Acute Inflammation
Whether
inflammation should be considered part of immunology is a problem for the teaching profession, not
for the body, which combats infection by all the means at its disposal,
including mechanisms also involved in the response to, and repair of, other
types of damage.
In this simplified scheme, which
should be read from left to right, are shown the effects of injury to
tissues (top left) and to blood vessels (bottom left). The small black rods
represent bacterial infection, a very common cause of inflammation and
of course a frequent accompaniment of injury. Note the central role of permeability
of the vascular endothelium in allowing access of blood cells and serum
components (lower half) to the tissues
(upper half), which
also accounts for the main symptoms of inflammation –
redness, warmth, swelling and
pain.
It can be seen that the ‘adaptive’
(or ‘immunological’) functions of antibody
and lymphocytes largely operate to amplify or focus pre- existing ‘innate’
mechanisms; quantitatively, however, they are so important that they frequently
make the difference between life and death. Further details of the role of
antibody and lymphocytes in inflammation can be found in Figs 34–39.
Note the central importance of the
tissue mast cells and macro- phages, and the blood-derived PMNs.
Inflammation is usually localized to the area of injury or infection.
Occasionally, e.g. in sepsis, uncontrolled inflammation becomes systemic, and
causes severe illness, organ failure and ultimately death. Sepsis remains a
serious risk after major surgery. If for any reason inflammation does not die
down within a matter of days, it may become chronic, and here the macrophage
and the T lymphocyte have dominant roles (see Fig. 37).
Mast cell A large
tissue cell with
basophilic granules containing vasoactive amines and heparin. It degranulates readily in response to
injury by trauma, heat, ultraviolet light, etc. and also in some allergic
conditions (see Fig. 35).
PG, LT Prostaglandins and leukotrienes: a family of
unsaturated fatty acids (MW 300–400) derived by metabolism of arachidonic acid,
a component of most cell membranes. Individual PGs and LTs have different but
overlapping effects; together they are responsible for the induction of pain,
fever, vascular permeability and chemotaxis of PMNs, and some of them also inhibit
lymphocyte functions. Aspirin, paracetamol and other non-steroidal
anti-inflammatory drugs act principally by blocking PG production.
Vasoamines Vasoactive amines, e.g. histamine and
5-hydroxytryptamine, produced by mast cells, basophils and platelets, and
causing increased capillary permeability.
Kinin system A series of serum peptides sequentially
activated to cause vasodilatation and increased permeability.
Complement A cascading sequence of serum proteins,
activated either directly (‘alternate pathway’) or via antigen–antibody
interaction (for details see Fig. 6).
C3a and C5a These stimulate release by mast cells of their
vasoactive amines, and are known as anaphylatoxins.
Opsonization C3b attached to a particle promotes sticking to
phagocytic cells because of their ‘C3 receptors’. Antibody, if present,
augments this by binding to ‘Fc receptors’.
CRP C-reactive protein (MW 130 000), a pentameric
globulin (or ‘pentraxin’) made in the liver which appears in the serum within
hours of tissue damage or infection, and whose ancestry goes back to the
invertebrates. It binds to phosphorylcholine, which is found on the surface of
many bacteria, fixes complement and promotes phagocytosis; thus it may have an
antibody-like role in some bacterial infections. Proteins whose serum
concentration increases during inflammation are called ‘acute-phase proteins’;
they include CRP and many complement components, as well as other
microbe-binding molecules and enzyme inhibitors. This acute-phase response can
be viewed as a rapid, not very specific, attempt to deal with more or less any
type of infection or damage.
PMN Polymorphonuclear leucocyte; the major mobile
phagocytic cell, whose prompt arrival in the tissues plays a vital part in
removing invading bacteria.
Mono Monocyte: the precursor of tissue macrophages
(MAC in the figure) that is responsible for removing damaged tissue as well as
microorganisms. The tissue macrophages are also an important source of the
inflammatory cytokines tumour necrosis factor α (TNF-α), IL-1 and IL-6 (see
below).
Lysosomal enzymes Bactericidal enzymes released from the lysosomes
of PMNs, monocytes and macrophages, e.g. lysozyme, myeloperoxidase and others,
also capable of damaging normal tissues.
Inflammatory cytokines The inflammatory response is orchestrated by several cytokines, which are produced by a variety of cell types. The
most important are TNF-α, IL-6 and IL-1. All these cytokines have many
functions (they are ‘pleiotropic’), including initiating many of the changes in
the vascular endothelium that promote leucocyte entry into the inflammatory
site. They also induce the acute phase response and, later, the process of
tissue repair. IL-1 is one of the few cytokines that acts systemically, rather
than locally; e.g. through its action on the hypothalamus, it is the main
molecule responsible for inducing fever. See Figs 23 and 24 for further details
of cytokines.
Chemotaxis C5a, C3a, leukotrienes and ‘chemokines’
stimulate PMNs and monocytes to move into the tissues. Movement towards the
site of inflammation is called chemotaxis, and is due to the cells’ ability to
detect a concentration gradient of chemotactic factors; random increases of
movement are called chemokinesis.
Chemokines These are a very large family of small polypeptides,
which have a key role in chemotaxis and the regulation of leucocyte
trafficking. There are two main classes of chemokines, based on the
distribution of conserved disulphide bonds. They bind to an equally large
family of chemokine receptors, and the biology of the system is further
complicated by the fact that many of the chemokines have multiple functions,
and can bind to many different receptors. Although some have been called
interleukins (e.g. IL-8), the majority have retained separate names. They shot
to prominence when it was discovered that some of the chemokine receptors (e.g.
CCR5 receptor) served as essential coreceptors (together with CD4) for HIV to
gain entry into cells (see Fig. 28).
Adhesion and cell traffic Changes in the expression of endothelial
surface molecules, induced mainly by cytokines, cause PMNs, monocytes and
lymphocytes to slow down and subsequently adhere to the vessel wall. These
‘adhesion molecules’ and the molecules they bind to fall into well-defined
groups (selectins, integrins, the Ig super family; see Fig. 10). These changes,
together with the selective local release of chemokines, regulate the
changes in cell traffic that underlie all inflammatory responses.
T lymphocyte T lymphocyte, undergoing proliferation and activation
when stimulated by antigen, as is the case in most infections. By releasing
cytokines such as interferon-γ (IFN-γ) (see Figs 23, 24), T cells can greatly
increase the activity of macrophages.
Clotting system Intimately bound up with complement and kinins
because of several shared activation steps. Blood clotting is a vital part of
the healing process.
Fibrin The end product of blood clotting and, in the
tissues, the matrix into which fibroblasts migrate to initiate healing.
Fibroblast An important tissue cell that migrates into the
fibrin clot and secretes collagen, an enormously strong polymerizing
molecule giving the healing wound its strength and elasticity. Subsequently new
blood capillaries sprout into the area, leading eventually to restoration
of the normal architecture.
