Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 425-439
REVIEW ARTICLE
Granulocyte Colony-Stimulating Factor to Prevent the Progression of
Systemic Nonresponsiveness in Systemic Inflammatory Response Syndrome
and Sepsis
By
Manfred Weiss,
Lyle L. Moldawer, and
E. Marion Schneider
From the Departments of Anesthesiology and Experimental
Anesthesiology, Universitätsklinikum, Ulm, Germany; and the
Department of Surgery, University of Florida College of Medicine,
Gainesville, FL.
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PUTATIVE ROLE OF GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) IN
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS) AND SEPSIS |
THE SYSTEMIC inflammatory
response syndrome (SIRS) constitutes the primary host response to a
variety of severe clinical insults, such as trauma, burns,
pancreatitis, or major surgical interventions.1 Distinct
from SIRS, the term sepsis is applied to the clinical state when
bacterial infections cause a systemic hyperinflammatory immune
response.1 However, this exaggerated host inflammatory
response may not lead to an efficient elimination of the infectious
agent; rather, it may contribute to a state of immune deactivation that
has been termed compensatory anti-inflammatory response syndrome
(CARS).2 Concomitantly, CARS may increase susceptibility to
secondary infections. The main pathways of the inflammatory circuit
during SIRS, sepsis, and CARS are summarized in Fig 1.
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| Fig 1.
The main pathways of the inflammatory circuits during
SIRS and sepsis are summarized. Exogenous G-CSF (dashed lines) can
interrupt a fulminant proinflammatory and anti-inflammatory response by
downmodulating the action of proinflammatory TNF- and IL-1, by
increasing IL-1ra (and soluble TNFR) secretion, by decreasing IL-8, by
improving IL-6 consumption via IL6R (p80), by upregulating HO-1, by
improving LPS clearance, and by modulating the incidence of apoptotic
hematopoietic cells.
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The overall aim of this review is to discuss the current rationale for
administering G-CSF to critically ill patients at risk of or with
sepsis/SIRS to improve neutrophil function and to modulate the
otherwise predestined release of inflammatory mediators. Thus, by
direct and indirect effects, G-CSF may prevent the fatal course of
sepsis in critically ill patients and promote recovery.
According to the general view, SIRS and sepsis are caused by trauma- or
infection-induced overproduction of tumor necrosis factor- (TNF-)
and interleukin-1 (IL-1).1 Severe sepsis with organ failure
may develop when endotoxin (lipopolysaccharide [LPS]) from
gram-negative bacteria and/or soluble products of gram-positive bacteria, mostly superantigens, lead to macrophage activation and
production of macrophage and T-cell-derived cytokines, including TNF-, IL-1, interferon-
(IFN-), and IL-12. In turn,
these cytokines may synergize with LPS to stimulate the release of
nitric oxide (NO) via NOS-2 in a variety of cell types.3-8
NO has been proposed as the direct mediator of the cardiovascular
failure in sepsis9 and septic shock.10 Although
NO is produced during sepsis from cytokine-regulated NOS-2, a strong correlation between NO production, organ failure, and an exaggerated proinflammatory response has only been documented in pediatric patients.11 In the majority of adult patients, a clear
correlation is more difficult to prove, which may be due to suppression
of TNF and IL-1 by anti-inflammatory cytokines, such as by IL-10, which
downregulates NO synthase activity and the synthesis of proinflammatory
mediators.12 NO synthase inhibition reduced TNF-stimulated
IL-8 production in a human endothelial cell line, whereas exogenously
added NO enhanced the release of IL-8.13 In addition, NO
synthase inhibition blocked IL-8 and IL-6 production in LPS-stimulated
human whole blood.14 Conversely, direct exposure of whole
blood to NO caused a dose-dependent stimulation of IL-8 but had no
effect on IL-6 release. Moreover, the hydroxyl radical scavenger
dimethyl sulfoxide (DMSO) prevented NO induction of IL-8, suggesting
the participation of the hydroxyl radical in the NO-induced IL-8
production.14 Thus, NO and reactive oxygen intermediates
(ROI) may play an essential role in the cytokine pattern in critically
ill patients with SIRS and sepsis.
In contrast, counterregulatory Th2 type cytokines, such as
IL-415 and transforming growth factor-
(TGF-),4,16 have been shown to prevent NOS-2 induction.
Importantly, the highly reactive peroxynitrite (ONOO
) is
formed as a reaction product of NO plus ROI (Fig 1). ROI either result
from xanthine oxidase activity17 or from neutrophils activated by bacteria or their soluble products. In addition to a
number of other effects, peroxynitrite causes microvascular permeability and edema formation, leading to clinical signs of septic
shock.18 As a potent oxidant, peroxynitrite reacts with lipids, thiols, DNA, and proteins and may constitute an inducer of
apoptosis, as examplified in a study with vascular smooth muscle cells.7,19
The fatal course of sepsis may be due to systemic immune dysregulation
and immunosuppression. In septic mice, apoptosis has been shown to
occur primarily in hematopoietic cells, such as T and B lymphocytes, as
well as in parenchymal cells, such as bowel, lung, and, to a lesser
extent, skeletal muscles and kidneys, but not in liver, brain, or
heart.20 Thus, widespread lymphocyte depletion by apoptosis
may contribute to lymphopenia observed in patients with sepsis and to
decreased elimination of bacteria and bacterial products in sepsis.
Moreover, it has been shown that endothelial cell apoptosis can occur
via an oxygen radical-dependent mechanism.21,22
Experimental work by Ayala et al23,24 as well as Hotchkiss
et al20 shows that systemic apoptosis of the immune system
is the most marked feature in experimental animals dying of multiple
organ failure during septic shock induced by massive bacterial
infection, as already proposed by Bone.2
In severely ill patients with sepsis, peripheral blood cell-derived
TNF- and IL-1 cytokine production after stimulation with LPS in
vitro was transiently downregulated and restored within 72 hours in
survivors, but there was no restoration in nonsurvivors.25 Thus, persistent downregulation of proinflammatory cytokine production could be related to increased mortality in critically ill patients with
sepsis. This downregulation may not result from the induction of
tolerance, but through the selective removal of immune cells capable of
producing these cytokines. Recent evidence suggests that, in addition,
FAS-ligand (FasL) may mediate apoptosis in selected cell populations.
