Once leukocytes have arrived at a site of infection or inflammation, they release mediators which control the later accumulation and activation of other cells. However, in inflammatory reactions initiated by the immune system, the ultimate control is exerted by the antigen itself, in the same way as it controls the immune response itself. For this reason, the cellular accumulation at the site of chronic infection, or in autoimmune reactions (where the antigen cannot ultimately be eradicated), is quite different from that at sites where the antigenic stimulus is rapidly cleared.
There are four major plasma enzyme systems which have an important role in haemostasis and control of inflammation. These are the complement system, the clotting system, the fibrinolytic (plasmin) system and the kinin system.
Inflammatory mediators are soluble, diffusible molecules that act locally at the site of tissue damage and infection, and at more distant sites. They can be divided into exogenous and endogenous mediators.
Bacterial products and toxins can act as exogenous mediators of inflammation. Notable among these is endotoxin, or LPS of Gram-negative bacteria. The immune system of higher organisms has probably evolved in a veritable sea of endotoxin, so it is perhaps not surprising that this substance avokes powerful responses. For example, endotoxin can trigger complement activation, resulting in the formation of anaphylatoxins C3a and C5a which cause vasodilation and increase vascular permeability. Endotoxin also activates the Hageman factor, leading to activation of both the coagulation and fibrinolytic pathways as well as the kinin system. In addition, endotoxin elicit T cell proliferation, and have been described as superantigen for T cells.
Endogenous mediators of inflammation are produced from within the (innate and adaptive) immune system itself, as well as other systems. For example, they can be derived from molecules that are normally present in the plasma in an inactive form, such as peptide fragments of some components of complement, coagulation, and kinin systems. Mediators of inflammatory responses are also released at the site of injury by a number of cell types that either contain them as preformed molecules within storage granules, e.g. histamine, or which can rapidly switch on the machinery required to synthesize the mediators when they are required, for example to produce metabolites of arachidonic acid.
Mononuclear phagocytes (monocytes and macrophages) are central to inflammation, as they produce many components which participate in or regulate the different plasma enzyme systems, and hence the mediators of the inflammatory response. They are also actively phagocytic and are involved in microbial killing, as are neutrophils. While the latter can be thought of as short-lived kamikaze cells that need to be continually replaced from the bone marrow, mononuclear phagocytes are long-lived and some can proliferate in situ. Other cells such as mast cells and basophils are much less phagocytic, but together with platelets, these cells are particularly important for secretion of vasoactive mediators. The function of these cell types is at least partially under the control of cytokines. All inflammatory cells have receptors for Fc domains of immunoglobulins and for complement components, and they possess specialized granules containing an immerse variety of products that are released perhaps by common mechanisms. Cytotoxic T lymphocytes and NK cells, in general, also possess granules which are important for their cytotoxic function. In general, lymphocytes are involved in the adaptive response to inflammation, and the early events of inflammation are mediated in part by molecules produced by cells of the innate arm of the immune system.
Early phase mediators are produced by mast cells and platelets. They are especially important in acute inflammation and include mainly histamine, serotonin and other vasoactive substances. Platelets may contribute to inflammatory responses resulting as a consequence of tissue injury, through a variety of mechanisms including:
To the early phase mediators
also belong chemoatractants (e.g. C5a) and cytokines such as
IL-1, IL-6, and TNF-
.
Late phase mediators are responsible for the regulation of vascular events occuring later -- from about 6--12 hours after initiation of inflammation. The later vascular events are mediated, at least in part, by products of arachidonic acid.
The chemical mediators of inflammation are summarized in Table 1.6. There is considerable functional redundancy of the mediators by inflammation. This explains why certain patients may have complete absence of a humoral component (e.g., complement component C3), yet minimal problems with increased susceptibility to infection.
Table 1.6: Mediators of inflammation
Edema formation can be separated from phagocyte recruitment.
Vasodilation in response to histamine,
bradykinin, PGE
and
PGI
, and complement fragments C3a and C5a results from a direct
action of these substances on endothelial cells and smooth muscle
vasculature with resulting leakage of plasma. This is accompanied
by release of mediators, such
as C5a, LTB
, and PAF, that act
directly on the phagocytic cells. In addition N-formyl peptides
are released from bacteria and mitochondria of damaged tissues.
These mediators are potent chemoattractants that mobilize
neutrophils, monocytes, and eosinophils, cause release of
lysosomal contents, and activate the respiratory burst of the
phagocytes with resulting production of toxic oxygen products.
Following intravenous endotoxin, a characteristic change in
body temperature and white blood count is observed. The body
temperature begins to increase after about one hour and reaches a
maximum at about four hours. The leukocyte count shows a
characteristic decrease at about 30 min, due to neutrophil and
monocyte adherence to endothelial cells in the lung and spleen.
This is followed by a leukocytosis characterized by the presence
of immature neutrophils at about four hours, which can persist
throughout 24 hr with gradual return to baseline by 48 hr. The
leukocytosis is predominantly due to mobilization of immature
neutrophils from the bone marrow. The critical components of the
inflammatory response -- fever, neutrophil margination in the
circulary vessels, and then mobilization from the bone marrow --
are associated with readily detected changes in circulating levels
of certain mediators of inflammation. For example,
TNF-
peaks
within two hours and is likely the predominant pyrogen associated
with the febrile response. Plasma levels of the chemoattractant
IL-8 increase early and peak by four hours. Early increases in
IL-8 may relate to the transient decrease in the neutrophil count
at 30 min (margination).
Mediator accumulation at local inflammatory processes in skin
blisters is somewhat different from the systemic effects following
intravenous endotoxin. Mediators detected in blister fluid within
3 to 5 hr of the inflammatory response
included LTB
, C5a, IL-8
and IL-6. In contrast
IL-1
, GM-CSF, and TNF-
were not detected
until after 8 hr in the blister. Thus the endotoxin and skin
blister models of inflammation demonstrate that there are clear
differences in the mediators that can be detected systemically and
locally.