A rationale for administering leukocyte endogenous mediator to protein malnourished, hospitalized patients

J. theor. Biol. (1984)

A Rationale Mediator

106, 119-133

for Administering Leukocyte Endogenous to Protein Malnourished, Hospitalized Patients

LYLE L. MOLDAWER,

JAVIER SOBRADO, GEORGE BRUCE R. BISTRIAN

L. BLACKBURN

AND

Nutrition/ Metabolism Laboratory, Cancer Research Institute, New England DeaconessHospital and Harvard Medical School, Boston, Massachusetts 02215, U.S.A. (Received 3 January 1983, and in revised form 28 July 1983) Leukocyte endogenous mediator is a low molecular-weight protein synthesized by circulating monocytes and fixed macrophages of the reticuloendothelial system. Exogenous administration of leukocyte endogenous mediator to a well-nourished animal stimulates both specific and nonspecific immune function and replicates the protein metabolic response to infection, characterized by fever and increased amino acid oxidation, skeletal protein degradation and synthesis of “acute-phase” proteins. Leukocyte endogenous mediator administration also affords protection against semilethal doses of bacteremia in the well-nourished animal. In the protein-depleted host, synthesis or release of leukocyte endogenous mediator in response to infection appears to be reduced and the attenuated metabolic response may be attributed, in part, to a deficit in its production. However, nutritional repletion of the malnourished patient results in restoration of the capacity to produce leukocyte endogenous mediator usually within three to seven days, if adequate dietary protein is provided. Since protein malnutrition is associated with increased incidence and severity of bacterial infections, we postulate that the reduced synthesis and/or release of leukocyte endogenous mediator in protein malnutrition is detrimental. In those critically-ill, malnourished patients who cannot endogenously synthesize leukocyte endogenous mediator, and for clinical reasons cannot be repleted rapidly or are already infected and/or undergoing operative stress, exogenous administration of leukocyte endogenous mediator should be considered along with nutritional support. Administration of this protein to a seriously-ill malnourished individual should produce a metabolic profile of fever, increased urinary nitrogen excretion and falls in serum albumin concentrations that are generally considered pathologic. However, administration of leukocyte endogenous mediator over short periods of time should also provide the anabolic impetus for the augmented Reprint requests should be directed to: Bruce R. Bistrian, Cancer Research Institute, Pilgrim Road, Boston, Massachusetts 02215, U.S.A.

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$03.00/O

@ 1984 Academic

Press Inc. (London) Ltd.

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synthesis of proteins beneficial to recovery. In most cases, these countervailing forces of anabolism and catabolism should be of benefit to the host if the response to infection and injury is viewed as a physiologic redistribution of endogenous nutrients to meet the more critical and immediate needs of the stressed patient. Introduction

Considerable evidence has accumulated to suggest that the metabolic response to infection in the well-nourished animal is a beneficial host response aimed at maintaining protein homeostasis (Blackburn, 1981; Powanda, 1977; Wannemacher, 1977). Several investigators have hypothe-

sized that the “catabolic” processes associated with infection or injury leading to loss of lean tissue result from the mobilization of protein reserves to provide precursors for new protein synthesis involved in wound healing and host defense. A multitude of systemic metabolic and physiologic events following infection or injury lead to the development of specific immune responses at the site of tissue injury (Mosher & Vaneri, 1980), promotion of wound healing (Gordon, 1973; Lewis, 1977) and a reduction in the possibility of an overwhelming secondary infection (Hau & Simmons, 1980). Similarities in the host metabolic response to a variety of invading pathogens, nonpathogenic inflammation (chemical or hormonal), and injury have suggested to many investigators that the metabolic response to infection, in its most basic form, functions independently of the type of external challenge. Studies have therefore been directed towards identifying a mediator or group of mediators responsible for the initiation of the host metabolic response (Beisel & Sobocinski, 1980; Powanda & Beisel, 1982; Kampschmidt, 1978; Bornstein, 1982). Leukocyte

Endogenous

Mediator

as an Initiator

Leukocyte endogenous mediator (LEM) or leukocytic pyrogen is a lowmolecular weight, heat-labile protein(s) released along with a multitude of other

proteins

from

phagocytic

cells during

infection

or inflammation.