Type 1 (Th1) T helper lymphocytes, activated by bacteria,
could be subsequently killed after FAS-ligand induction in the same or
in a different T-cell population, a process that has been termed
activation-induced cell death (AICD).26 AICD predominantly,
but not exclusively, occurs in Th1 cells.26,27 Whereas T cells exposing FAS are highly sensitive to AICD,
FAS-ligand-expressing cells are resistant.26,27 This may
lead to a selective survival of Th2 cells and a
preponderance of Th2 cells after proinflammatory response
during SIRS and sepsis. In turn, predominant depletion of
Th1 cells by apoptosis may contribute to the development of CARS. The term CARS is based on the presence of an inactivating and
compensatory response to the original inciting event, the proinflammatory response.2,28 This state of
immunosuppression also results in increased susceptibility to
infection,2 which may further contribute to an
infection-induced fatal course of sepsis.
Agents contributing to the anti-inflammatory response include
corticosteroids, prostaglandins, IL-4,15
IL-10,29 IL-11, IL13, TGF-,16 soluble
receptors to TNF (sTNF-R), and receptor antagonists to IL-1
(IL-1ra)30-33 (Fig 1). The inhibitory Th2 type cytokines IL-4, IL-10, and IL-13 downregulate monocyte activation states after encountering LPS.29,34,35
To analyze the relative contribution of SIRS alone or in combination
with infection, ie, sepsis, ex vivo cytokine production by neutrophils
isolated from patients who had undergone cardiac surgery with
cardiopulmonary bypass and from patients with sepsis were studied.
These stressful conditions related to inflammation, independent of
infection, rapidly dampened the reactivity of circulating neutrophils.
The release of IL-8 by neutrophils in both groups of patients was
significantly reduced whether activated by LPS or by heat-killed
streptococci.36 LPS-induced mediators such as IL-10 may be
responsible for the observed anergy in these patients. In sepsis,
immune deactivation is also mediated by activation of TGF- via
proteases, such as plasmin.37
Colony-stimulating factors, such as G-CSF and granulocyte-macrophage
colony-stimulating factor (GM-CSF), appear to constitute a separate,
unique class of mediators. These mediators not only trigger recruitment
of progenitors from stem cells, but also modulate adhesion receptor
expression as well as upregulate cell protective molecules. In
mesenchymal cells such as fibroblasts and mesothelial cells, the G-CSF
gene is clearly regulated in a coordinate manner with other genes
encoding cytokines such as GM-CSF and IL-6,38-40 ie, these
genes are all induced by the same stimuli with similar kinetics. After
exposure of cytokines, such as TNF, induced by infections, G-CSF and
GM-CSF are coinduced.38,39 In turn, both, G-CSF and GM-CSF
may stimulate common effector pathways,41,42 while
resulting effects of both cytokines may also differ significantly, as
will be discussed in detail below.
In the clinical setting, three considerations are required for the
successful treatment of patients with sepsis: (1) to stabilize blood
pressure and maintain regional organ and tissue perfusion, (2) to
modulate the hyperinflammatory immune response induced by specific
(infections; sepsis) or nonspecific (ROI; SIRS) stimulators, and (3) to
counteract systemic nonresponsiveness and anergy. The use of biological
response modifiers for the treatment of patients with SIRS and sepsis
is limited by the fact that the molecular nature of the inducer(s) is
not precisely known and is likely not a single common denominator. In
addition, differing clinical states have not yet been defined by
immunological parameters, and treatment protocols are up to now not
directed at a distinct immunological status of the patient.
These limitations become a challenge when biological response modifiers
are considered as interventional therapies. Can any one single
therapeutic approach help restore homeostasis in sepsis and SIRS
regardless of its timing? Clearly, monotherapies such as inhibitors of
TNF- or IL-1 are limited in this regard. The putative goal for
anti-inflammatory monotherapies has been to block or eliminate the
inducing agent(s) or to modulate the proinflammatory cytokine cascade.
The failure to demonstrate any benefit from such
treatments43,44 may be due in part to the erroneous
assumption that the pathogenesis of sepsis and SIRS in all patients is
essentially one of persistent, uncontrolled inflammation driven by the
overproduction of a single inflammatory mediator.2
An alternative approach to the anti-inflammatory monotherapies has been
to consider multipotent molecules, such as hematopoietic growth
factors, which can address the various immunologic responses simultaneously in the septic patient. One of the hematopoietic growth
factors, ie, G-CSF, plays a central role in proliferation, maturation,
and functional activation of neutrophils.42,45-50 G-CSF has
recently been shown to stimulate host immunity by increasing leukocyte
number and by upregulating neutrophil function in
postoperative/posttraumatic patients at risk of sepsis
(Fig 2).51 IL-6 and G-CSF
provide growth and survival signals to progenitors of the granulocyte lineage.52 G-CSF promoted mobilization and survival of
CD34+ stem cells in the bone marrow53 and in
the peripheral blood.54 This was due, at least in part, to
suppression of apoptosis.53,54 Also, incubation of
neutrophils from acquired immunodeficiency syndrome (AIDS) patients
with G-CSF in vitro significantly decreased apoptosis.55 In
patients with acute respiratory distress syndrome (ARDS), neutrophils
from bronchoalveolar lavage fluid (BAL) showed only modest signs of
apoptosis, presumably due to high amounts of G-CSF and GM-CSF as well
as other cytokines like IL-6 in BAL.56 Thus, G-CSF may
represent one of several survival factors for neutrophils to inhibit
apoptosis during SIRS and sepsis and to preserve neutrophil function.
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| Fig 2.
