroxytryptamine (serotonin). This is present in high concentration in mast cells
and platelets. It is a potent vasoconstrictor.
•Lymphokines. This family of chemical messengers released by Iymphocytes. Apart
from their major role in type IV hypersensitivity, Iymphokines may also have vasoactive
or chemotactic properties.
Role of the Neutrophil Polymorph
The neutrophil polymorph is the characteristic cell of the acute inflammatory infiltrate. The actions of
this cell will now be considered.
Movement
Contraction of cytoplasmic microtubules and gel/sol changes in cytoplasmic fluidity bring
about amoeboid movement. These active mechanisms are dependent upon calcium ions and
are controlled by intracellular concentrations of cyclic nucleotides. The movement shows a
directional response (chemotaxis) to various chemicals.
Adhesion to micro-organisms
Micro-organisms are opsonised (from the Greek word meaning 'to prepare for the table'), or
rendered more amenable to phagocytosis, either by immunoglobulins or by complement
components. Bacterial lipopolysaccharides activate complement via the alternative pathway,
generating component C3b which has opsonising properties. In addition, if antibody binds to
bacterial antigens, this can activate complement via the classical pathway, also generating
C3b. In the immune individual, the binding of immunoglobulins to micro-organisms by their
Fab components leaves the Fc component exposed. Neutrophils have surface receptors for
the Fc fragment of immunoglobulins, and consequently bind to the micro-organisms prior to
ingestion.
Phagocytosis
The process whereby cells (such as neutrophil polymorphs and macrophages) ingest solid
particles is termed phagocytosis. The first step in phagocytosis is adhesion of the particle to
be phagocytosed to the cell surface. This is facilitated by opsonisation. 'The phagocyte then
ingests the attached particle by sending out pseudopodia around it. These meet and fuse so
that the particle lies in a phagocytic vacuole (also called a phagosome) bounded by cell
membrane. Lysosomes, membrane-bound packets containing the toxic compounds described
below, then fuse with phagosomes to form phagolysosomes. It is within these that intracellular
killing of micro-organisms occurs.
Intracellular killing of micro-organisms
Neutrophil polymorphs are highly specialised cells, containing noxious microbial
agents, some of which are similar to household bleach. The microbial agents may be
classified as:
those which are oxygen-dependent
those which are oxygen-independent.
Oxygen-dependent mechanisms. The neutrophils produce hydrogen peroxide which
reacts with myeloperoxidase in the cytoplasmic granules in the presence of halide,
such as Cl, to produce a potent microbial agent. Other products of oxygen reduction
also contribute to the killing, such as peroxide anions (O2-), hydroxyl radicals (.OH)
and singlet oxygen (1O2).
Oxygen-independent mechanisms. These include Iysozyme (muramidase), lactoferrin
which chelates iron required for bacterial growth, cationic proteins, and the low pH
inside phagocytic vacuoles.
Release of lysosomal products
Release of Iysosomal products from the cell damages local tissues by proteolysis by
enzymes such as elastase and collagenase, activates coagulation factor XII, and
attracts other leukocytes into the area. Some of the compounds released increase
vascular permeability, while others are pyrogens, producing systemic fever by acting
on the hypothalamus.
Role of the Lymphatics
Terminal Iymphatics are blind-ended, endothelium-lined tubes present in most tissues in
similar numbers to capillaries. The terminal Iymphatics drain into collecting Iymphatics
which have valves and so propel Iymph passively, aided by contraction of neighbouring
muscles, to the Iymph nodes. The basal lamina of Iymphatic endothelium is incomplete,
and the junctions between the cells are simpler and less robust than those between
capillary endothelial cells. Hence, gaps tend to open up passively between the Iymphatic
endothelial cells,allowing large protein molecules to enter.
In acute inflammation, the Iymphatic channels become dilated as they drain away the
oedema fluid of the inflammatory exudate. This drainage tends to limit the extent of
oedema in the tissues. The ability of the Iymphatics to carry large molecules and some
particulate matter is important in the immune response to infecting agents; antigens are
carried to the regional Iymph nodes for recognition by Iymphocytes.
• Mycobacterium tuberculosis.
The red - stained, elongated organisms shown here are
M. tuberculosis within macrophages in a tuberculous
abscess. Mycobacteria have a thick, waxy cell wall that
protects them against the enzymic and other
mechanisms used by macrophages to inactivate
organisms. They are thus able to survive for prolonged
periods within macrophages and so are also protected
against other cellular and humoral mechanisms for
dealing with invading organisms. (Ziehl-Neelsen stain).
4. Syphilis.
This illustration shows the organisms Treponema
pallidum in a syphilitic lesion in the brain. Such
lesions are now rare, since the disease is treatable
with antibiotics such as the penicillins. (Levaditi
silver stain).
