Acute Phase Response. Introduction

Introduction. First described by the Greeks and the Romans, the humoral theory of inflammation held well into the 18th century. The work by Hunter, Virchow, Cohnheim, and Metchnikoff described in more detail the way the cells of the body contribute to this response. These descriptions formed the basis for our current understanding of the homeostatic response to injury. We are now aware that while the cellular components are integral to the response, there are a variety of humoral mediators that orchestrate the response.

After the body has been damaged by infection or insult, a series of local and systemic events occurs. At the local tissue level there is dilation and leakage of the blood vessels, particularly the postcapillary venules, giving rise to the redness due to the presence of intact red blood cells in the tissue, or hemoglobin in the event of hemorrhage and hemolysis.

There is aggregation of platelets in the vessels and an early flux and accumulation of neutrophils and monocyte/macrophages, with associated activation of these cells and release of tissue-damaging proteinases and other lysosomal enzymes. In addition, there is activation of most of the local tissue cellular components affected by the injury, with the release of significant amounts of various mediators, resulting in the initiation of a series of systemic responses.

It is these systemic changes, particularly the changes to the blood constituents, that are more appropriately termed the acute phase response. The changes include fever and pain and possible activation of the major biochemical pathways in the plasma, complement, and coagulation, as well as the kininogen/fibrinolysis sequence. There are changes in the cellular content of the blood, with increases in leukocyte counts and activation of many of the phagocytic cells. This activation, particularly of the peripheral blood monocytes, results in the release of a number of protein hormone-like polypeptides or cytokines, along with highly potent metabolites of arachidonic acid: the prostaglandins and leukotrienes.

The most prominent change is seen in the plasma protein constituents as a result of the response of the liver. The plasma shows a marked decrease in iron and zinc levels and a dramatic increase in the levels of a series of proteins, synthesized by the hepatocyte, termed the acute phase proteins. At the same time, there is a marked uptake of amino acids by the liver, apparently transferred from the muscles.

Discoveries in the 1980s demonstrated that the local cells release cytokines that not only mediate the systemic humoral changes, but also result in the cellular influx and activation seen in the acute phase. Thus, resident cells “talk” to mobile cells via these cytokines and directly cause the accumulation of inflammatory cells in the tissues. The acute phase response is part of the overall homeostatic response involving inflammation, tissue repair, and immune regulation.

It is a normal process which occurs frequently and has been preserved throughout phylogeny, implying its fundamental role in the survival of the organism. While documentation of the acute phase response in humans has depended on pathological examination, there have been major recent advances made in our understanding of the response using animal models of inflammation.

One model involves the intraperitoneal or intravenous injection of killed bacteria, the bacterial cell wall, or purified lipopolysaccharides, otherwise known as endotoxins. While the purified material is still relatively complex, it represents a standardized way of determining an in vivo response to challenge, which can also be used in vitro for correlation. Moreover, there are species and strain differences in response to lipopolysaccharides which can be exploited to better define the cellular and molecular mechanisms in inflammation.

A second model involves local injection of a chemical irritant (e.g., turpentine, carrageenan, or silver nitrate), or the deposition in tissue of insoluble agents (e.g., talc or celite). These agents illicit both local and systemic acute major responses and, depending on the species, might establish complicated chronic and secondary adaptive responses. Turpentine appears to cause acute phase responses in all species and strains.

A third model uses direct tissue injury, such as that caused by thermal application or X-irradiation, resulting in tissue necrosis. It is important to recognize that some aspects of the acute phase response can only be studied in vivo (e.g., fever or leukocytosis), while other aspects, including cellular or molecular mechanisms, can be studied in vitro. Techniques such as isolated hepatocyte cultures and chemotaxis assays have shown that specific molecules in circulation during the acute phase response can mimic the in vivo response in vitro, and they are thereby implicated in the primary response of the body to challenge.