1 Immunology and Disease Resistance Laboratory, United States Department of Agriculture-Agricultural Research Service, Beltsville 20705; and 2 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201
![]() |
ABSTRACT |
---|
Gram-negative bacterial sepsis remains a common, life-threatening event. The prognosis for patients who develop sepsis-related complications, including the development of acute respiratory distress syndrome (ARDS), remains poor. A common finding among patients and experimental animals with sepsis and ARDS is endothelial injury and/or dysfunction. A component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) or endotoxin, has been implicated in the pathogenesis of much of the endothelial cell injury and/or dysfunction associated with these disease states. LPS is a highly proinflammatory molecule that elicits a wide array of endothelial responses, including the upregulation of cytokines, adhesion molecules, and tissue factor. In addition to activation, LPS induces endothelial cell death that is apoptotic in nature. This review summarizes the evidence for LPS-induced vascular endothelial injury and examines the molecular signaling pathways that activate and inhibit LPS-induced endothelial apoptosis. Furthermore, the role of apoptotic signaling molecules in mediating LPS-induced activation of endothelial cells will be considered.
endotoxin; inflammation; nuclear factor-B; sepsis; vascular
injury
![]() |
INTRODUCTION |
---|
DESPITE ADVANCES IN ANTIMICROBIAL therapy and overall medical care, gram-negative bacterial sepsis remains a common, life-threatening event (163). Complications arising from sepsis include disseminated intravascular coagulation (133, 197, 201), systemic vascular collapse (88, 201), multiorgan failure (22, 23, 65), and the development of vascular leak syndromes, including acute respiratory distress syndrome (ARDS) (26, 27, 142, 144, 161). One common denominator to all of these complications is endothelial cell (EC) injury and/or dysfunction (46, 47, 80, 132, 148, 153).
The vascular endothelium serves as the key barrier between the
intravascular compartment and extravascular tissues and plays a
critical role in a large number of physiological and pathological processes (38). ECs are integrally involved in regulating
blood flow, coagulation, leukocyte trafficking, edema formation, wound healing, and angiogenesis. Because of their location at the
blood-extravascular tissue interface, ECs are constantly exposed to
circulating mediators that may perturb the above-mentioned endothelial
barrier functions. One such mediator that targets the endothelium is
bacterial lipopolysaccharide (LPS) or endotoxin, a highly
proinflammatory molecule that is a component of the outer envelope of
all gram-negative bacteria (17, 159, 176). LPS is released
from the surface of replicating and dying gram-negative bacteria into
the circulation, where it interacts with the endothelial lining of the
vessel wall (173, 176). Evidence exists that LPS, alone or
in concert with other endogenous factors, is responsible for much of
the EC injury and/or dysfunction associated with gram-negative sepsis.
First, LPS bioactivity has been detected in the bloodstream of
gram-negative septicemic patients, and in selected studies, levels of
circulating LPS predict the development of multiorgan failure,
including ARDS (26). Second, administration of LPS alone
to experimental animals reconstitutes the EC injury seen after
gram-negative bacterial challenge (27, 201). Third,
immunological and pharmacological interventions that specifically
target the LPS molecule protect against these same vascular
complications (6, 210, 211, 225). Finally, LPS directly
elicits several of the EC responses in vitro that are similarly evoked
during sepsis, including: 1) the production of the
proinflammatory cytokines IL-6 (77, 109), IL-8 (7, 77, 223), and IL-1 (57, 138); 2) the
increased surface expression of the adhesion molecules E-selectin,
intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion
molecule (VCAM)-1 (34, 59, 77, 108); and 3)
increased expression of tissue factor (42, 75). In
addition to activation, LPS induces EC-programmed cell death or
apoptosis (18, 21, 64, 67, 82, 95, 116, 143, 221),
an event that is believed to contribute to the pathogenesis of sepsis
and its attendant complications (82, 189). Several of the
signaling molecules involved in EC activation leading to increased
cytokine and adhesion molecule expression are similarly involved in LPS
proapoptotic signaling. Furthermore, there is evidence that LPS
proapoptotic signaling molecules have an additional role in
regulating LPS-induced NF-
B activation and nonapoptotic EC
responses to LPS. This review focuses on recent advances in the
elucidation of the mechanisms by which LPS elicits EC apoptosis
and the cross talk between signaling pathways leading to EC activation
and death.
![]() |
EVIDENCE FOR LPS-INDUCED EC APOPTOSIS |
---|
Apoptosis is an ATP-dependent form of cell death, morphologically characterized by chromatin condensation, nuclear fragmentation, cell shrinkage, and blebbing of the plasma membrane (76, 171). The end result of apoptosis is fragmentation of the cell into small membrane-bound bodies that are quickly cleared by phagocytotic cells (45, 181, 187). Biochemically, apoptosis is characterized by the activation of caspases, highly specific proteases that cleave a wide array of intracellular substrates (198). Activation of upstream caspases initiates a proteolytic cascade leading to DNA fragmentation and the cleavage of key regulatory proteins resulting in cell death. In contrast to apoptosis, necrotic cell death is an energy-independent process characterized by cell swelling and lysis (76, 171). Unlike apoptotic cells, necrotic cells release cellular constituents that elicit an inflammatory reaction in surrounding viable tissue.