Although LEM has been shown to be synthesized from many cell sources, it is primarily the monocyte and fixed macrophage that synthesize and release maximal quantities (Bodel, 1974). The circulating concentration of LEM during infection is remarkably low, generally in the range found for most hormones. It has been estimated that as little as 30-50 ng of human LEM will produce an increase of 1°C in body temperature in the rabbit and Dinarello

(1979) has suggested that these estimates are probably a log

concentration

high due to a failure to obtain pure preparations.

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LEM initiates a panopoly of metabolic responses during early inflammation and infection which stimulate host protein and trace mineral redistribution. This redistribution is associated with a reduction in plasma iron and zinc concentrations (Kampschmidt & Upchurch, 1969, 1970) and an increase in plasma copper levels, primarily those bound to ceruloplasmin. LEM production also induces fever, hence its name endogenous or leukocytic pyrogen (Bornstein, Bredenberg & Wood, 1963; Cheuk et al., 1972), increases “acute-phase” globulins (Wannemacher, Pekarek & Beisel, 1972), redistributes amino acids from skeletal muscle to the viscera (Yang et al., 1983), increases the release of neutrophils from bone marrow (Kampschmidt & Upchurch, 1977) and produces hyperinsulinemia and hyperglucagonemia (George et al., 1977; Keenan et al., 1982). Recently, evidence has accumulated to suggest that LEM is homologous with lymphocyte activating factor (interleukin 1) which is responsible for proliferation of lymphocytes in response to antigens (Rosenwasser, Dinarello & Rosenthal, 1979; Murphy, Simon & Willoughby, 1980). LEM or interleukin 1 appears to also induce macrophages to synthesize colony stimulating factor which in turn further stimulates macrophages to produce LEM, thereby amplifying LEM production (Kampschmidt, 1978). A representation of LEM-initiated pathways is presented in Fig. 1. Twue

damage ,

/fACrMrgO”lsms Ptqocytosls + LEM productlo”

I Muscle Ammo ocld release Increased proteu” breakdown 2” to prostaglondl” producton

1 L/VW Hypoferremlo Hyp~~mcem~~ Copper release OS cerubpbsm~n Amino acld uptake Increased lwer protan

No change

1” protein

connectwe flSSlle Amino acad release Increased protan breakdown

Pancrws Hyperglucogonenw HypernwJmemwa

synthesis

Increased nwsecretory proten synthws Acute phase reaction &m?

f”orroY

Release of neutrophlls Granubpows

Lymphocytes Increased blastogenests m respmse to mmgens

FIG.

1. Schematic

representation

Grarwlocytes

MWOphOg@S

Lactoferrl” release Lysozyme release Increased oxygen Dependent Boetervadol capoclty

Production shmulahng

Blood

of colony factor

substrafes

Hyperglycemia Hypcketonemut

of LEM-mediated

changes

in host metabolism.

1

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Because LEM has so many diverse functions, it should properly be considered a hormone. By strict definition, a hormone is any substance produced in one region of the body and transported to another where it induces a specific response. Conceptually, LEM fulfills these criteria since it is produced by macrophages at either the site of tissue damage or an invading pathogen and is released into the systemic circulation where it acts either directly or indirectly on many different tissues. In this manner, LEM serves to integrate and organize a multitude of different responses by various tissues and organs in response to phagocytosis. Therefore, LEM appears to be a very unique and potentially important At present it is unclear whether hormone, a “hormone of inflammation”. all of the metabolic responses to infection are host-initiated due to an endogenous stimulus like LEM or are produced directly by tissue damage or invading pathogen. Such a question is of considerable importance since an endogenous host response would imply some beneficial purpose, a physiologic response aimed at recovery and survival rather than a pathologic one directed by the infectious agent. Animal experiments support the thesis that these responses are primarily host-initiated. For example, the protein reponse observed following infection and injury in which skeletal protein and whole body protein breakdown, amino acid oxidation and hepatic protein anabolism are increased has been reproduced in a healthy animal simply by infusing LEM (Yang et al., 1983: Wannemacher et al., 1975; Powanda, 1977). Incubation of skeletal muscle preparations with LEM, in vitro, also stimulates both a prostaglandin E production and increased net proteolysis (Baracos et al., 1983). This increased mobilization and oxidation of body protein can be considered of benefit to the infected host, contrary to earlier suggestions (Moore & Ball, TABLE 1 The effect of LEM Liver &m/100