Comparison of the quantitative follow-up of FMLP-induced
(104 mol/L) oxygen radical production by isolated
neutrophils in the postoperative/posttraumatic period between the study
group and the control group. Oxygen radical production was assayed by
chemiluminescence measurements. Chemiluminescence response is expressed
as a percentage of the baseline value, ie, chemiluminescence response
at the first postoperative day (100%). In the study group, the
baseline value at the first postoperative day represents the
chemiluminescence response before infusion of rhG-CSF. Dosages of
rhG-CSF administered in the study group are indicated as bars on the x
axis. Each point of the curves is the mean ± SEM of the
chemiluminescence response of the 10 patients of the study group and of
the control group, respectively, at the various days. *P < .05 equals a statistically significant difference between
chemiluminescence response at the first postoperative day, ie, baseline
value, and the chemiluminescence response during the following days
within the study group and within the control group, respectively.
+P < .05 equals a statistically significant difference
between the chemiluminescence response of the study group and that of
the control group at the various postoperative days. ( ) Study group;
(×) control group. (Modified and reprinted with
permission.51)
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Besides these direct effects on granulocytes, G-CSF has been shown to
exert direct and indirect effects on other immunocompetent cells.
Direct effects are mediated by cells that express G-CSF receptors
(G-CSFR). G-CSFR were clearly detected by flow cytometry on adult human
peripheral granulocytes and monocytes, but not on
lymphocytes.57 Administered prophylactically, direct and indirect effects of G-CSF might block the hyperinflammatory cytokine cascade mediated by proinflammatory cytokines before culminating in
severe tissue damage. Moreover, these effects might help to restore
immune dysfunction and dysbalance in critically ill patients. The
addition of G-CSF promoted an anti-inflammatory response pattern in
several usually proinflammatory test systems. For example, T cells of
G-CSF-treated mice predominantly produced anti-inflammatory type-2
cytokines (IL-4 and IL-10).58 Moreover, G-CSF
administration to human volunteers increased Th2 type
cytokines in LPS-stimulated ex vivo blood cultures.59
Reduced Th1 cytokine and increased Th2 cytokine
expression are expected to downmodulate NOS-2 activation, as
schematically demonstrated in Fig 1.
As summarized in Fig 1, TNF- can stimulate IL-1 secretion in tissue
macrophages, and this cytokine in turn can activate IL-1ra production
to counteract IL-1-mediated inflammatory cascades.60 Exogenous G-CSF (dashed lines in Fig 1) rapidly stimulates IL-1ra production.59,61,62 The autocrine cytokine cascade of
inflammatory mediators could thus be interrupted.
Moreover, G-CSF promotes IL-6 use via increased expression and shedding
of the IL-6 receptor (IL-6R, p80), as shown independently in two
patient populations.63,64 Indeed, IL-6 and G-CSF may act
similarly by stimulating intracellular pathways, such as
phosphorylation of STAT3 transcription factor.65-69 G-CSF
and IL-6 cooperate and can even substitute for each other in
recruitment of myeloid cells in G-CSFR and IL-6 knock out mouse
models.52 G-CSF and IL-6 may act in a dual role to amplify
inflammatory responses when the inciting pathogen is present within the
host and to downmodulate the response when the pathogen has been
eradicated.68
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REGULATION OF G-CSF PRODUCTION IN INFECTION |
Bacterial endotoxin stimulates macrophages to produce proinflammatory
cytokines, such as TNF- and IL-1, which in turn stimulate fibroblasts and endothelial cells to produce G-CSF.70 Dunn
et al71 identified regulatory elements in the G-CSF
promotor activated by NF-IL-6 and NF-
B, and Smith et
al72 reported binding for the transcription factors PU.1
and C/EBP-. Consequently, TNF- synthesizing monocytes regulate
G-CSF production by autocrine effects that are probably different from
endothelial cells and fibroblasts. Inducers of G-CSF release may be
distinct in different cell types, ie, macrophages, fibroblasts, and
endothelial cells.
G-CSF serum concentrations have been reported to be less than 30 pg/mL
in most healthy persons73 and rarely exceed concentrations greater than 170 pg/mL70,73-76
(Table 1). Early during active infections,
such as pneumonia, cholecystitis, or urinary tract infection, and
sepsis, serum concentrations of G-CSF may increase rapidly to more than
50,000 pg/mL,70,74,77-80 but rapidly decrease due to
clearance through binding and use. After an infectious episode, G-CSF
serum concentrations returned to levels less than 200 pg/mL.70,74,79,80
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MARKERS OF IMMUNE DYSFUNCTION AND G-CSF RESPONSIVENESS IN STATES OF
SIRS AND SEPSIS: RATIONALE FOR THE APPLICATION OF G-CSF IN PATIENTS
WITH IMPAIRED NEUTROPHIL FUNCTION |
In recent years, G-CSF has been demonstrated to be effective and safe
in reducing the incidence of infection in high-risk patients, ie, after
myelosuppressive anticancer chemotherapy,45,81,82 as well
as in neutropenic and agranulocytotic patients.82-84 Its effectiveness is due in part to G-CSF's effects on increasing neutrophil count and functional receptors, such as G-CSFR as well as
monomeric Fc receptors. Moreover, G-CSF might be beneficial in
nonneutropenic patients with SIRS, infections, and sepsis with impaired
neutrophil function. In these nonneutropenic patients, high
concentrations of proinflammatory cytokines, such as TNF- and IL-1,
may cause accumulation of ROI in granulocytic effectors, thereby
causing increased apoptosis of neutrophils,85 inefficient phagocytic function, and thus a state of immune dysfunction.
