close

Вход

Забыли?

вход по аккаунту

?

586

код для вставкиСкачать
1828
A Festschrift Honoring the 90th Birthday on May 9, 1997, of
Jonathan Evans Rhoads, M.D., Editor Emeritus of Cancer
Cancer special section
Proinflammatory Cytokines, Nutritional Support, and
the Cachexia Syndrome
Interactions and Therapeutic Options
Lyle L. Moldawer, Ph.D.
Edward M. Copeland III,
BACKGROUND. Protein calorie malnutrition remains endemic in hospitalized patients with both acute and chronic inflammation secondary to either cancer,
M.D.
Department of Surgery, University of Florida
College of Medicine, Gainesville, Florida.
chronic infectious processes, surgical injury, trauma, or burns. For the patients who
cannot support themselves by enteral feeding, total parenteral nutrition remains an
essential tool to minimize nitrogen losses and replete the depleted patient. However, in patients with active inflammation, nitrogen retention and lean tissue accretion are often impaired during total parenteral nutrition. Production of humoral
factors, including proinflammatory cytokines, regulates many of the anabolic and
catabolic processes that accompany inflammation.
METHODS. The investigators’ experience with total parenteral nutrition and proinflammatory cytokines is reviewed.
RESULTS. Cytokines such as interleukin-1, tumor necrosis factor-a, and, in particular, interleukin-6 appear to play central roles in both the loss of skeletal muscle
protein and the initiation of the acute phase response to inflammation, as well as
in modulating the utilization of exogenously administered nutrients.
CONCLUSIONS. Although innovative second- and third-generation nutritional formulations for the acutely ill patient may represent one approach for improving
the effectiveness of total parenteral nutrition, understanding the humoral response
to inflammation and modifying cytokine actions pharmacologically may prove
equally effective in improving the utility of exogenously administered nutrients.
Future studies need to determine whether the effectiveness of exogenously administered nutrients in the patient with inflammation can be improved by efforts to
modulate the proinflammatory cytokine response through cytokine inhibitors or
antagonists. Cancer 1997;79:1828–39. q 1997 American Cancer Society.
KEYWORDS: protein calorie malnutrition, inflammation, parenteral nutrition, cytokine, anticytokine therapy.
I
Supported in part by grants GM-40586 and GM52532, awarded by the National Institute of
General Medical Sciences, U.S.P.H.S.
Address for reprints: Dr. Lyle L. Moldawer, Department of Surgery, P.O. Box 100286, University of Florida College of Medicine, Gainesville,
FL 32610.
Received January 16, 1997; revision received
February 18, 1997; accepted February 18, 1997.
nvestigation continues toward a better understanding of the relationships between proinflammatory cytokines, parenteral nutrition,
and the regulation of lean tissue and body fat accretion in the hospitalized patient. Since the successful advent of total parenteral nutrition in the U.S. led by Drs. Stanley J. Dudrick and Jonathan E. Rhoads,1
significant success has been achieved in the nutritional support of
the hospitalized and home-bound patient who cannot sustain himself
or herself by enteral means. For many patients, total parenteral nutrition has become an indispensable and life-saving therapeutic modality. The contributions made by Drs. Dudrick, Rhoads, and their coinvestigators to the development of total parenteral nutrition cannot be
overstated (see review).2 Not only did Dr. Dudrick et al. develop and
q 1997 American Cancer Society
/ 7b55$$1072
03-31-97 16:00:11
cana
W: Cancer
Cytokines and the Cachexia Syndrome/Moldawer and Copeland
initially refine an entirely new therapeutic modality
and provide a strong scientific justification for its use,
but they also provided the tools and leadership for the
early development of the field of parenteral nutrition.
Since the 1970s, total parenteral nutrition has become
a common and essential tool for the treatment of the
malnourished patient who cannot be supported enterally. In cancer patients with significant abnormalities
in cell-mediated immune function, total parenteral
nutrition has been given safely, and in many cases,
has improved immune responsiveness and permitted
completion of antineoplastic therapies in patient populations at would otherwise have failed their therapeutic regimens.3 – 5
The current challenge is to continue refining and
developing parenteral nutrition strategies to deliver
optimally the appropriate quantity and quality of nutrients required by hospitalized patients and to do so
in a manner that supports the host’s innate and acquired immune responses to injury or inflammation.
The 1970s and early 1980s were noted for an increasing
appreciation of the magnitude and frequency of lean
tissue wasting that occurred in critically ill patients
and patients with sepsis. As early as 1974, it was recognized that protein malnutrition was endemic in hospitalized surgical and medical patients.6,7 Due in great
part to the seminal studies of Drs. Dudrick, Rhoads,
and their colleagues, increasing enthusiasm arose for
the use of total parenteral nutrition as a means of
reducing lean tissue losses in critically ill patients who
could not be fed enterally.8,9 However, even at that
early time, it was recognized that patients with active
inflammation who were receiving total parenteral nutrition often accrued less body protein and in different
proportions than similarly depleted individuals without inflammatory stress.8,10 Several excellent publications by these investigators,11,12 as well as by Drs. Kinney and Elwyn,13,14 have suggested that aggressive nutritional support in patients with acute inflammation
was often ineffective at either repleting preexisting
protein losses or even preventing continued losses.
Studies have also demonstrated that weight gain in
cancer patients receiving total parenteral nutrition is
often predominantly water and fat, and lean tissue
gains are modest.15 – 17 Similarly, in protein-depleted
patients with sepsis syndrome or systemic inflammatory response syndromes (SIRS), nitrogen accretion is
either reduced or not evident despite administration
of total parenteral nutrition at levels estimated to meet
predicted protein and energy requirements.8,10
Since the original description of total parenteral
nutrition in the late 1960s, at least two lines of research
have been believed to increase the effectiveness of parenteral nutrition support in patient populations that
/ 7b55$$1072
03-31-97 16:00:11
cana
1829
have not responded optimally to standard formulations. One such approach has been to modify the parenteral composition and to consider alternative protein and energy sources that may be more optimally
used by the stressed patient. Such an approach has
led to the development of specialized modified amino
acid diets, such as branched chain amino acid-enriched, glutamine, arginine, and glycine-enriched, and
specialized amino acid or dipeptide formulations for
patients with individual organ dysfunctions, including
those of the hepatic, renal, and pulmonary systems.
Alternative nonprotein calorie sources for these patients have included medium chain triglycerides, fish
oil (omega-3 fatty acid) emulsions, short chain fatty
and oxo-acids, alcohol, and polyols. Although many
of these products have indeed found niches in the
parenteral nutrition market, their use has been limited
to specific patient populations and disease settings.
An alternative approach to the more efficient feeding of the stressed patient has been to understand
better the nature of the metabolic response to inflammation, and to pharmacologically modify that response to improve utilization of intravenously or
enterally administered nutrients. This has included
efforts to provide exogenous anabolic signals concomitant with total parenteral nutrition, including insulin,
growth hormone, insulin-like growth factor (IGF )-1,
testosterone, and anabolic steroids. Additional approaches have been to attenuate the catabolic signals
associated with injury and inflammation, such as the
increased production of prostanoids, corticosteroids,
catecholamines, and proinflammatory cytokines.
The goal of the authors’ current research is to gain
a better understanding of the humoral signals that regulate both the utilization of exogenously administered
nutrients, as well as endogenous substrate cycling and
protein kinetics. Protein mediators produced by inflammatory cells act in both a paracrine and endocrine
manner on most somatic tissues. The complexity and
importance of the communication between inflammatory cells and somatic tissues is only now being
fully recognized. Although exploration of the role that
cytokines play in the host response to inflammation
is an endeavor that has been underway for at least
20 years, considerable controversy still exists over the
mechanisms of lean tissue and body fat dissolution
that occur in the patient with either cancer or inflammation and whether humoral factors regulate this
process. Furthermore, no widely accepted consensus
has been reached as to the reason cancer patients or
patients with acute inflammation respond to total parenteral nutrition differently from similarly depleted individuals without cancer or inflammation, and
whether cytokines are directly involved.
