Within the spectrum of systemic reaction to inflammation two
physiological responses in particular are regarded as being
associated with
acute inflammation. The first involves the
alteration of the temperature set-point in the hypotalamus and the
generation of the febrile response. The second involves
alterations in metabolism and gene regulation in the liver. Three
cytokines that are released from the site of tissue injury
-- IL-1, TNF-
and IL-6 are considered to regulate the febrile
response, possibly as a protective mechanism. These cytokines
mediate fever through the
induction of PGE
. At the same time,
IL-1 and IL-6 can act on the adrenal pituitary axis to generate
adrenocorticotropic hormone (ACTH) and, subsequently, induce the
production of cortisol. This provides a negative feedback loop,
since corticosteroids inhibit cytokine gene-expression.
It is important to consider the acute phase response (and inflammation) as a dynamic homeostatic process that involves all of the major systems of the body, in addition to the immune, cardiovascular and central nervous system. Normally, the acute phase response lasts only a few days; however, in cases of chronic or recurring inflammation, an aberrant continuation of some aspects of the acute phase response may contribute to the underlying tissue damage that accopanies the disease, and may also lead to further complications, for example cardiovascular diseases or protein deposition diseases such as reactive amyloidosis.
The second important aspect of the acute phase response is the radically altered biosynthetic profile of the liver. Under normal circumstances, the liver synthesizes a characteristic range of plasma proteins at steady state concentrations. Many of these proteins have important functions and higher plasma levels of these acute phase reactants (APRs) or acute phase proteins (APPs) are required during the acute phase response following an inflammatory stimulus. Although most APRs are synthesized by hepatocytes, some are produced by other cell types, including monocytes, endothelial cells, fibroblasts and adipocytes. Most APRs are induced between 50% and several-fold over normal levels. In contrast, the major APRs can increase to 1000-fold over normal levels. This group includes serum amyloid A (SAA) and either C-reactive protein (CRP) in humans or its homologue in mice, serum amyloid P component (SAP). So-called negative APRs are decreased in plasma concentration during the acute phase response to allow an increase in the capacity of the liver to synthesize the induced APRs. The list of APRs is in Table 1.12.
Table 1.12: Acute phase reactants
APRs have a wide range of activities that contribute to host defence: they can directly neutralize inflammatory agents, help to minimize the extent of local tissue damage, as well as participate in tissue repair and regeneration. There is a rapid increase in the plasma concentration of many complement cascade components the activation of which ultimately results in the local accumulation of neutrophils, macrophages and plasma proteins. These participate in the killing of infectious agents, the clearance of foreign and host cellular debris, and the repair of damaged tissue. Coagulation components, such as fibrinogen, play an essential role in promoting wound healing.
Proteinase inhibitors neutralize the lysosomal proteases released following the infiltration of activated neutrophils and macrophages, thus controlling the activity of the proinflammatory enzyme cascades. The increased plasma levels of some metal-binding proteins help prevent iron loss during infection and injury, also minimizing the level of haem iron avaible for uptake by bacteria and acting as scavenger for potentially damaging oxygen free radicals.
The
major APRs in mammals include serum amyloid
A (SAA) and either C-reactive protein (CRP) or serum
amyloid P component 
depending on the species. Ironically,
of all the APRs, the activities of these three are among the least
well-known. Nevertheless, their interactions with other
well-defined defence systems and the magnitute and rapidity of
their induction following an acute phase stimulus, together with
their short half-lifes, suggest a particularly critical
requirement for these proteins very early in the establishment of
host defence. Significantly, individuals unable to synthesize
these proteins have not been described; these major APRs are
therefore likely to be of considerable clinical importance.
CRP and
SAP are pentraxins, proteins with
a characteristic pentameric organization of identical subunits
arraged as single and double annular pentagonal discs,
respectively. Generally, only one of these proteins is an APR in
a given mammalian species: in humans, normal plasma SAP levels are
approximately 30mg.L
and remain constant during inflammation
but CRP levels can increase up to 1000-fold from approximately
1mg.L
, depending on the disease and its severity. CRP was
originally named for its ability to bind the C-polysaccharide of
Pneumococcus and has since been shown to have a number of
calcium-dependent binding specificities and biological avtivities
related to nonspecific host defence. It acts as an opsonin for
bacteria, parasites and immune complexes, and can activate the
classical pathway of complement. SAP is the circulating form of
amyloid P component, which is a constituent of all types of
amyloid deposits.
SAA is the collective name given to a family of polymorphic proteins encoded by multiple genes in a number of mammalian species. Functionally, SAAs are small apolipoproteins that associate rapidly during the acute phase response with the third fraction of high-density lipoprotein (HDL3), on which they become the predominant apolipoprotein. SAA enhances the binding of HDL3 to macrophages during inflammation, concomitant with a decrease in the binding capacity of HDL3 to hepatocytes. It suggest that SAA may remodel HDL3 and act as a signal to redirect it from hepatocytes to macrophages, which can then engulf cholesterol and lipid debris at sites of necrosis. Excess cholesterol could thus be redistributed for use in tissue repair or excreted. Other putative protective roles for SAA are the inhibition of thrombin-induced platelet activation, as well as inhibition of the oxidative burst in neutrophils, which would help prevent oxidative tissue destruction.
The exquisite responsiveness of CRP to acute phase stimuli, along with its wide concentration range and ease of measurement, have led to plasma CRP levels being used to monitor accurately the severity of inflammation and the efficacy of disease management during an infection. Conversely, some diseases (e.g. systemic lupus erythematosus) are associated with relatively low plasma levels of CRP.
SAA and SAP are archetypal examples of plasma proteins that are likely to be beneficial during the transient acute phase response but which have detrimental effects in chronic inflammation. These major APRs have been implicated in a number of clinical conditions. Secondary, or reactive amyloidosis is the occasional consequence of a variety of chronic and recurrent inflammatory diseases, for example leprosy, tuberculosis, systemic lupus erythematosus and rheumatoid arthritis. It is characterized by the ultimately fatal deposition of insoluble fibrils in a number of tissues, including spleen, liver and kidney. Secondary amyloid deposits are composed mainly of amyloid A derived (probably by proteolysis) from the precursor SAA. Amyloid P component (AP), derived from SAP, is associated with secondary AA plaques and all other forms of amyloid deposits, including those present in Alzheimer's disease, AP has also been shown to act as an elastase inhibitor, which suggest a role for SAP on amyloid deposit in protecting the fibrils from degradation by proteolytic enzymes.
APR synthesis is under control performed by inflammatory mediators from which several cytokines and hormones specifically regulate the transcription of human APRs (Figure 1.5).
Figure 1.5:
Inflammatory mediators that modulate hepatic APR synthesis
in humans
These include TNF-
, IL-1, IL-6, IL-11, IFN-
, LIF, OSM,
CNTF, TGF-
, and glucocorticoids. In addition, insulin and akadaic
acid have recently been shown to act as inhibitors of the
cytokine-driven induction of some APRs. There is considerable
heterogeneity in the response of individual APR genes to the
listed cytokines. An important feature of the acute phase response
is that IL-1 and TNF-
stimulate, via the CNS, the synthesis of
glucocorticoids by the adrenal glands, which results in
co-operative enhancement of the IL-1 and
TNF-
-mediated induction
of APR synthesis in the liver. This effect is coincident with the
glucocorticoid-mediated down regulation of IL-1 synthesis by
macrophages, thereby creating a negative-feedback loop between the
immune and CNS systems to reduce de novo cytokine synthesis.
Most of the increase (or decrease, in the case of negative APRs)
in APR biosynthesis is due to increased (or decreased) gene
transcription.