Secondary phagocyte defects and reductions in neutrophil numbers and
functional impairment have been documented in a variety of clinical
states. Patients with impaired neutrophil function are at increased
risk to develop sepsis and to progress into septic shock and multiple
organ failure.86,87 Preexisting immunosuppression due to
the underlying disease has been reported in patients with diabetes,88,89 acute necrotizing
pancreatitis,90 or alcoholism.91 Acquired
immunosuppression and impairment of neutrophil function may result from
previous medication (immunosuppressive and cytostatic drugs), operative
trauma,92-94 blood transfusions,95 anesthetics, hypnotics, and sedatives96,97 as well as
sympathomimetics.98 Migration to an infectious focus,
ingestion, and killing of bacteria by neutrophils from critically ill
patients with SIRS and sepsis has been reported to be significantly
compromised.99-103
However, boosting numbers and functions of granulocytes, macrophages,
and lymphocytes is a prerequisite for withstanding microorganism invasion. Endogenous and exogenous G-CSF may be crucial for
host defense in patients with SIRS and sepsis to avoid progression into
severe sepsis with organ failure and septic shock by improving neutrophil functions and inhibiting neutrophil
apoptosis.23,24,55 In addition to stimulating the
proliferation and maturation of neutrophils,45 G-CSF
enhances chemotaxis,46 phagocytic activity,47 bactericidal function,47 respiratory
burst,42,49 and antibody-dependent cellular cytotoxicity
(ADCC)48 of isolated human neutrophils. Administration of G-CSF acts synergistically with antibiotics and
improves outcome of severe infections.104-106
G-CSF administration improved survival in several animal models of
sepsis,105-108 even when applied therapeutically after the onset of sepsis105 (Fig 3).
These animal data imply that stimulation of neutrophil function and
viability represents a major goal for treating patients with ongoing
infections.
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| Fig 3.
Cumulative mortality in septic rats treated with G-CSF at
the induction of sepsis or after 4 hours. *P < .05; logrank
test, n = 24 in all groups. In rats, polymycrobial peritonitis was
induced by a cecal perforation and 10 µg/kg recombinant human G-CSF
was administered intravenously every 12 hours, with the first dose at
sepsis induction or 4 hours postinduction. (Modified and reprinted with
permission.169)
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There is now increasing evidence that an inappropriate endogenous G-CSF
response may be associated with an adverse outcome to sepsis. For
example, low serum G-CSF concentrations (0 to 125 pg/mL) on admission
have been shown to be associated with fatal outcome in patients with
acute bacterial infections.78
In patients undergoing a successful response to infections, G-CSF serum
concentrations should be high immediately and decrease consecutively,
when G-CSF is used and neutrophil counts increase. In patients not
responding successfully to infections, serum G-CSF concentrations will
remain high, but neutrophil counts would not increase. Similar patterns
are expected to occur when patients are treated with exogenous G-CSF.
In patients with bacteremia80 or at the time sepsis was
diagnosed,79 endogenous G-CSF concentrations were found to
be markedly increased in all patients, both survivors and nonsurvivors. However, concentrations significantly decreased with recovery in the
survivors, but remained increased in the nonsurvivors. In the same
study, the levels of G-CSF, IL-6, and, to some extent, TNF- rapidly
decreased in nonfatal bacteremic infections within the first 24 hours;
however, concentrations remained increased or showed a more gradual
decrease in the nonsurvivors within 18 to 96 hours.80 In a
different study, application of exogenous rhG-CSF in 19 patients with
granulocytopenia complicated by sepsis increased granulocyte counts and
improved survival when G-CSF serum concentrations
decreased.109 However, in the five patients with
persistently high plasma G-CSF levels, leukocyte counts were not
increased and the patients died.109 Thus, either early
increased endogenous production or enhanced use of administered G-CSF
(ie, G-CSF responsiveness) correlated with the patients' successful outcome.
Thus, G-CSF responsiveness has to be monitored by leukocyte counts,
G-CSF serum concentrations, and G-CSF-responsive gene products (see
below) to ascertain successful treatment with exogenous G-CSF.
In a phase II study in patients at risk of or with sepsis, we
successfully identified patients who could and could not respond to
exogenous G-CSF administration. In responding patients, an increase in
G-CSF serum concentrations after exogenous application of rhG-CSF was
followed by an immediate decrease and a rapid increase of neutrophil
counts and CD64 expression.61 In nonresponders, in which
G-CSF substitution did not increase leukocyte counts, molecular
mechanisms have to be defined. Impaired G-CSFR expression may
contribute to nonresponsiveness. Whereas G-CSF induced increased G-CSFR expression,110 GM-CSF, TNF, LPS,
f-met-leu-phe (fMLP), phorbol ester (TPA), and C5a were shown to
downregulate the neutrophil G-CSFR in vitro.111 Binding
assays using 125I-labeled rG-CSF showed that the
number of rG-CSF binding sites on the surface of neutrophil progenitor
cells is regulated by cytoplasmic cAMP and protein kinase
A.112 Rapid internalization of G-CSFRs111 may
mask the amount of surface expression of G-CSFRs detected under
G-CSF-responsive conditions. These conditions explain results showing
reduced G-CSFRs in G-CSF-treated cell lines and neutrophils.113 Differential G-CSF responsiveness may
ultimately explain the failure to demonstrate beneficial effects on
nosocomial infections in a recently performed study in patients with
acute traumatic brain injury or cerebral hemorrhage prophylactically treated with G-CSF.114
Prophylactic administration with G-CSF appears to be superior to an
endogenous immune response to fight infection in critically ill
patients. During an infection, both G-CSF and GM-CSF are
produced.38,39 Both cytokines induce leukocyte maturation
and activation.41,42 In contrast to G-CSF, GM-CSF may cause
serious side effects when applied exogenously and thus independently of
G-CSF.45,115
G-CSF inhibited leukotriene E4
(LTE4) formation in humans in
vivo116 and potently reduced the activity of NOS-2 in
peritoneal macrophages.117 In contrast, GM-CSF upregulated
NOS-2118-122 and enhanced LTB4 generation of
neutrophils.123-125 McDonald et al126 showed
that IL-8 may be responsible for the synthesis of LTB4 and
platelet-activating factor after GM-CSF treatment. Thereby, the combined presence of IL-8 and of GM-CSF at inflammatory foci may
contribute to the amplification of the inflammatory response. GM-CSF
stimulated adhesion receptor expression, such as intercellular adhesion
molecule-1 (ICAM-1).127 However, G-CSF downregulated ICAM-1
on IL-1-stimulated human endothelial cells.128
Yong129 further showed that G-CSF, but not GM-CSF, promotes
transendothelial migration of neutrophils. ROI released by adherent
neutrophils may cause capillary leakage and lung toxicity, which
occurred in patients with sepsis treated with
GM-CSF.45,115 Massive IL-8 is considered to
indicate the amount of ROI induced in vitro.13,14
In contrast to GM-CSF, G-CSF is expected to downmodulate the
proinflammatory immune response, which otherwise might result in severe
tissue damage and organ failure. This rationale favors the
administration of G-CSF to critically ill patients at risk of sepsis
and before other proinflammatory cytokines are systemically present.