W: Cancer
1830
CANCER May 1, 1997 / Volume 79 / Number 9
During the past 20 years, the advent of total parenteral nutrition has enabled clinicians to support patients with sepsis syndrome more adequately, and at
the same time, has provided a tool for better understanding the intricate pathways involved in protein
metabolism that accompany inflammation, either in
the fed or fasted state. One salient feature of patients
with inflammation ranging from chronic cancer
cachexia to sepsis syndrome or SIRS is the exaggerated
protein loss. At one extreme, patients with sepsis or
SIRS who are in a fasting state often lose 10 to 20 g of
nitrogen per day in the urine, the equivalent of 300 –
400 g per day of lean tissue.18 Historically, this dissolution of lean tissue is seen as being pathogenic to the
host. Similarly, in the patient with a chronic illness,
such as cancer or tuberculosis, the quantities of protein lost over several months can also be significant.
In fact, when losses of lean tissue continue and result
in significant depletion of somatic and visceral proteins, the risk of morbidity and mortality from opportunistic infections increases.19
However, in a previously well nourished individual, the increased skeletal muscle proteolysis that occurs in sepsis or in SIRS serves acutely to meet the
energy and amino acid requirements of a stressed
host. In the past 20 years, with the advent of total
parenteral nutrition and aggressive enteral feedings,
efforts for the most part have focused on reducing
protein losses (nitrogen excretion) and improving secretory protein and immunologic function. Although
these previous studies have been informative, they
have often not taken into account the vast differences
in protein synthesis that occur in various body compartments during acute inflammation or sepsis.
In the previously well nourished patient, the three
primary goals of the host response to inflammation are
to stimulate antimicrobial functions, to reduce tissue
damage associated with either an infectious process,
surgical trauma, or tissue injury, and to provide adequate energy for wound healing and antimicrobial
functions. The response observed in terms of the wasting of lean tissue and body fat (skeletal muscle) and
the loss of body weight is a by-product of these three
functions. Total parenteral nutrition must support
these three goals to be optimally effective. Only
through a better understanding of the underlying
mechanisms that regulate this response can total parenteral nutrition formulations be optimally designed.
Functional Redistribution of Body Protein in Inflammation
To understand the dynamic protein changes that accompany the inflammatory response, one must understand the functional redistribution of body cell
mass that occurs.10 During inflammation, protein is
/ 7b55$$1072
03-31-97 16:00:11
cana
lost from skeletal muscle, connective tissue, and the
gut. Free amino acids, released from net protein catabolism in these organs or tissues enter the free amino
acid pools of the body and, in addition to serving as
a gluconeogenic fuel, serve as precursors for new protein synthesis in the liver and the hematopoietic system. Body protein is mobilized from skeletal muscle,
the gut, and connective tissue to the body’s free amino
acid pool.10 This increased mobilization of body protein is reflected in increased protein turnover and
plasma amino acid flux. Patients with trauma, bacterial infections, thermal injury, or sepsis syndrome often have rates of protein turnover 30 – 50% higher than
similar individuals without injury.20 – 22 In addition,
some patients with cancer show increased protein
turnover in the range of 10 – 20% when compared with
similar patients without cancer.23,24 In the septic patient, an increased fraction of this free amino acid
substrate is utilized for gluconeogenesis and/or oxidized directly with the nitrogen appearing in the urine
as urea. The amino acid that passes through the
plasma compartment from protein degradation, but
is not further oxidized or converted into new glucose,
is redirected for new protein synthesis. This component of amino acid substrate is usually not considered
to be essential to a successful recovery. However,
maintaining adequate levels of protein synthesis or
increasing protein synthesis in response to injury or
infection is essential for leukocytic proliferation, acute
phase protein synthesis, and tissue repair, which ultimately determine a successful outcome.
Studies conducted in the authors’ laboratories
several years ago are enlightening in this regard.25
When sepsis is induced in rats by the infusion of live
Pseudomonas, rates of amino acid oxidation, as measured by a constant infusion of L-[1-14C]leucine, are
markedly increased. Indeed, such animals are catabolic and oxidize amino acids at rates 40% higher than
similar fasted healthy animals. Although rates of
amino acid oxidation are accelerated, rates of whole
body protein synthesis are also increased. Despite the
net catabolic state in these animals, anabolic processes in various tissue compartments are also increased.
This pattern is also observed in rodents bearing
transplantable tumors. Kawamura et al. reported increased whole body protein turnover in cachectic rats
bearing transplantable tumors compared with pair-fed
nontumor-bearing controls.26 The increases in protein
turnover were not due to the tumor but were the result
of host tissues increasing their protein turnover rate.
In actuality, protein breakdown rates in the tumor
were very low and contributed only modestly to the
W: Cancer
Cytokines and the Cachexia Syndrome/Moldawer and Copeland
TABLE 1
Contribution of Individual Organs to Whole Body Protein Synthesis
in Septic and Tumor-Bearing Rats
Whole body synthesis
Healthya
Bacteremic
Healthyb
Tumor bearing
day, some body compartments are actually accruing
protein. These anabolic processes are directed primarily at maintaining homeostasis and stimulating antimicrobial functions.
Liver
(mmol/100 g/hour)
(g/day)
g/day
% of whole body
31.7 { 9.9
53.9 { 5.2*
31.3 { 0.7
42.0 { 1.8*
6.0 { 0.8
7.3 { 0.8*
ND
ND
1.3 { 0.3
2.0 { 0.3*
0.8 { 0.2
1.0 { 0.2
22%
27%
14%
12%
ND: not determined.
a
From Kawamura et al.26
b
From Pomposelli et al.25
increased whole body protein degradation observed
in these animals.27
The advantage of conducting these studies in rats
was the ability to examine protein synthesis rates in
individual compartments. In this case, it was possible
to ascertain protein synthetic rates in tissues having
rapid turnover rates such as the liver and to determine
the contribution individual organs make to whole
body protein synthesis. In septic rats, liver protein synthesis actually increased, and the contribution that
liver protein synthesis made to total protein synthesis
also increased (Table 1). After a septic insult (16 hours
after the infusion of bacteria), liver protein synthesis
increased by approximately 32%, yet carcass protein
synthesis remained essentially constant.25 In fact, the
majority of increases in whole body protein synthesis
could be explained by increases in liver protein synthesis. Moreover, the livers of these animals were approximately 10 – 20% larger with 10 – 20% more protein
than the livers of comparably fasted animals.
Similarly, in the tumor-bearing rat, fractional hepatic protein synthesis was increased 35% and the livers of these animals were 15% larger with significantly
greater protein content.26
Total hepatic protein and hepatic secretory acute
phase protein synthesis are also increased in cancer
and acute inflammation, whereas total secretory protein synthesis remains constant or is increased.28 Albumin synthesis declines in patients with cancer,29 infections, and sepsis, but this decline is offset to a large
extent by acute phase protein synthesis, which is often
increased.30,31
In general, although the protein response to inflammation, regardless of its source, is one of increased overall protein catabolism, anabolic processes
are occurring simultaneously. Whereas the septic or
burned patient may be losing 300 – 500 g of lean tissue
per day or the cancer patient õ50 g of lean tissue per
/ 7b55$$1072
03-31-97 16:00:11
1831
cana
The Role of Cytokines in Mediating the Acute Phase
Response
The question remains as to which mediators are produced during weight-losing conditions that regulate
these anabolic and catabolic processes. It is reasonable to focus first on the inflammatory mediators that
regulate the hepatic protein response to inflammation,
because the picture in the liver is most clear. In vitro
studies with hepatocyte cell cultures, as well as in vivo
studies, suggest that the primary mediators of the hepatic acute phase response include the proinflammatory cytokines, interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6). In particular,
IL-6 and members of the IL-6 superfamily (such as
leukemia inhibitory factor [LIF] oncostatin-M ciliary
neurotrophic factor [CNTF] and IL-11) appear to play
critical roles in regulating the integrated hepatic acute
phase protein response.32 – 39
Under in vitro conditions, all three families of
these cytokines decrease albumin synthesis, and, to a
variable extent, increase the synthesis of acute phase
proteins. This last statement must be qualified, because the pattern of protein synthesis in response to
IL-1, IL-6, and TNF-a varies depending on the cell
line and the experimental conditions. However, for the
most part, these three cytokines, when administered
to healthy animals can reproduce the acute phase responses observed in acute inflammation.28,40 This
overlapping biological response is due in part to the
fact that under in vivo conditions, TNF-a can induce
IL-141 and IL-6 biosynthesis,42 whereas IL-1 can induce
IL-6.43
Additional members of the IL-6 superfamily have
attracted considerable attention recently for their capacity to elicit an hepatic acute phase protein response. IL-6, CNTF, LIF, IL-11 and oncostatin-M all
share in common signal transduction via the glycoprotein (gp) 130 complex.44 – 48 They differ among themselves in the ligand-binding protein, but the ligand
receptor complex subsequently interacts with a common gp 130 to transduce the signal. For example, both
CNTF and LIF can share a common ligand-binding
receptor that then complexes with gp 130. By sharing
a single signal transduction pathway, all these members of the IL-6 super family share with IL-6 the ability
to induce an acute phase response (Table 2).