Chronic Inflammation
• Infectious organisms that can avoid or resist host defences and so persist in the tissue for a prolonged
period. Examples include Mycobacterium tuberculosis, Actinomycetes, and numerous fungi, protozoa
and metazoal parasites. Such organisms are in general able to avoid phagocytosis or survive within
phagocytic cells, and tend not to produce toxins causing acute tissue damage.
• Infectious organisms that are not innately resistant but persist in damaged regions where they are
protected from host defences. The common example here is of bacteria which grow in the pus within an
undrained abscess cavity, where they are protected both from host immunity and from blood-borne
theraputic agents, e.g. antibiotics. Some locations are particularly prone to chronic abscess formation,
e.g. bone, pleural cavities.
• Irritant non-living foreign material that cannot be removed by enzymic breakdown or phagocytosis.
Examples include a wide range of materials implanted into wounds (wood splinters, grit, metals and
plastics), inhaled (silica dust and other particles or fibres), or deliberately introduced (surgical
prostheses, sutures, etc.). Dead tissue components that cannot be broken down may have similar
effects, e.g. keratin squames from a ruptured epidermoid cyst or fragments of dead bone (sequestrum)
in osteomyelitis.
• In some cases the stimulus to chronic inflammation may be a "normal" tissue component. This occurs
in inflammatory diseases where the disease process is initated and maintained because of an
abnormality in the regulation of the body's immune reponse to its own tissues - the so-called auto-
immune diseases.
• For many diseases characterised by a chronic inflammatory pathological process the underlying cause
remains unknown. A good example here is Crohn's disease of the intestine.
Histological appearances in chronic inflammation:
The microscopic appearances of chronic inflammation vary considerably according to the site involved
and the causative stimulus. However, the general features are:
• Tissue destruction (necrosis) caused both by the causative agent and by the inflammatory process
itself.
• Attempts at reconstructing the damaged tissue occur simultaneously with the inflammatory
process. These can be considered under the general title of healing and repair. The attempts at
reconstruction may have different outcomes. If there is little tissue destruction then some organs
may be able to regenerate their original structure, or mild inflammation may terminate by resolution
without causing any structural damage. Commonly, however, the original structure cannot be re-
created and the damaged area undergoes repair.This involves removal of the destroyed tissue by
phagocytosis with proliferation of capillary blood vessels and lymphatics into the lesion together
with fibroblasts and collagen production (so-called granulation tissue), ending up with a dense
fibrous scar.
4. Plasma cells:
These distinctive looking cells have an
eccentrically placed nucleus with coarse, blotchy
staining of the chromatin, said to resemble a clock
face. The cytoplasm is rather blue staining
(basophilic), reflecting its high content of rough
endoplasmic reticulum with large numbers of
ribosomes containing ribosomal RNA. There is also
a prominent pale area of cytoplasm next to the
nucleus - the Golgi apparatus. Plasma cells are
mature, end-stage cells of the B-lymphocyte
lineage, specialised for antibody production and
secretion.
5.Lymphoid follicles:
This is a lymphoid follicle producing lymphocytes
within thyroid tissue during the chronic inflammatory
process which destroys the gland in Hashimoto's
Disease. The inflammation is triggered and maintained
by abnormal sensitivity of the immune system against
its own thyroid tissue - i.e. an auto-immune disease.
The follicle is a structured aggregate of lymphoid cells,
with a central region of large, pale - staining, actively
proliferating precursor cells and a mantle zone of
closely packed mature lymphocytes recognizable by
their small, round, intensely blue/black nuclei.
3. Mast cell
5. Platelet
7. Vascular endothelium
Granulomatous Inflammation:
Structure of a granuloma.
Granulomas are aggregates of particular types of chronic inflamatory cells which form nodules in the
milimetre size range. Granulomas may be confluent, forming larger areas.The essential components
of a granuloma are collections of modified macrophages, termed epithelioid cells, usually with a
surrounding zone of lymphocytes. (Epithelioid cells are so named by tradition because of their
histological resemblance to epithelial cells, but are not in fact epithelial; they are derived from blood
monocytes, like all macrophages.) Epithelioid cells are less phagocytic than other macrophages and
appear to be modified for secretory functions. The full extent of their functions is still unclear.
Macrophages in granulomas are commonly further modified to form multinucleate giant cells.These
arise by fusion of epithelioid macrophages without nuclear or cellular division forming huge single cells
which may contain dozens of nuclei. In some circumstances the nuclei are arranged round the
periphery of the cell, termed a Langhans-type giant cell (characteristically seen in tuberculosis); in
other circumstances the nuclei are randomly scattered throughout the cytoplasm - for example in the
foreign body type of giant cell which is formed in response to the presence of other indigestible foreign
material in the tissue.
Areas of granulomatous inflammation commonly undergo necrosis. The prototype example here is
caseous necrosis in tuberculosis.
• Foreign bodies:
Endogenous: e.g. keratin, necrotic boneor adipose tissue, uric acid
crystals (gout).
Exogenous: e.g. wood, grit, silica or asbestos dust, talc, suture
material, silicone, prostheses.