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FUNCTIONAL ANTIGENS MODULATED BY G-CSF |
Functional antigens on neutrophils, such as CD64, CD32,
CD16, and CD11b, defined by specific clusters of differentiation
(CD), can be easily monitored by flow cytometry. rhG-CSF reconstituted and increased functional antigen CD64 (monomeric Fc receptor; FcRI)
expression in postoperative/posttraumatic patients at risk of or with
sepsis,61 and the same increase of CD64 expression has been
described on immature and mature neutrophils in normals and patients
with malignancies130-132 (Table
2A). Functionally, exogenous G-CSF enhanced ADCC in
patients with advanced squamous cell carcinoma of the oral cavity and
pharynx through FcRI (CD64).130 Also, expression of
FcRII (CD32) increased when G-CSF was administered (Table
2B).132,133 Functionally, G-CSF enabled neutrophils to kill
hybridoma cell lines through FcRII (CD32).134 FcRIII
(CD16) expression was upregulated by exogenous G-CSF in healthy
volunteers75 and in patients with paroxysmal nocturnal
hemoglobinuria,135 but did not change61,133 and
even decreased131,132 in others (Table 2C). In human
newborn infants with presumed bacterial sepsis, functional activation
of neutrophils (C3bi = CD11b expression) was determined 24 hours after
the application of 10 µg/kg·d of rhG-CSF.136
Membrane-bound CD14 (mCD14) is a relevant surface antigen for effective
endotoxin clearance. An enhanced expression of CD14 on neutrophils has
been reported in healthy individuals after subcutaneous administration
of G-CSF.131,137 Improved re-expression of mCD14 has been
observed in G-CSF-treated postoperative/posttraumatic patients.64 The effects of G-CSF on mCD14 might explain a
better LPS clearance.138
The events leading to the upregulation of functional antigens by
endogenous and exogenous G-CSF are explained in part by STAT1 and STAT3
phosphorylation65 and by transcription factors PU.1 and
C/EBP-72 activated through the G-CSF receptor. Both
transcription factors play an important role in differentiation (PU.1)
and induction of regulatory genes, induced by increased cytoplasmic
cAMP112,139 and protein kinase A activation,112
including the G-CSFR itself.112 These molecular events are
relevant to understand specific as well as promiscous effects by G-CSF.
Clearly, CD64 appears to be a highly valid marker to follow
responsiveness to endogenous and exogenous G-CSF.
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FUNCTION OF G-CSF IN PROINFLAMMATORY STATES |
Effects of exogenous G-CSF on the cytokine response pattern.
There is some concern that G-CSF-induced increases in neutrophil count
and function might aggravate inflammatory responses and thus be harmful
for the host. This concern is based on the functional properties of
G-CSF to stimulate phospholipase A241 and to
stimulate oxidative burst formation in granulocytes.42 On
the other hand, these properties are most relevant to control infection
and to attenuate or even prevent an otherwise progressive immune
dysregulation. Direct effects (via G-CSF receptors on granulocytes and
monocytes, expression of CD64, increase in neutrophil counts, and
priming of neutrophil function) and indirect effects of G-CSF (clearance of endotoxin and bacteria and counterregulation of induction
of proinflammatory cytokines) can prevent nonspecific tissue damage,
especially by preserving endothelial cell function. Endothelial cell
damage is expected to occur through systemically high TNF-, IL-1, or
IL-8 (Fig 1). Clearly, IL-8 is a cytokine released upon oxidative
stress by almost every cell type.13,14 G-CSF treatment
attenuates circulating IL-8.61 Further support for this
concept of achieving less oxidative stress by G-CSF is provided in vivo
by animal studies, when exogenous G-CSF improved rather than worsened
organ function and survival in models using LPS- or live
bacteria-induced proinflammatory response and disease.140 Exogenous G-CSF increased microvascular flow and survival rate and
prevented neutrophil-mediated tissue damage in fulminant
intra-abdominal sepsis in rats, at least in part, by downmodulating the
potent vasoconstrictor endothelin-1.105 Hemoconcentration
and lactic acidosis were also attenuated, which is consistent with
reduced endothelial damage and plasma leakage.105
Table 3 summarizes the inflammatory
cytokine response pattern resulting from application of exogenous G-CSF
to animals.105,108,140-144 The relative contribution of
direct (via G-CSF receptors on monocytes) and indirect effects (better
control of infection, T cells) of G-CSF to this pattern has yet to be
clarified. Clearly, G-CSF is a member of the inflammatory cytokine
cascade and displays important regulatory properties by attenuating the
proinflammatory cytokine response that would otherwise predominate.
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Table 3.
