Originally published online as doi:10.1189/jlb.0503214 on October 13, 2003
Published online before print October 13, 2003
(Journal of Leukocyte Biology. 2004;75:408-412.)
© 2004
by Society for Leukocyte Biology
The chronic consequences of severe sepsis
Claudia F. Benjamim,
Cory M. Hogaboam and
Steven L. Kunkel1
Department of Pathology, University of Michigan, Ann Arbor
1 Correspondence: Department of Pathology, Medical Science I, University of Michigan, 1301 Catherine Street, Ann Arbor, MI 48109-0602. E-mail: slkunkel{at}umich.edu
ABSTRACT
The early events of severe sepsis set in motion a cascade of
events that significantly contributes to the morbidity and mortality
observed during the first few days of this syndrome. Although
sepsis is a deadly, acute disease, survivors also suffer long-term
consequences. Clinical data underscore subsequent high mortality
rates associated with patients who are long-term survivors of
the acute septic episode. Within 1 year of surviving severe
sepsis, there is a 26% predicted mortality rate, and many patients
succumb to lung complications. In this review, we focus on the
cellular and molecular mechanisms that dictate the longer-term
sequela of sepsis and related lung injury. We have established
a murine model of experimental sepsis [cecal ligation and puncture
(CLP)], which results in an approximate 60% survival rate. Our
studies have demonstrated that these survivors are susceptible
to a fungal infection with 100% mortality when challenged 3
days or 15 days post-recovery from the initial CLP. This increased
mortality correlates with changes in cytokines and Toll-like
receptor expression and alterations in lung leukocyte populations.
We hypothesize that the lung becomes predisposed to nosocomial
infections for extended periods of time after severe sepsis
via mechanisms that include alterations in inflammatory cytokines
and an increase in immunomodulatory chemokines, such as monocyte
chemoattractant protein-1 and C10. These mediators may alter
the innate-immune response by affecting dendritic cells and
macrophages, which could provide a mechanism for the immunosuppression
observed following sepsis.
Key Words: innate immunity • acquired immunity • long-term • lung • chemokines • Toll-like receptors
INTRODUCTION
General consensus supports the idea that the acute inflammatory
response is intimately linked to innate immunity and occurs
over a relatively restricted chronological period. This traditional
notion of the limited time frame of a functional acute inflammatory
response has historically been supported by the temporal expression
of a set of inflammatory mediators and leukocyte subpopulations.
For example, within minutes of in vivo lipopolysaccharide (LPS)
challenge to the peritoneum, mRNA expression for early response
cytokines, such as tumor necrosis factor
(TNF-
), can be detected
in mononuclear phagocytic cells followed by the expression of
more distal cytokines and chemokines. This is followed by the
recruitment of polymorphonuclear cells, which occurs within
hours. Over the subsequent 24- to 48-h period, cytokine, chemokine,
and leukocyte levels will subside, and any alteration in local
tissue will be repaired [
1
,
2
].
It is interesting that this scenario is dependent on the quantity (amount) and quality (complexity of the challenge composition) of the initial antigen or pathogen. An increase in the amount of the challenge will result in a heightened, acute cytokine and leukocyte response, and an increase in the complexity may lead to a prolonged response. An additional factor that determines the course of an acute inflammatory response is the severity of the host’s response to the inciting agent. This aspect of the response has important consequences for the short-term course of the acute reaction but also appears to play a key role regarding the host response to a subsequent challenge that occurs long after the initial severe acute reaction. An interesting correlation exists between the severity of the initial, acute inflammatory response and the ability of the host to deal with a longer term, chronic challenge [3
, 4
].
One of the best examples of the chronic effects of severe acute inflammation is presented by data modeled from human septic populations. A variety of investigations have studied the short-term (less than 30 days) sequelae of the septic response and have reported mortalities of 30–50% [5
]. Findings such as these have resulted in labeling this syndrome as a deadly, acute disease. However, additional investigations have noted that the septic population is at a significant risk of dying of nonseptic causes for up to 8 years after the initial hospitalization [3
, 4
]. Thus, the initial, severe response sets in motion a dysregulated, immune/inflammatory response, which has long-lasting implications regarding how the host can respond to and deal with other challenges. The chronic problems of severe acute inflammation are not limited to disorders such as sepsis but are found in a wide array of human diseases, including the long-term consequences of ischemia/reperfusion injury post-organ transplant [6
], the alterations post-recovery from severe respiratory syncycial virus (RSV) [7
, 8
], and the changes found in burn and trauma injury [9
, 10
] (Table 1 ). This review will focus on the chronicity of severe acute inflammatory responses.