The authors have observed very recently that administration of the neurotrophin CNTF produces a hepatic acute phase response of magnitude comparable
W: Cancer
1832
CANCER May 1, 1997 / Volume 79 / Number 9
TABLE 2
Similarities among Different Proinflammatory Cytokines in Their
Ability to Induce Acute Phase Responsesa
TNFa
IL-1
IL-6
CNTF
LIF
Hepatic acute
phase protein
response
Anorexia
in vivo
Cachexia
in vivo
In vitro
muscle
proteolysis
Strong
Strong
Very strong
Very strong
Strong
Modest
Strongb
None
Very strong
Unknown
Modestb
Strongb
None
Very strong
Strong
None
None
None
None
Unknown
TNF-a: tumor necrosis factor-a; IL-1: interleukin-1, IL-6: interleukin-6; CNTF: ciliary neurotropic factor;
LIF: leukemia inhibitory factor.
a
Summarized from Moldawer et al.,40 Espat et al.,47 Moldawer et al.,77 and unpublished data of Moldawer et al.
b
Tolerance rapidly develops (within 3 days) to administered tumor necrosis factor-a and interleukin-1.
to that observed with IL-6 administration.47 Doses as
low as 25 mg/kg body weight of CNTF administered
subcutaneously in the mouse can produce an increase
in serum amyloid A, P, and a1 -acid glycoprotein concentrations and hypoalbuminemia. Furthermore,
doses tenfold higher produce profound anorexia and
lean tissue wasting. On a per mole basis, CNTF produces far greater reductions in food intake and greater
losses in lean tissue than comparable amounts of IL6. A ready explanation for this increased responsiveness to CNTF versus IL-6 is currently unclear, but
recent studies from the authors’ group suggest that
CNTF suppresses neuropeptide Y (NPY) expression
and protein release in the anterior hypothalamus (unpublished data). CNTF receptors are found in hypothalamic tissues known to produce NPY. Both systemic
as well as intracerebroventricular administration of
CNTF produces inhibition of NPY synthesis and release in a dose-dependent fashion. Because NPY is a
potent orexigenic agent,48 suppression of NPY expression by CNTF can explain to a large degree the anorexia that subsequently develops.
Other members of the IL-6 superfamily are known
to regulate both the anabolic acute phase response
and development of cachexia. Mice overexpressing LIF
develop a cachexia-like syndrome,49 and LIF and oncostatin-M are both inducers of a hepatic acute phase
response.32,50
Thus, an appreciable number of humoral factors
can regulate food intake and the hepatic acute phase
response. Furthermore, other mediators, including
classic macroendocrine agents, play a contributory
role in this process. For example, corticosteroids increase hepatic availability of amino acids for protein
synthesis by stimulating amino acid uptake.51 Scatter
/ 7b55$$1072
03-31-97 16:00:11
cana
factor/HSF is another paracrine mediator that appears
to stabilize transcriptional messages that are involved
in the acute phase response.
The problem with ascribing specific tissue responses to individual cytokines is that considerable
overlap and redundancy exists in the cytokine network. As stated previously, administration of either
TNF-a or IL-1 will induce the synthesis of a variety
of other proinflammatory cytokines, including IL-6.
Thus, studies that employ pharmacologic administration of recombinant cytokines frequently cannot discriminate between biologic responses induced directly
by the administered cytokine, and those induced by
mediators stimulated by that cytokine. Furthermore,
inflammation often elicits a cytokine cascade in which
several cytokines are induced simultaneously.52
For example, in primates or rodents with endotoxemia, bacteremia, or hemorrhagic shock, it is not uncommon to detect TNF-a, IL-1, IL-6, IL-8, IL-10, and
IL-12 heterodimer simultaneously (as well as other
members of the IL-8 family, KC/GRO).53,54 Under such
conditions, it is difficult to resolve the contribution
that each of these mediators is playing in the acute
phase response.
In Vivo Studies with Cytokine Inhibition
If there is clear evidence of simultaneous upregulation of IL-1, IL-6, and TNF-a, as well as other humoral mediators, the question arises as to how to
identify the role of individual cytokines in mediating
acute phase or any in vivo responses. In addition,
in many acute inflammatory processes, there is local
paracrine production of IL-1 and TNF-a, but not in
the systemic circulation. Thus, the failure to detect
IL-1 or TNF-a in the plasma during inflammation
may not represent evidence that these proteins are
being produced.
For example, burned, septic rats that are extremely
catabolic manifest an acute phase response, and die
of sepsis in 7 to 9 days. However, neither IL-1 nor
TNF-a are regularly detected in the circulation of these
animals, although both proteins (and their respective
mRNA) can be found in the livers and spleens of these
animals.55,56 So the question that has persisted for the
past several years is which of the inflammatory mediators contributes to individual acute phase responses
and the development of cachexia. The authors have
spent most of their effort examining the role that IL1, TNF-a, and members of the IL-6 superfamily play
in the acute phase responses to acute myositis secondary to a turpentine abscess. The turpentine abscess is
a model of acute inflammation that has been used
commonly in the past as a method of inducing an
acute phase response.57,58 After a turpentine abscess,
W: Cancer
Cytokines and the Cachexia Syndrome/Moldawer and Copeland
mice lose weight and become anorexic. They manifest
an acute phase response, but neither IL-1 nor TNFa are detectable in the circulation, although IL-6 is
present.59 However, the authors have recovered IL-1a
mRNA from the wounds of these animals by reverse
transcriptase polymerase chain reaction.
The authors’ initial approach was to prevent IL-1
binding to its receptor with a monoclonal antibody
directed against the functional IL-1 receptor. There
are two IL-1 receptors, identified as the type I (p80)
and the type II (p68) receptor. Only the type I receptor
is functional, in that it transmits a signal.60,61 There
also exists a secondary membrane protein termed the
IL-1 receptor accessory protein that appears to bind
IL-1a and IL-1b and this ligand receptor accessory
protein binds to the p80 receptor.62 In contrast, the
IL-1 type II receptor is a decoy receptor.61 It shares
structural homology in the extracellular domain of the
type I receptor, but has no apparent intracellular signaling component. IL-1a and IL-1b both bind with
equal affinity to the type I and type II receptor, but
binding to the type II receptor does not transduce a
signal.
During sepsis and after surgical injury, the extracellular domain of the IL-1 type II receptor is shed and
circulates.83,64 This extracellular domain retains ligand
binding capacity, and in this regard serves as an inhibitor of IL-1 functions.
Therefore, rather than develop antibodies against
both IL-1a and IL-1b, Chizzonite et al. at HoffmannLa Roche developed a monoclonal antibody directed
against the extracellular domain of the IL-1 type I receptor.60 By passively immunizing mice with this antibody, the authors could block IL-1’s binding to the
bioactive type I receptor and prevent its actions.