Effects of G-CSF on Bacterial Products, Cytokines, and
Survival Administered Before Induction of Sepsis in Animals
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Another secondary feature of exogenous G-CSF administration is its
effects on T cells. In mice, G-CSF has been shown to polarize T-cell
subpopulations towards an increased anti-inflammatory type-2 cytokine
response (characterized by the cytokines IL-4 and IL-10) and a reduced
proinflammatory type-1 cytokine production (IL-2 and
IFN-)58 (Table 4). In a
similar pattern, G-CSF administration altered serum concentrations of
cytokines in healthy volunteers145 and ex vivo cytokine
production of whole blood in response to gram-positive and
gram-negative bacterial products,59,145 respectively, in
that more anti-inflammatory and less proinflammatory cytokines were
released (Table 4). Although, G-CSF administration to healthy volunteers caused a reproducible increase of proinflammatory mediators, such as TNF-, after ex vivo and in vivo stimulation with LPS, the
increases of counterregulatory and anti-inflammatory cytokines, such as
the soluble p55 and p75 TNF receptors (sTNF-Rs) and IL-1ra, were
significantly higher.62,145 Similarly, Hartung et
al59 found more anti-inflammatory cytokines, such as
IL-1ra, sTNF-R-type I and -type II, and IL-10, but less proinflammatory
cytokines, such as TNF and IFN-, in blood cultures stimulated with
bacterial products from volunteers treated with 480 µg G-CSF applied
subcutaneously.
G-CSF exerts differential effects on cytokine release in human
endotoxemia when administered either intravenously forn 2 hours or
subcutaneously for 24 hours before endotoxin.62 When
administered 2 hours before endotoxin, G-CSF actually augmented an
LPS-induced inflammatory cytokine response, whereas when administered
24 hours before LPS challenge, G-CSF attenuated the LPS-induced
proinflammatory state and caused significant downregulation of
inflammation (Table 4).62 A direct explanation implies the
involvement of a G-CSF-induced transcription of gene product(s) that
functions to regulate the proinflammatory effects induced by endotoxin.
If G-CSF causes modulation of LPS-receptor expression, such as CD14,
the anti-inflammatory gene product(s) may be either involved in
endotoxin removal or in neutralizing oxidative stress.62
Further experimental work is necessary to understand the regulatory
pathways induced by G-CSF in the absence of a proinflammatory stimulus.
Results are fundamental to work out a prophylactic G-CSF treatment
schedule applicable to patients at risk of sepsis.
Modulation of adhesion receptors of neutrophils and the endothelium
by G-CSF.
Adhesion molecules, such as selectins, regulate the primary binding of
neutrophils to the endothelium and 2-integrins are necessary for subsequent transendothelial migration.146-149
G-CSF may decrease selectin expression and diminish binding to and
enhance transmigration of neutrophils through the endothelium.
Therefore, G-CSF may prevent endothelial damage by avoiding adhesion of
activated neutrophils to inflamed vascular endothelium.
Downregulation of L-selectin by G-CSF may be beneficial during distinct
pathological inflammatory responses, which are associated with the
adhesion of hyperactivated neutrophils to the endothelium. L-selectin-deficient mice were resistant to LPS-induced toxic shock
and death, because neutrophil, lymphocyte, and monocyte migration to
the peritoneum in response to an inflammatory stimulus was
significantly inhibited.150 In healthy volunteers,
exogenous G-CSF reversibly downregulated surface expression of
L-selectin (synonymous [syn.]: leukocyte adhesion molecule-1
[LAM-1]) on human neutrophils151 and a specific surface
metalloproteinase, called L-selectin sheddase, may be
involved.152 In 11 postoperative/posttraumatic patients at
risk of or with sepsis and treated with rhG-CSF, L-selectin expression
on granulocytes was downregulated within 24 to 48 hours.61
Increased plasma concentrations of soluble E-selectin, indicating
endothelial damage, were closely associated with multiple organ
dysfunction and death in patients with SIRS.153 Patient survival was zero when soluble E-selectin levels were greater than 30 U/mL.153 Exogenous G-CSF may have been protective to the
endothelium, because in postoperative/posttraumatic patients at risk of
or with sepsis, soluble E-selectin showed a sharp increase when rhG-CSF was reduced from 1 to 0.5 µg/kg·d.154
The intercellular adhesion molecule (ICAM-1; CD54) is expressed on the
surface of inflamed endothelial cells and plays an important role in
specific binding for transmigration of activated granulocytes.147-149 An increase in soluble ICAM (sICAM)
may also be indicative of endothelial damage. In this context, it has
been reported that sICAM-1 serum concentrations were increased in adult patients with sepsis and corresponded with severity of disease, with
subsequent organ failure, and possibly also with
outcome.155 In postoperative/posttraumatic patients at risk
of or with sepsis,61 sICAM concentrations were relatively
stable during the infusion of rhG-CSF at 1 µg/kg·d; however, levels
increased when rhG-CSF was tapered to 0.5 µg/kg·d and after
cessation of rhG-CSF. Nethertheless, extrapolating sICAM concentrations
to endothelial damage remains controversial, because ICAM-1 is also
expressed and can be shed from monocytes.156
Despite upregulation of CD11b/18, G-CSF had no effect on neutrophil
adhesion but was a powerful stimulator of
transmigration.129 In whole blood cultures, a time- and
G-CSF concentration-dependent upregulation of the expression of CD11b
has been observed.75 In healthy volunteers, the nadir in
circulating neutrophils occurred 30 minutes postinjection of 300 µg
G-CSF subcutaneously and coincided with significant upregulation of the
expression of CD11b on circulating neutrophils.75 This
effect was short-lasting in that CD11b was maximally expressed at 2 hours postinjection and returned to baseline levels at 4 hours
postinjection.75
Taken together, diminished but not abolished binding of preactivated
neutrophils to endothelial cells and enhanced transmigration, induced
by exogenous rhG-CSF, might effectively protect the endothelium from
injury by hyperactivated neutrophils.
| |
G-CSF IN PATIENTS WITH PNEUMONIA AND IMPAIRMENT OF NEUTROPHIL
FUNCTION |
The encouraging results in nonneutropenic patients have supported
expanding the application of G-CSF into nonneutropenic, critically ill
patients with secondary functional impairment of neutrophils.
G-CSF should benefit the course of disease in patients with pneumonia
and subsequent organ dysfunction (Table 5).