THE CHRONICITY OF SEVERE ACTUE INFLAMMATION AND SUBSEQUENT CLINICAL COMPLICATIONS
The above clinical data support the view that a number of long-term
consequences are associated with surviving severe sepsis. It
is interesting that this is not the only clinical example of
acute inflammation subsequently interphasing with chronic inflammatory
disorders. As shown in
Table 1
, there are a number of clinical
instances whereby an initial severe acute inflammatory event
has been associated with distal chronic complications. Pediatricians
who deal with severe acute RSV infections in very young children
are clearly mindful of the longer term but ill-understood clinical
complications, which these children have in dealing with severe
chronic asthma. Transplant surgeons are aware of the problems
that place a solid organ transplant at long-term risk if during
the initial surgery, the donor organ has severe acute ischemia
reperfusion injury. Burn and trauma physicians are cognizant
of the patients who recover from the acute and severe inflammatory
events of burn injury yet are susceptible to chronic clinical
complications later in life. One of the uniting themes of the
above clinical examples is that there appears to be a correlation
with the severity of the initial acute inflammatory event that
caused alterations in the innate and/or acquired immune system,
which is manifested for not only months but often years after
the initial severe insult. The mechanism(s) that are responsible
for the chronic consequences of severe acute inflammation are
presently not well understood; however, incriminating factors
likely include alterations in the normal levels and activity
of chemokines, cytokines, Toll-like receptors (TLRs), and dendritic
cells (DCs).
CHEMOKINES IN CLINICAL AND EXPERIMENTAL SEPSIS
Over the past decade, a number of chemokines have been identified
that possess interesting biological activities in innate and
acquired immune response. Although chemokines clearly play a
crucial role in the initiation and maintenance of inflammation
via leukocyte recruitment, these protein mediators are involved
in other immune-related processes, such as angiogenesis, cell
activation, healing, repair, and end-stage fibrosis [
11
]. Chemokines
have been divided into four subfamilies based on their unique
sequence homology and the position of cysteine residues in the
protein; the CC and CXC chemokine families comprise the largest
groups with diverse activities [
11
]. Elevations in numerous
CXC and CC chemokines have been detected in clinical diseases,
such as asthma, pneumonia, colitis, central nervous system infection,
gastritis, and sepsis. These clinical studies have provided
the impetus to study the role of chemokines in established animal
models of human diseases, including sepsis [
12
].
In this review, we focus on the putative role of chemokines in the pulmonary immunosuppression following experimental sepsis. Investigations into the long-term consequence of sepsis in survivors, especially with regard to the fate of immune activity of the lung, have been lacking, although clinical studies have demonstrated considerable morbidity and mortality associated with these individuals. It is noteworthy that a number of clinical studies support the observation that the long-term morbidity and mortality of sepsis patients are dependent on the severity of the initial insult [3
, 4
]. These investigations demonstrated that the more severe the initial septic event, the more morbidity and mortality were found in these particular patients. We propose that the immunosuppression associated with sepsis is, in part, a result of the prolonged activities of immunomodulatory chemokines such as CCL2 [monocyte chemoattractant protein-1 (MCP-1)], CCL17 [thymus and activation-regulated chemokine (TARC)], and C10 (CCL6), all of which are induced by interleukin (IL)-13 and IL-4. Thus, the pulmonary immune response in septic patients may be inappropriately skewed toward the T helper cell type 2 (Th2) cytokine pattern. This hypothesis is in keeping with published data showing that chemokine receptors have been found to be differentially associated with Th1/Th2 subsets [13
], and CC chemokines appear to alter the outcome of the immune responses through altering the balance of Th1 and Th2 immune activation [14
]. We contend that the balance of proinflammatory and modulatory CXC and CC chemokines is critical following a septic challenge, as this balance drives the response toward an efficient response (i.e., infection resolution) or toward an exaggerated release of immunomodulatory chemokines (i.e., inappropriate immune response and death). Herein, we provide data and discussion regarding the manner in which chemokines modulate the pulmonary innate-immune response after sepsis.