Using this technique, the authors were able to address the question of endogenously induced IL-1’s role
in mediating the acute phase responses to turpentineinduced myositis. The results were quite impressive.59
Blocking the IL-1 type I receptor reduced by at least
90% the increase in the murine acute phase proteins
amyloid A, amyloid P, C3, and seromucoid. Thus, it
can be concluded that despite an inability to reproducibly detect IL-1 in the circulation of mice after a
turpentine abscess, an endogenous IL-1 response is
contributing to the hepatic acute phase response.59
What is surprising is that IL-1 receptor blockade
did not attenuate the corticosterone response to turpentine abscess, nor did it block the hypoalbuminemia
that develops with this model. In contrast, administration of IL-1 to healthy animals will induce a generalized glucocorticoid response43 and decrease albumin
concentrations.65 Clearly, other mediators induced
during a turpentine abscess can also mediate these
/ 7b55$$1072
03-31-97 16:00:11
cana
1833
processes, and blockade of IL-1 alone is inadequate to
blunt these responses.
If a similar approach is employed to block the IL1 type II receptor with a monoclonal antibody directed
against its extracellular domain, attenuation of the hepatic acute phase response is not observed.66 Rather,
exacerbation of the acute phase response is observed.
In retrospect, this enhancement of the acute phase
response with type II receptor blockade is not unexpected, given the fact that the type II receptor can be
an inhibitor of IL-1 binding to the bioactive type I
receptor. By blocking the type II receptor, endogenously produced IL-1 is effectively directed to the bioactive type I receptor.
Recently, these findings have been confirmed with
transgenic mice either lacking a functional IL-1b or
IL-1 type I receptor gene.67,68 Mice lacking either of
these genes have a markedly attenuated acute phase,
anorexia, and weight loss responses to turpentine abscess than phenotypically wild-type mice. These animals also have reduced antimicrobial functions when
compared with wild-type mice in terms of susceptibility and mortality to listeriosis.
A similar approach has been employed to determine the role TNF-a in mediating these responses to a
turpentine abscess.59 In this case, a purified polyclonal
antibody raised against murine TNF-a in prior studies
was effective in preventing endotoxin-induced shock
in the mouse.69 However, passive immunization of
mice with this antibody against TNF-a had no effect
on either the anorexia, weight loss, or acute phase
protein responses to a turpentine abscess. Similarly,
mice lacking functional TNF receptors respond to a
turpentine abscess with a normal acute phase, anorexia, and cachexia response.67 Thus, TNF-a, if endogenously produced, does not appear to play a role
in regulating these responses in this model.
Blocking an IL-1 mediated response (but not TNFa) in this model attenuated the systemic IL-6 response.
In fact, the magnitude of the IL-6 blockade paralleled
the decline in acute phase response.59 This raised the
possibility that IL-1’s induction of the hepatic acute
phase protein response to a turpentine abscess may
be mediated through the systemic release of IL-6. This
is indeed the case.70 When mice are passively immunized with a monoclonal antibody against murine IL6, the hepatic acute phase protein response is completely blocked. Furthermore, when mice are passively
immunized with both a monoclonal antibody against
the type I receptor and against IL-6, no further decline
occurs in the acute phase response. This suggests that
IL-1 and IL-6 are working through a common pathway.
Others have shown that the hepatic acute phase re-
W: Cancer
1834
CANCER May 1, 1997 / Volume 79 / Number 9
TABLE 3
Effect of Antibody Treatment on the Acute Phase Response to a
Turpentine Abscess (Unpublished data of Moldawer and Kaibara)
Turpentine abscess
/Anti IL-6 MoAb
/Anti CNTF As
/Anti LIF As
Change in
acute phase
protein respa
Change in
food intake
Change in
body weight
/450%
ú95%
No effect
No effect
065%
/42%
No effect
No effect
012%
/55%
No effect
No effect
Resp: response; IL-6: interleukin-6; MoAb: monoclonal antibody; CNTF: ciliary neurotropic factor; AS:
LIF: leukemia inhibitory factor.
a
Acute phase protein response represents the average of the increase in amyloid P, amyloid A, and
a1-acid glycoprotein levels.
sponse to a variety of inflammatory processes is dependent on IL-6.71 – 73
Because the IL-6 family is so diverse, and IL-6
superfamily members such as CNTF and LIF have the
capability of producing cachexia when administered
to healthy animals, it was important to determine
whether other members of the IL-6 superfamily were
contributing to the systemic acute phase response. In
fact, some investigators have reported that these other
members of the IL-6 superfamily actually circulate in
inflammatory diseases.74 To address this point, mice
were passively immunized with either a monoclonal
antibody against murine IL-6 or purified polyclonal
antibodies against rat LIF75 or CNTF. The results were
unequivocal in demonstrating that only an endogenous IL-6 response, and neither LIF nor CNTF, contributed to any of the host responses to a turpentine
abscess (Table 3). Thus, at least in this model of acute
inflammation, an endogenous CNTF or LIF response,
which was inhibited by polyclonal antibodies, had no
effect on the acute phase responses to a turpentine
abscess.
Thus, the turpentine abscess model has shown the
existence of a clearly defined cytokine network that
regulates the induction of an hepatic acute phase protein response. A turpentine abscess is associated with
local IL-1 production, which in turn induces a systemic
IL-6 response. This IL-6 response appears to regulate
directly the synthesis of a variety of positive acute
phase reactants, including amyloid A, amyloid P, C3,
and seromucoid. However, the fall in albumin concentrations observed in this model does not appear to be
dependent on these two cytokines, alone or together.
In terms of the hemopoietic system, the neutrophilia and leukocyte dyscrasia responses that accompany sepsis also appear to be partially dependent on
a TNF-a and IL-1 response. Administration of IL-1 or
/ 7b55$$1072
03-31-97 16:00:11
cana
TNF-a to rats will reproduce the neutrophilia, lymphopenia, and monocytopenia that accompany sepsis.42,43,76
The authors reported that TNF-a, unlike IL-1, also
has the ability to increase red cell degradation and
suppress erythropoiesis.77 Similarly, in baboons with
lethal gram negative bacteremic shock, the authors
observed that TNF-a blockade with a novel TNF receptor immunoadhesin blocks the lymphopenia and monocytopenia that develop in this model.53 Similar results were not observed with IL-1 receptor blockade,
suggesting that this monocytopenia is dependent on
a TNF-a and not an IL-1 response.78
Regulation of Skeletal Muscle Protein in Cachexia
Much less is known concerning the mediators involved in the skeletal muscle changes that accompany
sepsis, although recent studies have suggested that the
proinflammatory cytokines TNF-a and IL-1 are indirectly involved. Historically, several competing
hypotheses have attempted to explain the progressive
losses of lean tissue and skeletal muscle. The 1970s
and early 1980s were noted for an increasing appreciation of the magnitude and frequency of skeletal muscle
protein wasting that occurred in critically ill and septic
patients. Dogma at the time insisted that the losses of
skeletal muscle protein in critically ill patients were
due principally to either an increased production of
the catabolic hormones and/or an acute energy deficit
in skeletal muscle.79 – 81 Studies demonstrated that the
changes in plasma concentrations of glucocorticoids,
insulin, glucagon, and catecholamines observed in
critically ill patients, were associated with increased
losses of skeletal muscle protein and negative nitrogen
balance.82,83 Similarly, studies by O’Donnel et al. and
Cerra et al. suggested that in septic individuals, an
acute energy deficit was present in skeletal muscle
and a subsequent autocannibalism was providing
branched chain amino acids as a preferred fuel for
skeletal muscle protein.84,85
However, it was the study of Clowes et al. that first
raised the concept that the losses of skeletal muscle
protein in sepsis were an unavoidable result of nonspecific host immune stimulation and cytokine production.86 This concept, that humoral products of the
immune system could regulate skeletal muscle protein
balance, did not originate entirely in a void. The late
1970s and early 1980s were characterized by a growing
appreciation that many components of the host nonspecific inflammatory response to infection were regulated by protein products of inflammatory cells. By
that time, several laboratories had demonstrated that
leukocyte-derived protein products initiated the febrile, hepatic acute phase, and trace mineral and leu-
W: Cancer
Cytokines and the Cachexia Syndrome/Moldawer and Copeland
kocyte responses to infection.87 – 95 In fact, the authors
published two articles96,97 demonstrating that when
partially purified cytokine preparations were infused
into healthy rodents, increased whole body protein
breakdown, myofibrillar protein, and collagen degradation were all increased.