Physiologic Inactivated LEM

saline LEM

on liver weight and protein synthesis weight gm BWI

2.8110.16 2.93 f 0.09 3.50*0.28!4$

t Nonsecretory hepatic protein. 5 p < 0.05 versus physiologic saline $ p < 0.05 versus inactivated LEM. (Data of Yang et al., 1983).

Total liver protein (mg)

Total livelsynthesis (mg/dayl

l‘uSi6Y 1390 + 60 1980 * 224%

1172~lY5 1195*62 2239* 3258:

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1952), since it provides amino acids for new protein synthesis and for the glucose requirements of healing tissues. In addition to increases in whole body amino acid oxidation and net protein catabolism, the increased liver weight, protein content and synthesis rate observed after most forms of stress can be reproduced simply by exogenous administration of LEM (Table 1). The data from healthy rats infused with phagocyte-derived factors is consistent with previous work which suggests a movement of amino acids from the plasma into the hepatocyte and an increase in certain plasma protein concentrations following LEM treatment (Wannemacher, Powanda & Dinterman, 1974). Coupled with the known increase in some secretory protein synthetic rates following LEM administration, except albumin synthesis which remains unchanged (Hooper et al., 1981), the findings clearly suggest that LEM provides the signal for increased protein synthesis in visceral tissues during infection. The source of amino acids for the hepatic and immunologic protein synthesis during this period appears to be serum albumin, skeletal muscle and connective tissue. Although rates of protein synthesis in skeletal muscle are unchanged by addition of LEM (Baracos et al., 1983; Yang et al., 1983), in vitro rates of muscle protein degradation or in viva estimates of myofibrillar and connective tissue breakdown, as measured by urinary 3-methylhistidine and hydroxyproline excretion, respectively, are increased significantly (Fig. 2). Such increases in net catabolism of skeletal muscle are of a similar pattern and magnitude to those reported in septic man (Long et al., 1981).

I rll (b)

ImChVOted

LEM

LEM

Salne

Imctwuted LEM LEM

2. Increased 3-methylhistidine and hydroxyproline excretion Rats were infused for 24 hours with LEM or heat inactivated LEM. et al. (1983). (a) NT methylhistidine excretion. (b) Hydroxyproline FIG.

0

in rats administered LEM. Data obtained from Yang excretion.

The changes in trace mineral metabolism, including decreases in plasma iron and zinc concentrations and an increase in plasma copper levels which have been consistently observed in infection have also been reproduced by

