The acute phase response

Abstract Mild infection or sublethal dose of endotoxin elicit a brief elevation, of growth hormone (GH)and prolactin (PRL) in the serum. These hormones are pro-inflammatory and immunostimulatory. In severe trauma, sepsis and shock, GH and PRL are suppressed, whercas glucocorticoids and catecholamines are elevated. Under these conditions an, acute phase response is induced by immune-derived cytokines, primarily IL-1, IL-6, TNFα, which elicit a neuroendocrine response and initiate major metabolic alterations. Fever and catabolism prevails, whereas the synthesis of acute phase proteins in the liver, cell proliferation in the bone marrow, and protein synthesis by leukocytes is elevated. This is an emergency reaction to save the organism after the adaptive immune system has failed to contain and eliminate the infectious agent. During sepsis and endotoxin shock the systemic activation of the complement system and of leukocyte-derived relaasing enzymes, tissue-derived brake-down products and highly toxic cytokines seriously threaten survival. Glucocorticoids regulate pro-inflammatory cytokine production and potentiate the secretion of acute phase proteins into the serum. Some of these proteins, such as C reactive protein, LPS binding protein and mannose binding protein are designed to combine with microorganisms and trigger their destruction by the activation of the complement system and of phagocytes. The increased production of some complement components also helps host resistance. The rise in serum fibrinogen promotes blood clotting, which can serve to isolate the invading agent by triggering thrombosis in infected tissues. A number of enzyme inhibitors are produced as acute phase proteins, which are likely to serve to curb the nonspecific damage inflicted by enzymes released from activated phagocytes and from damaged cells. Catecholamines are elevated, which serve to inhibit inflammatory responses and to promote, even initiate, the acute phase response. Serum leptin is also increased, which governs energy metabolism and it is a major stimulator of the immune system. If the acute phase reaction fails to protect the host, shock will develop. Patients with subclinical adrenal insufficiency succumb to septic shock almost invariably if glucocorticoid therapy is not given. However, glucocorticoid treatment of septic patients with normal adrenal function has not been helpful. During the acute phase response the T-cell regulated adaptive immune response is switched off and natural immune mechanisms are amplified several hundred to a thousand times within 24–48 hours. This phenomenon has been designated as immunoconversion. Immunoconversion is initiated by immune derived cytokines, and involves profound neuroendocrine and metabolic changes, all in the interest of host defence. Thus, natural immunity is essential for a first and last line of defence and the neuroendocrine system is an important promoter and regulator of this fundamental form of immune defence