Subsequent studies by Hasselgren et al., KeHelhut
and Goldburg, and the authors subsequently ruled out
IL-1 as acting directly on skeletal muscle to increase
proteolysis98 – 101 as proposed by Clowes et al.86 In fact,
all of the recombinant cytokines tested individually
in in vitro muscle preparations to date have failed to
replicate the results obtained with partially purified
biologic preparations.
However, this is not to conclude that these cytokines are not involved in the skeletal muscle wasting
that accompanies acute inflammation. Not only are
these cytokines catabolic when administered in vivo to
animals,40,65,97,102 but blocking an IL-1 or IL-6 response
after a turpentine abscess reduces the carcass protein
losses that occur. Clearly, an endogenous IL-1 and IL6 response contributes to this lean tissue wasting, but
not through any direct action on skeletal muscle protein. What remains unresolved is identification of the
pathway by which IL-1 and IL-6 mediate these losses
of lean tissue.
Similarly, several groups have now shown that
anticytokine therapies are effective in reducing skeletal muscle proteolysis in other models of endotoxemia
or sepsis. Some investigators have attempted to suppress TNF-a production through the use of amrinone
or pentoxifylline, which inhibit TNF-a production.
When pentoxifylline or amrinone were administered
to rats after intraabdominal abscess formation or gram
negative bacteremia, the inhibition in protein synthesis normally observed in these models was prevented.103 – 105 Similarly, Zamir et al. demonstrated that
when septic rats were pretreated with antibodies
against TNF-a, losses in both total muscle and myofibrillar protein were reduced, although not eliminated.106 Similarly, treatment of rats with IL-1 receptor
antagonist (IL-1ra) reduced, in a dose-dependent fashion, endotoxin-induced increases in myofibrillar and
total muscle protein breakdown.107
Voisin et al. examined some of the cellular mechanisms by which TNF and IL-1 inhibition in vivo may
spare skeletal muscle protein in septic rats. These investigators examined the translational efficiency in the
gastrocnemius muscle of septic rats treated with either
IL-1ra or inhibitors of TNF production.104 Increases in
free ribosomal subunits observed in septic rats were
abolished by IL-1ra treatment,108 suggesting that IL-1
or factors induced by IL-1 directly affect peptide chain
/ 7b55$$1072
03-31-97 16:00:11
cana
1835
in the sepsis-mediated inhibition of peptide chain initiation and elF-2Be expression.
The authors believe that part of the answer rests
with the proinflammatory cytokine’s interactions with
the hypothalamic, pituitary axis and also through IGF1 production and action. Not only do the proinflammatory cytokines down-regulate hepatic IGF-1 production in response to growth hormones, but IL-1 and
TNF-a alter the pattern of IGF binding proteins that
regulate IGF-1 bioactivity.109 Infusions of TNF into the
rat can reduce the plasma concentrations of IGF-1,
alter IGF1 BP concentrations and decrease IGF-1 content in liver muscle and the pituitary gland.110 Similarly, treatment of septic rats with IL-1 receptor antagonist attenuated the decrease in IGF-1 and increase
in IGF1BP,and also prevented the changes in IGF-1
concentrations observed in individual organs.111 The
antianabolic properties of IL-1 and IL-6 could thus
be mediated in part through alterations in the IGF-1
pathway.
Similarly, in rats treated with RU38486 and TNFa, muscle proteolysis was markedly attenuated, albeit
not normalized.99,112 Surprisingly, neither RU38486 nor
adrenalectomy significantly attenuated the protein catabolism associated with IL-1 administrations.99,113
These findings suggest that the glucocorticoid response to acute inflammation may also participate in
the increased net proteolysis observed in this tissue.
CONCLUSIONS
Acute inflammation or serious injury elicits a variety
of inflammatory mediators, but the actions of a single
cytokine cannot explain entirely the changes in protein metabolism that occur. TNF-a, IL-1, and IL-6 play
pivotal roles in the anabolic pathways that regulate
nonspecific immunity and the acute phase response,
and IL-6 may be the direct mediator of the hepatic
anabolic protein responses. In contrast, the increased
skeletal muscle protein wasting that accompanies sepsis is likely indirectly controlled by proinflammatory
cytokines, although the mechanisms by which these
agents act on tissue remains unclear.
It is now possible to explore the utility of cytokine
antagonists in catabolic patient populations receiving
nutritional support. Inhibitors of TNF-a synthesis or
processing, anti-TNF-a monoclonal antibodies, soluble TNF receptor constructs, and TNF receptor immunoadhesins are all currently being studied in clinical
trials for human sepsis and SIRS, rheumatoid arthritis,
and for the cachexia associated with human immunodeficiency virus and opportunistic infections. Furthermore, the IL-1 inhibitor, IL-1 receptor antagonist has
been studied in patients with sepsis/SIRS or rheumatoid arthritis.
W: Cancer
1836
CANCER May 1, 1997 / Volume 79 / Number 9
Unfortunately, results with anticytokine therapies in human sepsis/SIRS have shown only limited
success in improving survival. Initial findings of improved outcome with the IL-1 receptor antagonist114 could not be confirmed by a randomized prospective Phase III trial.115 Similarly, studies with
anti-TNF-a antibodies or immunoadhesins have
only shown modest effectiveness in specific subgroups.116 – 118 Several theoretic concerns have limited interpretation of these negative clinical trials,
including the reliance on 28-day all-cause mortality
as the primary outcome variable, the relatively
short half-life of the these molecules and their single dosing regimen, and the fact that treatments
have been initiated several hours after the initial
inflammatory insult. More important, the reliance
on monotherapies for a disease or syndrome in
which clear evidence exists for increased production of a variety of cytokines has raised significant
questions.
In addition, inhibition of TNF synthesis with
pentoxifylline has been evaluated in patients with
acquired immunodeficiency syndrome-related
cachexia with only modest benefits.119 The most encouraging clinical results with cytokine inhibitors
to date have been derived from the rheumatoid arthritis trials with anti-TNF-a antibodies, TNF receptor immunoadhesins, and IL-1 receptor antagonist. In these studies, preliminary reports have suggested that several of these anticytokine therapies
are effective (at least in the short term) in reducing
both the local as well as systemic manifestations of
the disease. Not only are the number and severity
of inflamed joints reduced with these treatments,
but erythrocyte sedimentation rates and acute
phase protein levels (measures of systemic inflammation) are also attenuated. These findings are
encouraging because they suggest that for some inflammatory processes, anticytokine moieties represent potentially new therapeutic modalities. The
utility of these agents in protein-wasting diseases,
with and without adequate exogenous nutritional
support, needs to be determined and defined.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
REFERENCES
1.
2.
3.
4.
Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Long-term
total parenteral nutrition with growth, development, and
positive nitrogen balance. Surgery 1968;64:134–42.
Copeland EM. Jonathan E. Rhoads lecture. Intravenous hyperalimentation and cancer. A historical perspective. JPEN
J Parenter Enteral Nutr 1986;10:337–42.
Copeland EM, Daly JM, Dudrick SJ. Nutrition and cancer.
Int Adv Surg Oncol 1981;4:1–13.
Copeland EM, Daly JM, Ota DM, Dudrick SJ. Nutrition, cancer, and intravenous hyperalimentation. Cancer 1979;
43:2108–116.
/ 7b55$$1072
03-31-97 16:00:11
cana
23.
24.
25.
Issell BF, Valdivieso M, Zaren HA, et al. Protection against
chemotherapy toxicity by IV hyperalimentation. Cancer
Treat Rep 1978;62:1139–1143.
Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J.
Prevalence of malnutrition in general medical patients.
JAMA 1976;235:1567–70.
Bistrian BR, Blackburn GL, Hallowell E, Heddle R. Protein
status of general surgical patients. JAMA 1974;230:858–60.
Blackburn GL, Bistrian BR. Nutritional care of the injured and/
or septic patient. Surg Clin North Am 1976;56:1195–1224.