The neutrophil has been strongly implicated in the pathogenesis of
inflammatory lung injury,50 and there has been theoretical
concern that G-CSF and neutrophil activation might exacerbate lung
injury. Exogenous G-CSF clearly worsened lung injury and survival when
applied during very severe pulmonary infection in rats.50
In other studies in which lung injury was exacerbated in G-CSF-treated
animals and humans, a beneficial survival effect remained significant (Table 5).50,157,158 In ethanol-treated rats with
experimentally induced pneumonia, all control animals, but less than 10 % of the G-CSF-treated rats died.159 Also, exogenous
G-CSF improved survival in models in which pneumonia was induced in
aminals by various microorganisms, such as Klebsiella
pneumoniae,159 Streptococcus pneumoniae,160,161
and Pseudomonas aeruginosa.162 In a canine model of
peritonitis and septic shock, G-CSF application did not aggravate
sepsis-related pulmonary dysfunction despite increases in circulating
as well as lung lavage neutrophils.141 In mice, exogenous
rhG-CSF has been shown to decrease LPS-induced pulmonary edema and
alveolar capillary leakage.140 In a canine model of peritonitis and septic shock, exogenous G-CSF did not aggravate sepsis-related pulmonary dysfunction despite increased circulating as
well as lung lavage neutrophils.141
In human volunteers, rhG-CSF pretreatment prevented the accumulation of
neutrophils in the lung during the first 2 hours after endotoxin
administration.62 This prevention occurred in the presence
of increased CD11b and CD18 expression on the neutrophils, ie, under
otherwise proadhesive conditions.62 In neutropenic patients, G-CSF application predominantly resulted in an improvement in
pulmonary function.91,157,158,163 G-CSF has also been
proven to benefit nonneutropenic patients with pneumonia and subsequent organ dysfunction. In a study involving 756 hospitalized patients with
community-acquired pneumonia, rhG-CSF accelerated clearance of
pulmonary infiltrates and reduced the occurrence of serious complications: empyema, ARDS, disseminated intravascular coagulation, and septic shock.164 The frequency of nosocomial pneumonia
was higher in patients with acute traumatic brain injury or cerebral hemorrhage prophylactically receiving 300 µg/d rhG-CSF
(4/14) than in the controls (2/17); however, the difference
with respect to the control group was not statistically
significant.114 For several reasons, this study was
underpowered to detect a difference and thus not ideal to evaluate a
potential benefit or adverse effect from the prophylactic application
of G-CSF in patients with high risk for nosocomial infections. In a
different study with a small number of postoperative/posttraumatic
patients at risk of or with sepsis, the application of rhG-CSF did not
affect pulmonary function.165 Combined with the molecular
events discussed above, G-CSF is unlikely to promote nonspecific
adhesion of activated neutrophils to inflamed tissues and thus cause
tissue damage as long as other proinflammatory mediators such as
TNF-, IL-1, and GM-CSF are low or absent.
The present studies in humans and animals stress the importance of the
appropriate timing, dosage, and patient selection for a prophylactic
treatment protocol with G-CSF in pneumonia. G-CSF prophylactically
administered after hemorrhage in mice improved survival from pneumonia
due to Pseudomonas aeruginosa; however, the protective effect
was highly dependent on the dosing schedule used.162 In a
nonneutropenic infection model of Streptococcus pneumoniae
pulmonary infection, rhG-CSF improved lung clearance in both
splenectomized and sham-operated mice compared with controls; however,
rhG-CSF improved survival in the splenectomized mice but not in the
sham-operated mice.160 In ethanol-fed rats, G-CSF was
unable to provide protection against fatal Pneumococcal
pneumonia despite increasing the numbers of circulating
neutrophils.161
Recently, a dramatic increase in mortality has been reported when mice
were pretreated with G-CSF before induction of pneumonia with
Klebsiella pneumoniae.166 In vitro, G-CSF increased
capsular polysaccharide (a bacterial virulence factor) production of
Klebsiella pneumoniae, resulting in impaired phagocytic uptake
and killing by neutrophils.166 Hemorrhagic shock in rats
was accompanied by acute lung injury with neutrophil infiltration and
an increase of G-CSF mRNA levels in the lung produced mainly by
bronchial epithelial cells.167 G-CSF instillation into rat
lungs mediated neutrophil recruitment, pulmonary edema, and hypoxia,
indicating that local production of G-CSF may be involved in lung
damage and ARDS.168
Thus, depending on certain circumstances, application of G-CSF for
prophylaxis and therapy of pneumonia may be beneficial or detrimental.
Appropriate dosage, timing, and indication are not yet clearly defined
to gain maximal beneficial effects with minimal side effects in
patients. In summary, recent studies114,164,166,168 indicate the need for additional controlled studies to define the role
of G-CSF in community-aquired and nosocomial pneumonia.
| |
PRESENT AND FUTURE USE OF G-CSF IN CRITICALLY ILL PATIENTS |
At present, exogenous G-CSF is widely used and has been proven to be
effective and safe in reducing the incidence of infection and sepsis in
immunocompromised patients with nonmyeloid tumors after
myelosuppressive anticancer chemotherapy45,81,82 as well as
in neutropenic and agranulocytotic patients.82-84
In human newborn infants with presumed bacterial sepsis, application of
G-CSF significantly increased C3bi (CD11b) expression of their
neutrophils, indicating functional activation.136 In nonneutropenic, posttraumatic/postoperative patients with a high risk
of sepsis, none of the patients treated with rhG-CSF developed sepsis;
however, three patients in the control group did.51 In
fulminant intra-abdominal sepsis in rats, mortality decreased from 92%
to 46% and to 42%, respectively, with the first dose of G-CSF at
sepsis induction or 4 hours postinduction, ie, during manifested
sepsis, respectively (Fig 3).169 Based on animal studies, G-CSF should be effective not only in prophylaxis, but also in treatment of sepsis.
In future use, G-CSF may be effective in nonneutropenic critically ill
patients suffering from yet unrecognized impairment of neutrophil
function and tissue injury. Beneficial effects of exogenous G-CSF have
been observed on the resolution of infection, especially pneumonia, and
subsequent sepsis, multiple organ dysfunction, and septic shock. These
effects of exogenous G-CSF result directly from a better control of
infection and indirectly from an amelioration of an overwhelming,
damaging, proinflammatory response.