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LEM administration (Keenan et al., 1982; Hoffman-Goetz & Kluger, 1979a; Sobocinski et al., 1978). There is considerable speculation about the functional significance of these changes in trace mineral concentrations. Garibaldi (1972) and others (Weinberg, 1975; Kochan, 1977; Payne & Finklestein, 1978) have suggested that the growth potential of some pathogenic bacteria might be related to the availability of certain limiting trace minerals, particularly iron. The growth of many species of bacteria, such as E. coli, Listeria monocytogenes and Aeromonas hydrophilia is increased by raising the concentration of iron within the physiologic range. A decrease in iron concentration also depresses the growth of some bacteria, particularly at elevated or febrile temperatures (Garibaldi, 1972). The redistribution of plasma zinc to the liver induced by LEM supports host defense in several respects. First, zinc redistribution may aid tissue repair since zinc is known to have a critical role in wound healing (Rehmet, Norman & Smith, 1974). Zinc has also been implicated as a cofactor in the synthesis of some “acute-phase” proteins in the liver and sequestration of zinc might also have a detrimental effect on the growth of pathogens since it is a normal component of microbial membranes and organelles (Sugarman, 1983). Many mechanisms have been proposed for the apparent beneficial effect of a small elevation in body temperature that is generally observed during infection and is produced by LEM administration. A general benefit can be the direct effect of temperature on the growth of some pathogenic organisms since in some instances, raising the temperature of an in vitro preparation by 2-3°C results in a substantial growth reduction of the pathogen (Lwoff, 1969; Kluger, Ringler & Anver, 1975). Fever may also stimulate other aspects of the host’s defense system. There is considerable evidence that the mobility of the leukocytes is enhanced by increasing body temperature (Sebag, Reed & Williams, 1977; Craig & Sutter, 1966). Some investigators have reported an increased bactericidal capacity of leukocytes at elevated temperatures. For example, Sebag et al. (1977) have shown that elevations in the temperature of leukocytes led to an increased killing power for some bacteria, but not for others. Craig & Sutter (1966) reported that as the temperature of the phagocyte is increased from 26-36°C the percent bacteria ingested and the killing function of the phagocytes increased in a parallel fashion. Another area of leukocyte function which may be enhanced by small elevations in temperature is lymphocyte blastogenesis. It is known that T-lymphocytes undergo proliferation and transformation in response to different stimulants (including antigens and mitogens) and are thus capable of participating in various aspects of the immune response. Work by Roberts

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& Steigbigel (1977) and by Ashman & Nahmias (1977) have shown that temperatures approximating febrile conditions in humans result in the enhancement and acceleration of lymphocyte proliferation and mitogenic response. Many species of pathogenic bacteria are able to obtain adequate amounts of iron from their growth media by producing iron-chelating secondary metabolites, collectively known as siderophores. The temperature optimum for siderphore biosynthesis is much narrower than for primary cellular metabolism (Weinberg, 1975). The capacity for producing these ironchelators decreases with increasing temperatures in the range of normal to febrile body temperatures in mammals. Garibaldi (1972) has suggested that a fever might be beneficial since it results in a decreased growth rate of micro-organisms which are already in an iron-poor environment. LEM Production

During

Protein-Malnutrition

It would appear then that the majority of alterations in host protein and trace mineral metabolism observed during infection and injury in the wellnourished animal are initiated by LEM and serve to alter host metabolism in a beneficial manner. One of the few exceptions to this uniform response is the case of the protein-depleted host. In their classical studies on the interaction between nutrition and infection, Scrimshaw, Taylor & Gordon (1968) observed that protein-malnourished individuals are often afebrile despite an obvious bacteremia. Other investigators have reported a lack of fever in protein-malnourished children and a relative hyperferremia (Brooke, 1972; Brenton, Brown & Wharton, 1967). Closer examination reveals that many of the metabolic responses to infection or injury, including loss of body protein, granulocytosis and hypercupremia are attenuated in the protein-malnourished individual (Munro & Cuthbertson, 1943; Trowell, Davies & Dean, 1954). Although protein-malnutrition may mute the response to infection simply because there is reduced quantity of endogenous nutrients that can be mobilized in defense of the host, recent evidence has suggested that much of this decreased response may be a result of reduced production of LEM. Preliminary studies reported that protein-malnutrition interferes with the synthesis or release of LEM in response to infection (Hoffman-Goetz & Kluger, 1979a,6). Recent work in protein-depleted rabbits demonstrated a failure to develop normal fevers following a gram negative infection which was accompanied by increased mortality. The attenuated fever was attributed to a reduction in the amount of LEM being synthesized and released from phagocytic cells in response to the gram negative bacteremia