Dudrick SJ, Copeland EM. Parenteral hyperalimentation.
Surg Annu 1973;5:69–95.
Clowes GH Jr., O’Donnell TF, Blackburn GL, Maki TN. Energy metabolism and proteolysis in traumatized and septic
man. Surg Clin North Am 1976;56:1169–84.
Dudrick SJ, Copeland EM, Daly JM, et al. A clinical review
of nutritional support of the patient. JPEN J Parenter Enteral
Nutr 1979;3:444–51.
Copeland EM, Dudrick SJ. Intravenous hyperalimentation in
inflammatory bowel disease, pancreatitis, and cancer. Surg
Annu 1980;12:83–101.
Kinney JM, Elwyn DH. Protein metabolism and injury. Annu
Rev Nutr 1983;3:433–66.
Elwyn DH. Nutritional requirements of adult surgical patients. Crit Care Med 1980;8:9–20.
Bennegard K, Eden E, Ekman L, Schersten T, Lundholm K.
Metabolic balance across the leg in weight-losing cancer
patients compared to depleted patients without cancer.
Cancer Res 1982;42:4293–9.
Edstrom S, Bennegard K, Eden E, Lundholm K. Energy and
tissue metabolism in patients with cancer during nutritional
support. Arch Otolaryngol Head Neck Surg 1982;108:697–9.
Burt ME, Aoki TT, Gorschboth CM, Brennan MF. Peripheral
tissue metabolism in cancer-bearing man. Ann Surg 1983;
198:685–91.
Long CL, Blakemore WS. Energy and protein requirements
in the hospitalized patient. JPEN J Parenter Enteral Nutr
1979;3:69–71.
Harvey KB, Moldawer LL, Bistrian BR, Blackburn GL. Biological measures for the formulation of a hospital prognostic
index. Am J Clin Nutr 1981;34:2013–22.
Birkhahn RH, Long CL, Fitkin D, Jeevanandam M, Blakemore WS. Whole-body protein metabolism due to trauma in
man as estimated by L-[15N]alanine. Am J Physiol 1981;
241:E64–71.
Birkhahn RH, Long CL, Fitkin D, Geiger JW, Blakemore WS.
Effects of major skeletal trauma on whole body protein turnover in man measured by L-[1,14C]-leucine. Surgery 1980;
88:294–300.
Long CL, Jeevanandam M, Kim BM, Kinney JM. Whole body
protein synthesis and catabolism in septic man. Am J Clin
Nutr 1977;30:1340–4.
Jeevanandam M, Legaspi A, Lowry SF, Horowitz GD, Brennan MF. Effect of total parenteral nutrition on whole body
protein kinetics in cachectic patients with benign or malignant disease. JPEN J Parenter Enteral Nutr 1988;12:229–36.
Pisters PW, Brennan MF. Amino acid metabolism in human
cancer cachexia. Annu Rev Nutr 1990;10:107–32.
Pomposelli JJ, Palombo JD, Hamawy KJ, Bistrian BR, Blackburn GL, Moldawer LL. Comparison of different techniques
for estimating rates of protein synthesis in vivo in healthy
and bacteraemic rats. Biochem J 1985;226:37–42.
W: Cancer
Cytokines and the Cachexia Syndrome/Moldawer and Copeland
26. Kawamura I, Moldawer LL, Keenan RA, et al. Altered amino
acid kinetics in rats with progressive tumor growth. Cancer
Res 1982;42:824–9.
27. Tayek JA, Istfan NW, Jones CT, Hamawy KJ, Bistrian BR,
Blackburn GL. Influence of the Walker 256 carcinosarcoma
on muscle, tumor, and whole-body protein synthesis and
growth rate in the cancer-bearing rat. Cancer Res 1986;
46:5649–54.
28. Ternell M, Moldawer LL, Lonnroth C, Gelin J, Lundholm KG.
Plasma protein synthesis in experimental cancer compared
to paraneoplastic conditions, including monokine administration. Cancer Res 1987;47:5825–30.
29. Andersson CE, Lonnroth IC, Gelin LJ, Moldawer LL, Lundholm KG. Pretranslational regulation of albumin synthesis
in tumor-bearing mice. The role of anorexia and undernutrition. Gastroenterology 1991;100:938–45.
30. Moyer ED, Border JR, McMenamy RH, Caruana J, Chenier
R, Cerra FB. Multiple systems organ failure: V. Alterations
in the plasma protein profile in septic trauma-effects of intravenous amino acids. J Trauma 1981;21:645–9.
31. Wannemacher RWJ. Protein metabolism: applied biochemistry. In: Ghadimi H, editor. Total parenteral nutrition:
premises and promises. New York: John Wiley and Sons,
1975:85–153.
32. Kordula T, Rokita H, Koj A, Fiers W, Gauldie J, Baumann H.
Effects of interleukin-6 and leukemia inhibitory factor on
the acute phase response and DNA synthesis in cultured rat
hepatocytes. Lymphokine Cytokine Res 1991;10:23–6.
33. Gauldie J, Northemann W, Fey GH. IL-6 functions as an
exocrine hormone in inflammation. Hepatocytes undergoing acute phase responses require exogenous IL-. J Immunol
1990;144:3804–8.
34. Schooltink H, Stoyan T, Roeb E, Heinrich PC, Rose JS. Ciliary
neurotrophic factor induces acute-phase protein expression
in hepatocytes. FEBS Lett 1992;314:280–4.
35. Nesbitt JE, Fuentes NL, Fuller GM. Ciliary neurotrophic factor regulates fibrinogen gene expression in hepatocytes by
binding to the interleukin-6 receptor. Biochem Biophys Res
Commun 1993;190:544–50.
36. Fey GH, Hattori M, Northemann W, et al. Regulation of rat
liver acute phase genes by interleukin-6 and production of
hepatocyte stimulating factors by rat hepatoma cells. Ann
N Y Acad Sci 1989;557:317–29.
37. Baumann H, Strassmann G. Suramin inhibits the stimulation of acute phase plasma protein genes by IL-6-type cytokines in rat hepatoma cells. J Immunol 1993;151:1456–62.
38. Ramadori G, Sipe JD, Dinarello CA, Mizel SB, Colten HR.
Pretranslational modulation of acute phase hepatic protein
synthesis by murine recombinant interleukin 1 (IL-1) and
purified human IL-1. J Exp Med 1985;162:930–42.
39. Perlmutter DH, Dinarello CA, Punsal PI, Colten HR.
Cachectin/tumor necrosis factor regulates hepatic acutephase gene expression. J Clin Invest 1986;78:1349–54.
40. Moldawer LL, Andersson C, Gelin J, Lundholm KG. Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 1988;254:G450–6.
41. Dinarello CA, Cannon JG, Wolff SM, et al. Tumor necrosis
factor (cachectin) is an endogenous pyrogen and induces
production of interleukin 1. J Exp Med 1986;163:1433–50.
42. Van Zee KJ, Stackpole SA, Montegut WJ, et al. A human
tumor necrosis factor (TNF) a mutant that binds exclusively
to the p55 TNF receptor produces toxicity in the baboon. J
Exp Med 1994;179:1185–91.
43. Fischer E, Marano MA, Barber AE, et al. Comparison be-
/ 7b55$$1072
03-31-97 16:00:11
cana
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
1837
tween effects of interleukin-1 alpha administration and sublethal endotoxemia in primates. Am J Physiol 1991;
261:R442–52.
Thoenen H, Barde YA, Davies AM, Johnson JE. Neurotrophic
factors and neuronal death. Ciba Found Symp 1987;126:82–
95.
Davis S, Aldrich TH, Stahl N, et al. LIFR beta and gp130 as
heterodimerizing signal transducers of the tripartite CNTF
receptor. Science 1993;260:1805–8.
Davis S, Yancopoulos GD. The molecular biology of the
CNTF receptor. Curr Opin Cell Biol 1993;5:281–5.
Espat NJ, Auffenberg T, Rosenberg JJ, et al. Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity
to induce an acute phase response. Am J Physiol 1996;
271:R185–90.
