Sepsis and Tumor Necrosis

that Cannot

Be

Factor Bedfellows Ignored

tremendous research effort has been expended by surgeons in the past half century to understand the mediators and modulators associated with severe infection. It has been reasoned that if the mechanisms underlying the hypotension, fluid sequestration, coagulation abnormalities, accelerated erosion of lean body mass, depressed immunity, impaired wound repair, and progressive tissue and organ damage could be defined, then therapeutic strategies could be developed to counteract these adverse events. Nature has, however, been singularly reluctant to share with us these secrets. The afferent signals that initiate changes during critical illness are clearly active at concentrations close to the lower limits of detection, using the most sophisticated, state-of-the-art assay techniques. Furthermore, unlike conventional hormones, these signals often are generated locally within fixed tissues and initiate important alterations in the cells of origin or adjacent tissues without appearing in the circulation. Despite these limitations, 'mediator research' has described a number of important active molecules-for example we have now identified up to 10 interleukins and the list is growing. But how do we know which of these molecules is clinically significant? This fundamental issue was recognized many years ago by the great British physiologist, Sir Henry Hallett Dale, who commented, 'The discovery in artificial extract from an organ or tissue of a substance which on artificial injection produces a pharmacodynamic effect provides only a first item of presumptive evidence in support of a theory that the action of this substance plays a part in normal inflammation." Tremendous enthusiasm is generated whenever novel mediators are characterized and this has been the case with the discovery of histamine, cortisone, and more recently fibronectin, interleukin- 1, and many others. However, when the criteria originally proposed by Koch to demonstrate a relationship between an infective agent and a particular disease are applied, it has been difficult to argue convincingly for a major role for many of the more recently described mediators in critical illness. The single exception has been tumor necrosis factor (TNF/cachectin), a polypeptide product of activated reticuloendothelial cells, whose importance appears to be enhanced rather than diminished by the passage of time. In fact the criteria originally proposed by Koch have now been shown to be fulfilled by this cytokine, about which the following points can be made: (1) It can be found in the circulation at the onset of critical infective illness. Early attempts to demonstrate TNF in the circulation were largely unsuccessful. However it has been recognized that the TNF signal appears as a shortlived pulse in the circulation and that the signal declines rapidly, frequently with the onset of symptoms. Circulating TNF has now been demonstrated during the prodome and at the onset of critical infective illness of many etiologies, and in selected infections, TNF concentrations will predict with remarkable accuracy whether death will occur.2'3 (2) TNF administration initiates alterations indistinguishable from those that occur after bacterial invasion. Administration of recombinant TNF to mammals induces death from circulatory collapse, renal failure, and disseminated intravascular coagulation. Autopsy findings are identical to those observed after severe gram-negative septicemia.' When TNF was infused into cancer patients in a phase 1 treatment protocol, the entire spectrum of changes associated with acute bacterial infection were observed, ranging from a mild flu-like illness to circulatory collapse and 'shock lung,' depending on the administered dose.5 Sublethal TNF infusions in dogs also initiated the characteristic hormonal and metabolic abnormalities associated with sepsis.6 (3) TNF is one of the first mediators to appear during lethal infection. Multiple mediators are present in the circulation of the dying host and these include interleukin- 1, interleukin-6, and products of the cyclooxygenase pathway. However the detection of TNF in the blood stream markedly antedates the appearance of all these other mediators in all appropriate experimental and clinical situations studied to date. Because TNF is known to stimulate the induction of many of the other mediators and pathways in vitro, there is a growing belief that TNF is the initial signal in lethal A

sepsis.

(4) Neutralization of TNF prevents death following lethal gram-negative bacteremia. Tracey and coworkers,7 demonstrated that pretreatment of primates with a neutralizing monoclonal antibody against TNF prevents death following an otherwise lethal dose of virulent Escherichia coli organisms. Similar findings have been reported in other mammals.8

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Ann. Surg. - December 1990

It is clear from the growing evidence that TNF plays a major role in the host response to infection and accounts for many of the deleterious effects of septicemia. Some individuals, however, have voiced concern about modifying the host response to infection; they fear that the administration of anti-TNF antibody may somehow render the host vulnerable because of potentially beneficial effects of this cytokine. Certainly TNF has been conserved more strongly during mammalian evolution than has insulin, suggesting that in some circumstances it may be beneficial, not detrimental. Various theories have been proposed for the existence of TNF, including the suggestion that it is an endogenous 'cyanide capsule' to eliminate wounded or infected members of the herd and thus ensure survival of the fittest. All of these theories remain speculative, but the bulk of evidence supports the belief that during critical illness the induction of TNF within the circulation is an essential factor in determining death. The speed with which TNF research has advanced has been the result of close collaboration between surgeons, basic molecular biologists, pharmaceutical companies and human use committees. These interactions have allowed important research that focuses on the pathogenesis of critical illness to progress in a very short period of time. This collaboration will be even more necessary now that we have the pharmacologic tools to modify the basic signals involved in the mediation of infectious illness.

References 1. Dale HH. Progress in autopharmacology. A survey of present knowledge of chemical regulation of certain functions by natural constituents of the tissues. Bull Johns Hopkins Hosp 1933; 53:329-347. 2. Girardin E, Grau G, Dayer J, et al. Tumor necrosis factor and interleukin- 1 in the serum of children with severe infectious purpura. New Engl J Med 1988; 319:397-400. 3. Graue GE, Taylor TE, Molyneux ME, et al. Tumor necrosis factor and disease severity in children with Falciparum Malaria. New Engl J Med 1989; 320:1586-1591. 4. Tracey K, Beutler B, Lowry S, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470-474. 5. Michie HR, Spriggs DR, Manogue KR, et al. Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings. Surgery

1988; 104:280-286. 6. Evans D, Jacobs D, Revhaug A, Wilmore D. The effects of tumor necrosis factor and their selective inhibition by ibuprofen. Ann Surg 1989; 209:312-21. 7. Tracey K, Fong Y. Hesse D, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330:662-664. 8. Mathison J. Wolfson E, Ulevitch R. Participation of tumor necrosis factor in the mediation of Gram-negative bacterial lipopolysaccharide induced injury in rabbits. J Clin Invest 1988; 81:1925-1937.

HAMISH R. MICHIE, F.R.C.S. Oxford, United Kingdom DOUGLAS W. WILMORE, M.D., F.A.C.S. Boston, Massachusetts