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because similar malnourished animals produced a normal fever when administered LEM obtained from well-nourished rabbits. Other studies have shown that protein-depleted rabbits also failed to sequester plasma iron during infection (Hoffman-Goetz & Kluger, 1979b) and this too could be attributed to a primary defect in LEM production. In the protein-depleted patient that is unstressed and has functioning organ systems, the capacity to produce LEM, in vitro, is also attenuated and restoration of endogenous LEM production can be achieved rapidly by total parenteral nutrition (Hoffman-Goetz et al., 1981). LEM obtained from leukocytes of patients with hypoalbuminemic malnutrition before total parenteral nutrition produces only minimal fever and a relatively unchanged plasma iron concentration when administered to rabbits (Figs 3, 4). When LEM is harvested from these same patients after one and seven days of nutritional support and injected into rabbits, restoration of normal fever and reduction in plasma iron concentrations occurs. These findings imply that intravenous nutritional suport therapies can restore in vitro LEM production very rapidly, far earlier than other indices of nutritional repletion such as cell-mediated immunity, serum albumin and transferrin concentrations or body composition. The greatest incidence of protein-malnutrition in hospitalized patients occurs in the critically ill who generally have a long hospitalized course

2

3 Hours

4

5

6

FIG. 3. Fever curves from rabbits administered leukocyte endogenous mediator obtained from malnourished patients before or one and seven days following nutritional support. Rabbits produced an attenuated fever when administered LEM obtained from malnourished patients prior to nutritional support. Refeeding patients with intravenous hyperalimentation restored in uirro capacity to synthesize LEM (Hoffman-Goetz et al., 1981). Injection at 0 hours. O---O, pre TPN of sample (n = 5); O---O, 1 day TPN of sample (n = 5); ApA, 7 day TPN of sample (n = 5).

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FOG. 4. Changes in blood iron ished patients prior to and after malnourished patients produced were rapidly restored to normal 1981). Kwashiorkor patients, n

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concentrations in rabbits administered LEM from malnourone and 7 days of nutritional support. LEM obtained from only small reductions in iron concentration in the rabbit which by intravenous nutritional support (Hoffman-Goetz et al., = 5.

where adequate dietary intake is difficult to obtain (Bistrian et al., 1975; Butterworth & Blackburn, 1975). In this group of patients, the incidence of protein-calorie malnutrition is high; some estimates have suggested that 50-75 % of this population have some degree of moderate to severe proteinmalnutrition. Furthermore, because of concomitant organ failure, protein and fluid intakes are usually restricted and adequate dietary intake is rarely obtained. We have previously investigated the capacity of leukocytes from 15 critically ill patients in the intensive care unit to produce LEM (Keenan et al., 1982). None of the patients had received nutritional support for at least one week prior to investigation and were protein-malnourished, as assessed by serum albumin concentration of less than 2.7 g/dl. The patients could be classified as critically ill and six of the fifteen ultimately died within the course of their hospital stay. The capacity to produce LEM was assayed from peripheral leukocytes following stimulation of phagocytosis, in vitro, with Zymosan A and intravenous injection of the resultant LEM into rats. Hyperthermia, reduction in plasma zinc concentrations and granulocytosis in the rat were used as bioassays for evaluating in do LEM production. Samples of blood were obtained prior to and after three and seven days of parenteral nutrition support. In this study (Table 2), patients were judged capable of producing LEM (Responders) if the percentage of polymorphonuclear leukocytes in the blood of rats injected with LEM was greater than 52%, a minimum value obtained when LEM from ten volunteers was injected into similar animals. Using this criterion, eight patients could be classified as responders and of

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TABLE 2 in calorie and protein intake between malnourished, patients capable and incapable of producing LEM

Responders (n = 8) Nonresponders (n = 7) p values, by t-test: Keenan er al., 1982.)

t

Caloric intake (kcal/day)

Protein intake km/day)

Septic (N)

1450 f 200+ 750 f 130t

822 11t 35*38

4 2

p
9: p ~0.01;

$ p (0.05,

by

,$

critically-ill

analysis.