Clark JT, Sahu A, Kalra PS, Balasubramaniam A, Kalra SP.
Neuropeptide Y (NPY)-induced feeding behavior in female
rats: comparison with human NPY ([Met17]NPY), NPY analog ([norLeu4]NPY) and peptide YY. Regul Pept 1987;17:31–
9.
Metcalf D, Gearing DP. Fatal syndrome in mice engrafted
with cells producing high levels of the leukemia inhibitory
factor. Proc Natl Acad Sci USA 1989;86:5948–52.
Richards CD, Brown TJ, Shoyab M, Baumann H, Gauldie J.
Recombinant oncostatin M stimulates the production of
acute phase proteins in HepG2 cells and rat primary hepatocytes in vitro. J Immunol 1992;148:1731–6.
Low SY, Taylor PM, Hundal HS, Pogson CI, Rennie MJ.
Transport of L-glutamine and L-glutamate across sinusoidal
membranes of rat liver. Effects of starvation, diabetes and
corticosteroid treatment. Biochem J 1992;284:333–40.
Fong Y, Moldawer LL, Shires GT, Lowry SF. The biologic
characteristics of cytokines and their implication in surgical
injury. Surg Gynecol Obstet 1990;170:363–78.
Espat NJ, Cendan JC, Beierle EA, et al. PEG-BP-30 monotherapy attenuates the cytokine-mediated inflammatory cascade
in baboon Escherichia coli septic shock. J Surg Res 1995;
59:153–8.
Zhu X-L, Ayala A, Zellweger R, Morrison MH, Chaudry IH.
Peritoneal macrophages show increased cytokine gene expression following haemorrhagic shock. Immunology 1994;
83:378–83.
Marano MA, Moldawer LL, Fong Y, et al. Cachectin/TNF
production in experimental burns and Pseudomonas infection. Arch Surg 1988;123:1383–8.
He W, Fong Y, Marano MA, et al. Tolerance to endotoxin
prevents mortality in infected thermal injury: association
with attenuated cytokine responses. J Infect Dis 1992;
165:859–64.
Ballmer PE, McNurlan MA, Southorn BG, Grant I, Garlick PJ.
Effects of human recombinant interleukin-1 beta on protein
synthesis in rat tissues compared with a classical acutephase reaction induced by turpentine. Rapid response of
muscle to interleukin-1 beta. Biochem J 1991;279:683–8.
Neufeld HA, Pace JG, Kaminski MV, et al. A probable endocrine basis for the depression of ketone bodies during infectious or inflammatory state in rats. Endocrinology 1980;
107:596–601.
Gershenwald JE, Fong YM, Fahey TJ, et al. Interleukin 1
receptor blockade attenuates the host inflammatory response. Proc Natl Acad Sci USA 1990;87:4966–70.
Chizzonite R, Truitt T, Kilian PL, et al. Two high-affinity
interleukin 1 receptors represent separate gene products.
Proc Natl Acad Sci USA 1989;86:8029.
W: Cancer
1838
CANCER May 1, 1997 / Volume 79 / Number 9
61. Sims J, Gayle M, Slack J, et al. Interleukin 1 signaling occurs
exclusively via the type I receptor. Proc Natl Acad Sci USA
1993;90:6155–9.
62. Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA,
Ju G. Molecular cloning and characterization of a second
subunit of the interleukin 1 receptor complex. J Biol Chem
1995;270:13757–65.
63. Giri JG, Wells J, Dower SK, et al. Elevated levels of shed type
II-IL-1 receptor in sepsis. Potential role for type II receptor
regulation of IL-1 responses. J Immunol 1994;153:5802–9.
64. Pruitt JH, Copeland EM, Moldawer LL. Interleukin-1, interleukin-1 receptor antagonist and interleukin-1 receptors
in sepsis, shock and the systemic inflammatory response
syndrome. Shock 1995;3:235–51.
65. Tocco BR, Moldawer LL, Jones CT, Gerson B, Blackburn GL,
Bistrian BR. The biological activity in vivo of recombinant
murine interleukin 1 in the rat. Proc Soc Exp Biol Med
1986;182:263–71.
66. Oldenburg HSA, Keller B, Lazarus D, et al. Interleukin-1
binding to its type I, but not type II receptor, modulates the
in vivo acute phase response. Cytokine 1995;7:510–6.
67. Solorzano CC, Kaibara A, Pruitt JH, et al. Mice lacking a
functional IL-1 type I but not a TNF type I receptor exhibit
an attenuated acute phase response in acute inflammation.
Surg Forum 1996;47:72–3.
68. Fantuzzi G, Dinarello CA. The inflammatory response in interleukin-1 beta-deficient mice: comparison with other cytokine-related knock-out mice. J Leukoc Biol 1996;59:489–93.
69. Sherry BA, Gelin J, Fong Y, et al. Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of
cachexia in tumor models. FASEB J 1989;3:1956–62.
70. Oldenburg HS, Rogy MA, Lazarus DD, et al. Cachexia and
the acute-phase protein response in inflammation are regulated by interleukin-6. Eur J Immunol 1993;23:1889–94.
71. Kopf M, Baumann H, Freer G, et al. Impaired immune and
acute-phase responses in interleukin-6-deficient mice. Nature 1994;368:339–42.
72. Strassmann G, Fong M, Windsor S, Neta R. The role of interleukin-6 in lipopolysaccharide-induced weight loss, hypoglycemia and fibrinogen production, in vivo. Cytokine
1993;5:285–90.
73. Strassmann G, Jacob CO, Evans R, Beall D, Fong M. Mechanisms of experimental cancer cachexia. Interaction between
mononuclear phagocytes and colon-26 carcinoma and its
relevance to IL-6-mediated cancer cachexia. J Immunol
1992;148:3674–8.
74. Waring P, Wycherley K, Cary D, Nicola N, Metcalf D. Leukemia inhibitory factor levels are elevated in septic shock and
various inflammatory body fluids. J Clin Invest 1992;
90:2031–7.
75. Alexander HR, Wong GG, Doherty GM, Venzon DJ, Fraker
DL, Norton JA. Differentiation factor/leukemia inhibitory
factor protection against lethal endotoxemia in mice: synergistic effect with interleukin 1 and tumor necrosis factor. J
Exp Med 1992;175:1139–42.
76. Hawes AS, Fischer E, Marano MA, et al. Comparison of peripheral blood leukocyte kinetics after live Escherichia coli,
endotoxin, or interleukin-1 alpha administration. Studies
using a novel interleukin-1 receptor antagonist. Ann Surg
1993;218:79–90.
77. Moldawer LL, Marano MA, Wei H, et al. Cachectin/tumor
necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo. FASEB J 1989;3:1637–43.
78. Fischer E, Marano MA, Van Zee KJ, et al. Interleukin-1 recep-
/ 7b55$$1072
03-31-97 16:00:11
cana
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
tor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host
responses to sublethal endotoxemia. J Clin Invest 1992;
89:1551–7.
Long CL, Schaffel N, Geiger JW, Schiller WR, Blakemore WS.
Metabolic response to injury and illness: estimation of energy and protein needs from indirect calorimetry and nitrogen balance. JPEN J Parenter Enteral Nutr 1979;3:452–6.
Kinney JM, Gump FE, Long CL. Energy and tissue fuel in
human injury and sepsis. Adv Exp Med Biol 1972; 33:401 –
7.
Long CL. Energy balance and carbohydrate metabolism in
infection and sepsis. Am J Clin Nutr 1977;30:1301–10.
Wilmore DW. Hormonal responses and their effect on metabolism. Surg Clin North Am 1976;56:999–1018.
Wilmore DW, Long JM, Mason AD Jr., Skreen RW, Pruitt BA.
Catecholamines: mediator of the hypermetabolic response
to thermal injury. Ann Surg 1974;180:653–69.
O’Donnel TF, Clowes GH Jr., Blackburn GL, Ryan NT, Benotti PN, Miller JD. Proteolysis associated with a deficit of
peripheral energy fuel substrates in septic man. Surgery
1976;80:192–200.
Cerra FB, Siegel JH, Coleman B, Border JR, McMenamy RR.