IMMUNOSUPPRESION FOLLOWING SEPSIS
A major research focus of several laboratories, including our
own, is to elucidate the mechanisms that influence the developing,
pathologic changes that occur during the initiation and maintenance
of experimental sepsis. We have learned a considerable amount
about the factors that initiate the early inflammatory events
associated with sepsis, and these factors include a number of
proinflammatory cytokines (including IL-1 and TNF). However,
less is known about the long-term effects of sepsis on the immune
system, particularly in the lung. This paucity led us to develop
a murine model of severe sepsis induced by cecal ligation and
puncture (CLP), a model that more closely mimics the clinical
scenario. Following CLP surgery, C57Bl/6 mice were given 3 days
of an antibiotic treatment regiment, which increased survival
from 0 to 60%. The survivors were subsequently challenged with
Aspergillus fumigatus on the third day after CLP surgery. In
this model, CLP groups, but not the sham surgery group, were
clearly predisposed to the fungus challenge. The CLP survivors
were also susceptible to a bacterial challenge with
Pseudomonas aeruginosa (60% mortality) on the third day after CLP surgery.
It is interesting that in a similar manner, all mice that survived
the original septic episode died rapidly after a fungal challenge
on day 15 after CLP surgery.
An assessment of the lungs of the mice surviving sepsis and receiving a subsequent fungal, pulmonary challenge demonstrated an interesting immune conundrum. In the CLP group that received A. fumigatus challenge, at day 3 or 15 post-surgery, a significant increase in the recruitment of leukocytes (i.e., macrophages and neutrophils) into the lung was apparent, as compared with the sham control animals. It is interesting that mice subjected to sham surgery effectively contained the fungus (Fig. 1A
), whereas CLP mice were clearly not able to eliminate the fungal challenge, as evidenced by the presence of A. fumigatus conidia (or spores) and hyphae (Fig. 1B)
. Fungal growth to this degree is usually observed in severely immunocompromised patients or immunosuppressed animals [15
16
17
]. These data suggest that a disconnect exists between the expression of inflammatory mediators needed to recruit leukocytes to the lung and the ability of the recruited leukocytes to destroy the fungal challenge.
This disconnect was confirmed by transmission electron microscopic
analysis of lung samples at day 2 after
A. fumigatus challenge
in sham and CLP mice (
Fig. 2
). Dead or dying conidia (i.e.,
ghosts) were apparent in macrophages and neutrophils from the
sham group
(Fig. 2A)
, but in the CLP group, phagocytosed, intact
conidia were observed
(Fig. 2B)
. We also observed numerous
hyphal elements in the lung of the CLP group but not in the
sham group
(Fig. 2C)
.
The reason for the impairment in the fungal killing in the CLP
group is not presently apparent and is the subject of ongoing
studies. Gene array analyses have revealed that a number of
proinflammatory [examples include the p35 subunit of IL-12,
IL-6, interferon (IFN), and IL-1ß] genes were up-regulated
in the sham group challenged with
A. fumigatus compared with
the sham group challenged with saline. However, no difference
in the expression of these genes was observed in the CLP group
challenged with the fungus compared with the sham group challenged
with fungus. It is interesting that CCL2 transcript expression
was greatly increased in CLP mice challenged with
A. fumigatus.
This finding has led us to investigate whether the sustained
generation of CCL2 may lead to the suppression of macrophage
activation. In support of this hypothesis are recent studies
documenting that activated macrophages can be divided into three
heterogeneous groups with distinct immunological functions.
First, the "classic" or activated macrophage releases TNF, IL-1,
IL-6, IL-12, and nitric oxide (NO) and has the ability to kill
and degrade intracellular microorganism. Second, the "alternatively
activated" macrophage releases IL-10 and IL-1ra, which does
not produce NO, protects the host from an overzealous inflammatory
response, and is involved in tissue repair. Third, the type
II macrophage, which releases large amounts of IL-10 and induces
T cells to produce IL-4, but this cell also produces IL-6 and
TNF [
18
,
19
]. The differential activation of macrophages may
explain the "paralysis" of these cells in sepsis. Supporting
this concept is evidence that macrophages remain active after
sepsis, but their repertoire of mediators is shifted away from
those best suited for fighting pathogens [
18
,
19
].