Ischemia/reperfusion injury is also a frequent consequence of surgical
injury, hemorrhagic shock, and trauma. Improved endotoxin elimination
by exogenous G-CSF138 may contribute to the recently described endothelial cell protection by the immediate induction of
IL-1ra. This latter property of G-CSF extends the therapeutic potential
to ischemia/reperfusion injury. Short, clinically relevant visceral
ischemia produced TNF-- and IL-1-dependent lung injury in
mice.170 Recently, in rats with visceral
ischemia/reperfusion injury, treatment with rhG-CSF increased
survival, reduced serum TNF- induction, reduced myeloperoxidase
activity in the ileum and in the lung, and improved mean
arterial blood pressure.117 Such results may be explained
by our recent observation that G-CSF stimulated hemoxygenase-1 (HO-1)
expression in microvascular endothelial cells in vitro (unpublished
observation). If HO-1 induction by G-CSF is a general
phenomenon in endothelial cells, then this may represent an important
response against oxidative damage.
G-CSF has been demonstrated to alleviate neutropenia in patients with
advanced AIDS or AIDS-related complex receiving
zidovudine.83 In addition, the prophylactic use of G-CSF
may prevent endotoxin-induced shock in AIDS patients. The incidence of
infection with gram-negative bacteria is increased in AIDS patients who
suffer from accelerated leukocyte apoptosis and defective neutrophil
functions.55,171 Accelerated apoptosis contributes to
impaired neutrophil function in AIDS patients.55 However,
incubation with G-CSF in vitro significantly decreased apoptosis in
neutrophils of these patients.55 In addition, repeated
pretreatment with rhG-CSF successfully protected mice with
retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS)
from hypersensitivity to LPS-induced lethal shock, and this protective
effect coincided with the suppression of IFN- production.144
Application of rhG-CSF may also find widespread use in critically ill
patients, because no serious side effects have been observed in
multiple therapeutic trials in immunocompromised, agranulocytotic,
neutropenic, and nonneutropenic
patients.45,51,61,82,136,164,165 G-CSF is well-tolerated,
and the most common side effects, bone pain and occasionally reported
skin rash, appear to be dose-dependent.45,82 Transgenic
mice that overexpressed G-CSF had a 100-fold increase in G-CSF serum
concentrations (1,041 ± 242 pg/mL in sera) and peripheral
neutrophils. These G-CSF-overexpressing transgenic mice developed
osteoporosis because of increased osteoclastic activity. Thus, high
G-CSF serum concentrations could have a negative influence on bone
homeostasis in vivo when active over extended periods of
time.172
Animal studies suggest that prolonged therapy with G-CSF may also have
anti-inflammatory effects in colitis. Inflammatory bowel disease is
associated with mucosal neutrophil recruitment and activation, mediated
in part by arachidonic acid metabolites. G-CSF attenuates the immune
response to sepsis and ameliorates glycogen storage disease Ib-related
colitis. In immune complex colitis in rabbits, treatment with rhG-CSF
resulted in a marked decrease of proinflammatory mediators, such as
LTB4 and thromboxane B2 (TXB2), but
mucosal generation of the protective prostaglandin E2
(PGE2) was preserved.173
In critically ill patients with a secondary functional impairment of
host defense, G-CSF improved leukocyte recruitment and, in addition,
appears to activate a number of cell protective mechanisms awaiting
more detailed investigations.
| |
CONCLUSIONS |
The present data support the hypothesis that G-CSF treatment may be
extended to a group of critically ill patients with secondary impairment of neutrophil function occurring as a result of extensive tissue damage, oxidative stress, and/or ischemia/reperfusion. G-CSF both augments the replication and function of neutrophils. G-CSF
also stimulates the elimination of endotoxin and attenuates the
hyperinflammatory state by increasing IL-1ra and by intermittently modulating the adhesion receptor L-selectin. These events would counteract the progression of sepsis and, presumably, the incidence and
severity of multiple organ dysfunction. Refinement in the use of G-CSF,
either prophylactically or in states with acute infection, reperfusion,
or severe tissue injury relies on the experimental as well as clinical
evidence that G-CSF stimulates neutrophil function and concomitantly
attenuates an uncontrolled inflammatory response. However, the
successful administration of G-CSF to nonneutropenic patients with
impairment of neutrophil function will strongly depend on optimal
timing and dosage. The prophylactic administration of G-CSF to surgical
patients with low G-CSF serum concentrations will result in appropriate
serum concentrations of about 1,000 pg/mL G-CSF in responding patients when administered at about 1 µg/kg·d.51,61,165 These
doses are associated with beneficial effects on neutrophil function in
the absence of granulocytosis greater than
50,000/µL.51,61,165
An ongoing inflammation is possibly also targeted by G-CSF with
beneficial effects if the G-CSF administration is associated with its
efficient use. Evidence of use includes functional activation (CD64
expression, phagocytic activity, and less apoptosis), decreased L-selectin expression on neutrophils, and a concomitant increase of
serum IL-1ra as well as a decrease of serum proinflammatory cytokine
concentrations (such as IL-8). Thus, the definition of subgroups of
patients sensitive to G-CSF treatment, which by now includes cases with
pneumonia, diabetes, acute necrotizing pancreatitis, alcoholism, AIDS,
and ischemia/reperfusion injury, may further extend our understanding
of immunomodulatory effects by this hematopoietic growth factor.
Additional controlled studies with critically ill patient populations
at a high risk to encounter severe infections and sepsis are necessary
to further define and use the regulatory properties of G-CSF in a
window of effective treatment protocols.
| |
FOOTNOTES |
Submitted July 21, 1997;
accepted September 22, 1998.
Supported by GM-40586-II awarded by the National Institute of General
Medical Sciences, US Public Health Services.
Address reprint requests to Manfred Weiss, MD, Department of
Anesthesiology, Universitätsklinikum, Steinhövelstr. 9, D-89075 Ulm, Germany.
| |
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Putative role of granulocyte...
Regulation of g-csf production...