Septic autocannibalism. A failure of exogenous nutritional
support. Ann Surg 1980;192:570–80.
Clowes GH Jr., George BC, Villee CA Jr., Saravis CA. Muscle
proteolysis induced by a circulating peptide in patients with
sepsis or trauma. N Engl J Med 1983;308:545–52.
Pekarek RS, Powanda MC, Wannemacher RWJ. The effect of
leukocytic endogenous mediator (LEM) on serum copper
and ceruloplasmin concentrations in the rat. Proc Soc Exp
Biol Med 1972;141:1029–31.
Pekarek RS, Wannemacher RW Jr., Beisel WR. The effect of
leukocytic endogenous mediator (LEM) on the tissue distribution of zinc and iron. Proc Soc Exp Biol Med 1972;140:685–
8.
Wannemacher RW Jr., Pekarek RS, Klainer AS, et al. Detection of a leukocytic endogenous mediator-like mediator of
serum amino acid and zinc depression during various infectious illnesses. Infect Immun 1975;11:873–5.
Kampschmidt RF, Pulliam LA. Effect of human monocyte
pyrogen on plasma iron, plasma zinc, and blood neutrophils in rabbits and rats. Proc Soc Exp Biol Med 1978;
158:32 – 5.
Merriman CR, Pulliam LA, Kampschmidt RF. Comparison
of leukocytic pyrogen and leukocytic endogenous mediator.
Proc Soc Exp Biol Med 1977;154:224–7.
Kampschmidt RF, Upchurch HF. Effect of leukocytic endogenous mediator on plasma fibrinogen and haptoglobin. Proc
Soc Exp Biol Med 1974;146:904–7.
Klempner MS, Dinarello CA, Gallin JI. Human leukocytic
pyrogen induces release of specific granule contents from
human neutrophils. J Clin Invest 1978;61:1330–6.
Dinarello CA, Renfer L, Wolff SM. Human leukocytic pyrogen: purification and development of a radioimmunoassay.
Proc Natl Acad Sci USA 1977;74:4624–7.
Hooper DC, Steer CJ, Dinarello CA, Peacock AC. Haptoglobin and albumin synthesis in isolated rat hepatocytes. Response to potential mediators of the acute-phase reaction.
Biochim Biophys Acta 1981;653:118–29.
Sobrado J, Moldawer LL, Bistrian BR, Dinarello CA, Blackburn GL. Effect of ibuprofen on fever and metabolic changes
induced by continuous infusion of leukocytic pyrogen (interleukin 1) or endotoxin. Infect Immun 1983;42:997–1005.
W: Cancer
Cytokines and the Cachexia Syndrome/Moldawer and Copeland
97. Yang RD, Moldawer LL, Sakamoto A, et al. Leukocyte endogenous mediator alters protein dynamics in rats. Metabolism
1983;32:654–60.
98. Hasselgren PO, James JH, Benson DW, Li S, Fischer JE. Is
there a circulating proteolysis-inducing factor during sepsis?
Arch Surg 1990;125:510–4.
99. Zamir O, Hasselgren PO, James H, Higashiguchi T, Fischer
JE. Effect of tumor necrosis factor or interleukin-1 on muscle
amino acid uptake and the role of glucocorticoids. Surg Gynecol Obstet 1993;177:27–32.
100. Kettelhut IC, Goldberg AL. Tumor necrosis factor can induce
fever in rats without activating protein breakdown in muscle
or lipolysis in adipose tissue. J Clin Invest 1988;81:1384–9.
101. Moldawer LL, Svaninger G, Gelin J, Lundholm KG. Interleukin 1 and tumor necrosis factor do not regulate protein balance in skeletal muscle. Am J Physiol 1987;253:C766–73.
102. Fong Y, Moldawer LL, Marano M, et al. Cachectin/TNF or
IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol 1989;256:R659–65.
103. Breuille D, Farge MC, Rose F, Arnal M, Attaix D, Obled C.
Pentoxifylline decreases body weight loss and muscle protein wasting characteristics of sepsis. Am J Physiol 1993;
265:E660–6.
104. Voisin L, Gray K, Juransinski CV, et al. Altered expression
of eukaryotic initiation factor 2B in skeletal muscle during
sepsis. Am J Physiol 1996;270:E43–50.
105. Juransinski CV, Kilpatrick L, Vary TC. Amrinone prevents
muscle protein wasting during chronic sepsis. Am J Physiol
1997;268:E636–41.
106. Zamir O, Hasselgren PO, Kunkel SL, Frederick J, Higashiguchi T, Fischer JE. Evidence that tumor necrosis factor participates in the regulation of muscle proteolysis during sepsis. Arch Surg 1992;127:170–4.
107. Zamir O, Hasselgren PO, O’Brien W, Thompson RC, Fischer
JE. Muscle protein breakdown during endotoxemia in rats
and after treatment with interleukin-1 receptor antagonist
(IL-1ra). Ann Surg 1992;216:381–5.
108. Vary TC, Voisin TC, Cooney RN. Regulation of peptide-chain
initiation during sepsis by interleukin-1 receptor antagonist.
Am J Physiol 1997;270:E513–20.
109. Lazarus DD, Moldawer LL, Lowry SF. Insulin-like growth
factor-1 activity is inhibited by interleukin-1 alpha, tumor
necrosis factor-alpha, and interleukin-. Lymphokine Cytokine Res 1993;12:219–23.
/ 7b55$$1072
03-31-97 16:00:11
cana
1839
110. Fan J, Char D, Bagby GJ, Gelato MC, Lang CH. Regulation
of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor. Am J Physiol 1995;269:R1204–
12.
111. Lang CH, Fan J, Cooney R, Vary TC. IL-1 receptor antagonist
attenuates sepsis-induced alterations in the IGF system and
protein synthesis. Am J Physiol 1996;270:E430–7.
112. Hall AM, Angeras U, Zamir O, Hasselgren PO, Fischer JE.
Interaction between corticosterone and tumor necrosis factor stimulated protein breakdown in rat skeletal muscle,
similar to sepsis. Surgery 1990;108:460–6.
113. Zamir O, Hasselgren PO, von Allmen D, Fischer JE. The effect
of interleukin-1 alpha and the glucocorticoid receptor
blocker RU 38486 on total and myofibrillar protein breakdown in skeletal muscle. J Surg Res 1991;50:579–83.
114. Fisher CJ Jr., Slotman GJ, Opal SM, et al. Initial evaluation
of human recombinant interleukin-1 receptor antagonist in
the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA SepsisSyndrome Study Group [see comments]. Crit Care Med
1994;22:12–21.
115. Fisher CJ Jr., Dhainaut J-FA, Opal SM, et al. Recombinant
human interleukin 1 receptor antagonist in the treatment
of patients with sepsis syndrome: results from a randomized,
double-blind, placebo-controlled trial. JAMA 1994;271:
1836–43.
116. Fisher CJ Jr., Opal SM, Dhainaut JF, et al. Influence of an
anti-tumor necrosis factor monoclonal antibody on cytokine
levels in patients with sepsis. The CB0006 Sepsis Syndrome
Study Group [see comments]. Crit Care Med 1993;21:318–
27.
117. Fisher CJ Jr., Agosti JM, Opal SM, et al. Treatment of septic
shock with the tumor necrosis factor receptor:fc fusion protein. N Engl J Med 1996;334:1697–1702.
118. Abraham E, Wunderink R, Silverman H, et al. Efficacy and
safety of monoclonal antibody to human tumor necrosis
factor a in patients with sepsis syndrome: a randomized,
controlled, double-blind, multicenter clinical trial. JAMA
1995;273:934–41.
119. Dezube BJ, Lederman MM, Spritzler JG, et al. High-dose
pentoxifylline in patients with AIDS: inhibition of tumor necrosis factor production. National Institute of Allergy and
Infectious Diseases AIDS Clinical Trials Group. J Infect Dis
1995;171:1628–32.
W: Cancer
Документ
Категория
Без категории
Просмотров
4
Размер файла
160 Кб
Теги
586
1/--страниц
Пожаловаться на содержимое документа