POTENTIAL STRATEGIES FOR OVERCOMING IMMUNOSUPPRESSION
Recent evidence shows that TLRs recognize specific patterns
of microbial components, and these receptors appear to regulate
innate and adaptive immunity. There are several inherent levels
of sophistication built into the TLRs, as different microbial
structures are recognized by different TLRs. For example, TLR1
binds triacyl lipopeptides (bacteria, mycobacteria); TLR2 binds
lipoprotein/lipopeptides, lipoteichoic acid (Gram-positive bacteria),
and zymosan (fungus); TLR3 binds double-stranded RNA (virus);
TLR4 binds LPS (Gram-negative bacteria); TLR5 binds flagellin
(bacteria); TLR6 binds diacyl lipopeptides (mycoplasma); and
TLR9 binds CpG DNA (bacteria). The ligands for TLR7, TLR8, and
TLR10 are presently unknown. Activation of specific cells via
TLRs can serve as potent signals for the expression of a number
of mediators necessary to initiate and maintain an inflammatory
response. In particular, the activation of the TLR2 or TLR4
pathway increases the expression of CXC (IL-8) and CC chemokines
(regulated on activation, normal T expressed and secreted and
MCP-1) [
20
,
21
]. It is interesting that the expression of
TLRs is not limited to leukocytes, as fibroblast and epithelial
cells have been shown to have functional TLR2 and TLR4, and
when activated, these receptors are involved in the expression
of significant levels of chemokines [
20
,
22
,
23
]. The activation
of TLRs leading to chemokine production is likely an important
step required to rapidly engage the innate-immune response,
thereby allowing the participation of specific leukocytes in
the inflammatory response. However, more recent studies in our
laboratory suggest that chemokines may account for the dysregulation
of the TLR expression on macrophages from CLP mice. The dynamic
interaction between chemokines and TLRs is likely an important
cascade that may ultimately control the host’s response
to a foreign agent. It is elucidating that the manner in which
chemokines regulate TLR expression may provide important clues
to effective therapies in sepsis.
Chemokine modulation of DC recruitment to lung
Determining the overall contribution of DCs to the immunosuppression after sepsis is an area of ongoing investigation. Studies directed at the long-term fate of lung DCs are now appearing in the literature. For example, Wysocka et al. [24
] showed that mice primed with LPS and then challenged with a lower LPS dose contained a significant reduced number or CD11chigh IL-12-producing cells. As IL-12 is a critical cytokine needed to drive a Th1 response, the loss of DC cells from the lung may be an important factor in the impaired antipathogen or innate response in the CLP mice challenged with A. fumigatus. In addition, Barton and Medzhitov [25
] have demonstrated a relationship among TLR activation, DCs, and the manner in which TLR–DCs control the adaptive immune response. DC subsets differ from each other via the expression of distinct sets of pattern-recognition receptors (such as TLRs) and by the cytokine/chemokines they produce upon maturation. In our immunosuppression model, we are presently examining whether modification of chemokine levels alters the presence and/or level of activity of DCs in the lung. Once again, this type of study may be directly relevant to clinical sepsis, where it has been shown that DC levels are reduced [25
]. In addition to DCs, monocytes have been identified to play an interesting role in septic patients, as deactivation of this cell population has been reported to be associated with immunosuppression [26
]. In particular, monocyte human leukocyte antigen (HLA)-DR expression is down-regulated during sepsis and is associated with a worse clinical outcome. The suppression of HLA-DR can be reversed by IFN-
treatment, which in turn improves the clinical course of the disorder.
CONCLUDING REMARKS
The preceding review suggests that severe diseases with a poor,
long-term outcome may be a result of a dysregulated, inflammatory
response. Sepsis is a severe acute disease that can result in
immunosuppression, which leads to a secondary infection, thereby
amplifying the risk of death. There is a critical need for mechanistic
studies directed at understanding the immunosuppression induced
by sepsis, mostly important for the elucidation of therapies
that could enhance protective immunity against opportunistic
pathogens.
Figure 3
outlines our evolving hypothesis in which
a severe, overwhelming innate-immune response by the host (i.e.,
caused by rupture of the intestine) against enteric microorganisms
affects organs including the lung. Within the lung, the release
of inflammatory mediators such chemokines ultimately leads to
a deviation in the inflammatory response. Although this response
is clearly needed to shut down an exacerbated, inflammatory
response as a result of sepsis, it is ultimately deleterious
in the case of a secondary infectious insult. We also propose
that cytokines (i.e., IL-13, IL-4, IL-10) and chemokines (i.e.,
C10, MCP-1, TARC) have major roles in the regulation of TLRs
on macrophages and DCs during sepsis. The phenotype and activation
state of macrophages may also be affected as described above.
Understanding the cross-talk between soluble mediators and inflammatory
cells may lead to immunotherapies that revert the immunosuppression
and increase the survival rate following severe sepsis.
ACKNOWLEDGEMENTS
This study was supported in part by NIH Grants P50 HL60289 and
HL31237 and by a CNPq fellowship. We thank Robin Kunkel for
her artistic assistance. We also thank Holly Evanoff, Aaron
Berlin, and Pamela Lincoln for their technical assistance.
Received May 12, 2003;
revised July 18, 2003;
accepted September 9, 2003.
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TOP
ABSTRACT
INTRODUCTION
, Macrophages; PMN, polymorphonuclear; SIRS, systemic inflammatory response syndrome; CARS, compensatory anti-inflammatory response syndrome.