Survived (N) 7% I!: (Data

of

these eight, only one expired during the course of their hospital stay. In contrast, of the seven patients who failed to synthesize adequate quantities of LEM, five died. The patients who maintained or restored their capacity to synthesize LEM in vitro received greater quantities of dietary protein and calories than those who either failed to or lost their capacity (Table 2). Although the cause of death in a clinical setting is complex, the findings suggest that the capacity to produce LEM in vitro may be associated with other biological functions that are critical to survival. Additional studies will be required to confirm these observations and determine whether reduced LEM production played a causative role in the demise of these patients. However, the work is consistent with earlier studies from rats where prophylactic LEM administration improved survival against subsequent Salmonella typhimurium infection (Kampschmidt & Pulliam, 1975). Powanda has also reported that a sterile abscess which induces endogenous LEM production also affords complete protection against lethal Streptococcus pneumoniae infections (Beisel, 1977). It is theorized that the inability of these patients to produce LEM did not allow a normal response to the presence of infection and may be an important reason why the malnourished patient has increased morbidity and mortality to pathogenic bacteria. Since protein-malnutrition is associated with increased incidence and severity of bacterial infections, we postulate that the reduced synthesis or release of LEM in protein-malnutrition can have pathologic consequences and thus, attempts to treat the proteinmalnourished individual should be aimed at restoring the host’s capacity to synthesize and release LEM, or to administer LEM exogenously. In the protein-depleted, critically ill patient where complete nutritional support is not possible and an improved response is desired, exogenous administration of LEM should be considered. A protein-depleted patient undergoing

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a planned stressful event such as emergency surgery or the severely malnourished, infected individual would be likely candidates. It should be noted that protein-malnourished patients are not the only individuals with an apparent attenuated capacity to synthesize and release LEM or interleukin 1. Studies in patients with systemic lupus erythematosus (SLE) have shown that their blood monocytes produce less LEM when compared to LEM from normal control subjects (Linker-Israeli et&., 1983). Although the patients’ nutritional status was not documented in this report, protein malnutrition is common in SLE and it is at present unclear whether the disturbances in LEM production were entirely a result of the primary disease process or accompanying malnutrition. Of primary importance would be to identify those patients who are not endogenously synthesizing adequate quantities of LEM, since administration of LEM to a well-nourished, infected patient or to a protein-malnourished, noninfected patient would be of less benefit. The well-nourished individual should be synthesizing adequate quantities endogenously in response to infection, as reflected by fever, and in the noninfected, protein-depleted patient, a stimulus to mobilize protein and redistribute trace minerals would not be required or even potentially beneficial. Exogenous

Administration

of LEM

The quantity of LEM required to activate nonspecific and specific immune responses in protein depleted patients would be determined by the development and maintenance of fever. Although LEM infusions activate numerous host responses, the quantities required to do so appear to differ markedly. For example, in rodents the febrile response is least sensitive to exogenous administrations of LEM requiring significantly greater amounts than needed to induce a trace mineral redistribution or granulocytosis (Dinarello, 1984). Indeed, in some species, a febrile response is frequently not produced when LEM is administered in quantities sufficient to activate other aspects of nonspecific immunity (Kampschmidt, 1978). It would therefore seem appropriate to infuse sufficient quantities in malnourished patients to generate a fever of approximately 0*6-1°C. In this manner, by activating fever, initiation of other aspects of nonspecific immunity would be assured. Infusions of LEM to a protein-depleted patient either bacteremic or undergoing surgical stress would produce a response generally considered to be pathophysiologic since a fever would ensue and the patient would have increased losses of body nitrogen and other lean tissue constituents, as well as a reduction in serum albumin concentrations. Historically, such responses have been considered detrimental (Rhoads & Alexander, 1955)

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and attempts have been made using antipyretics (Baracos et al., 1983) and anticatabolic hormones and substrates (Woolfson, Heatley & Allison, 1979) to reduce this loss. More recent thought has, however, suggested that in the short term (l-3 days), these responses are beneficial to the recovering patient. It is understood that adequate nutrient support would be begun simultaneously with the LEM and that, for this reason, exogenous LEM should be necessary for only brief periods of less than one week. Of particular concern to many investigators is whether a protein-depleted patient has adequate reserves of energy, protein and trace minerals to mobilize in response to LEM administration. Indeed, in a recent preliminary report, Hoffman-Goetz & Bell (1983) suggested that in a malnourished rabbit model, LEM administration and nutritional support were both required to produce a maximal acute-phase protein response. One can justifiably argue that the loss of capacity to produce LEM in protein malnutrition may be an adaptive mechanism aimed at preserving the few remaining body reserves. The energy required to generate a fever and the mobilization of body protein to sustain increased visceral protein synthesis and immune function in response to LEM may be deleterious to an individual who has insufficient quantities of protein and energy stores. In the case of the chronically infected child who is protein malnourished and is afebrile with relative hyperferremia and attenuated granulocytosis, he may be responding in an adaptive manner which promotes survival. However, these factors would not be normally operative in the critically ill hospitalized individual in industrialized society. The amounts of body nitrogen lost over three to four days of LEM administration are quantitatively unimportant in terms of whole body protein status and a large proportion of patients suffer from a kwashiorkor-like syndrome of malnutrition where adequate calorie stores are available (Bistrian et al., 1974). In most cases, losses of body nitrogen would be secondary in importance to the more immediate need for amino acids to support visceral protein synthesis. Feeding the patient should restore endogenous LEM production to near normal after several days (Keenan el al., 1982) and eliminate the need for continued exogenous administration. Furthermore, the provision of amino acids would supplement those mobilized endogenously in the acute phase and carbohydrate and fat would complement mobilized energy stores. Limitations

Further development of this concept is limited by the inability to obtain sufficient purified product. At present, most studies have utilized either monocytic supernatants or only partially purified preparations, and

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administration of such crude products into humans cannot be recommended. Complicating the matter further is the fact that although there is considerable cross-species and even cross-class reactivity, more than one species of LEM appears to exist. Studies with LEM or interleukin 1 have repeatedly shown heterogeneity in charge properties with ~1s varying from 4.5 to 7.1 and in molecular weight between 15 000 and 60 000 daltons (for review, see Dinarello, 1984; Kampschmidt, 1978). Purification of human preparations has only recently been described and the recovery of product is generally less than 5% (Lachman, 1983). The quantities of purified LEM necessary to complete clinical trials is at present unknown but would be sufficiently large to warrant investigation into alternative methods of preparation and purification. Based on body weight comparisons between man and rodents, it could be estimated that as much as 350-1400 ng of purified product would be required for a single dose. At present, the LEM or interleukin 1 used for exogenous administration is principally synthesized in uitro from monocytic cell lines. However, due to its proteinaceous nature, large scale production would be most efficiently achieved through genetic engineering, primarily with recombinant DNA technology. Such a technique would also obviate some of the complications associated with using large quantities of blood products, including possible transmission of hepatitis antigen and acquired immune deficiency syndrome. Conclusions A sizable fraction of critically ill patients have some evidence of moderate to severe protein malnutrition. These individuals also appear to have a reduced capacity to synthesize or release LEM and are at increased risk of morbidity and mortality. Because of concomitant organ failure, complete nutritional repletion is difficult in certain circumstances and exogenous administration of LEM should be considered. Administration of LEM to these patients will result in fever, increased urinary excretion of nitrogen and other elements, as well as a decrease in some nutritionally important plasma proteins. Although LEM will produce a metabolic profile usually associated with pathophysiology, it will also result in the sequestration of trace minerals from bacteria, the mobilization of amino acids from skeletal and connective tissue for “acute-phase” protein synthesis, the stimulation of both nonspecific and specific immunity and the provision of additional substrates for energy expenditure. By infusing LEM into the bacteremic patient who fails to endogenously synthesize this peptide, the physician is providing a stimulus for the body to promote a concerted and integrated response to the invading pathogen.

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