LPS induces apoptosis in bovine and ovine ECs in vitro (18, 64, 94, 95) and elicits human EC apoptosis in the absence of new gene expression (164). That LPS-induced EC death is apoptotic in nature has been confirmed by several criteria, including morphological changes (64), DNA laddering (18, 99), TdT-mediated dUTP nick end labeling (18, 94, 95), nuclear histone release (15, 21), caspase activation (15, 19), and poly(ADP-ribose)polymerase cleavage (21, 36). Several studies have demonstrated that purified LPS itself, in the absence of host-derived mediators, evokes EC injury and/or apoptosis (18, 36, 64, 67, 82, 95, 116, 221). The ability of LPS to induce EC apoptosis in the absence of non-EC-derived host mediators is compatible with a direct effect. Furthermore, neutralizing antibodies to other known death receptors expressed on EC, including TNF type 1 receptor (TNFR1), Fas, and death receptor 3 (DR3), fails to inhibit LPS-induced apoptosis (36). Finally, LPS-induced EC apoptosis occurs independently of new protein synthesis, thereby precluding the involvement of upregulated gene products (84).
![]() |
CLINICAL RELEVANCE AND IN VIVO EVIDENCE |
---|
Endothelial apoptosis has been implicated in the pathogenesis of several disease states, including atherosclerosis (30), hypertension (73), congestive heart failure (204), and systemic capillary leak syndrome (12). Several studies have reported that EC injury and/or death is a key pathological finding during bacterial sepsis. First, injection of Escherichia coli into rabbits (47) or baboons (40, 41) induces severe microvascular injury and EC detachment. Second, increased numbers of apoptotic ECs are detected in the pulmonary capillaries of a murine model of sepsis (93, 217). Third, evidence of EC injury is observed in postmortem biopsies obtained from patients who have died of sepsis-related ARDS (148). Fourth, an increase in circulating EC is observed in septic patients, and the magnitude of this increase correlates negatively with survival (153).
There are several reports that purified LPS elicits EC injury and
apoptosis in vivo. EC injury and/or detachment from the vascular wall has been reported after LPS injection into mice (124), rats (172, 192), rabbits (47,
69, 145), dogs (72, 127), sheep (27,
149), and primates (14). Liver sinusoidal ECs
obtained from LPS-treated rats display enhanced activation of
caspase-3, a central apoptotic effector protease (49).
Disseminated EC apoptosis has been reported in the lung, liver,
thymus, and intestine of mice challenged with LPS (67, 82, 116,
122). Finally, injection of a broad spectrum caspase inhibitor
decreases EC apoptosis in the lung after LPS administration and
improves survival in a murine model of acute lung injury
(116). The combined in vitro and in vivo data implicate
apoptosis as a key component of the EC response to LPS.
However, the extent to which LPS directly induces EC apoptosis
in human systems either alone or in concert with other known
apoptosis-inducing proinflammatory cytokines, such as TNF-
and/or IL-1
, remains unclear.
![]() |
CELL SURFACE RECOGNITION OF LPS |
---|
As the name implies, LPS is composed of both lipid and polysaccharide components. The lipid portion is composed of a unique lipid, lipid A, which is the most widely conserved region of the LPS molecule (174). It is well established that the lipid A moiety of LPS is responsible for its proinflammatory properties (174). Lipid A alone is capable of eliciting EC responses identical to those induced by LPS (16, 50, 193). Agents that specifically target the lipid A moiety of LPS inhibit EC activation (16, 52) and protect against the development of vascular complications in endotoxin shock models (6, 210). Similar to activation, the lipid A moiety is also responsible for the proapoptotic properties of the LPS molecule (84). Neutralization of lipid A with polymyxin B completely abrogates LPS-induced EC apoptosis (18, 19, 64).
An early identified receptor implicated in cellular recognition of LPS
was membrane-associated CD14 (mCD14) (202). mCD14 is a
glycoprotein found on cells of monocytic origin and to a lesser extent
on neutrophils. Although LPS can directly bind mCD14, its affinity for
the receptor is greatly increased when LPS is complexed with the acute
phase protein LPS-binding protein (LBP) (159). ECs, which
lack mCD14, are activated by LPS in the presence of LBP and soluble
CD14 (sCD14), the latter of which is released from mCD14-bearing cells
(9, 74). It has been proposed that LBP facilitates the
transfer of LPS to sCD14 and that this LPS-sCD14 complex is recognized
by ECs (202, 205). Similar to EC activation, a requisite
role for sCD14 in mediating LPS-induced apoptosis has been
established. In the absence of sCD14, ECs are resistant to LPS-induced
apoptosis (9, 64, 219). In the presence of CD14-containing serum, anti-CD14 antibodies inhibit LPS-induced EC
cytotoxicity (9, 64, 219). Because CD14 is a glycosyl phosphatidylinositol-anchored protein and lacks an intracellular cytoplasmic domain, it was postulated that another transmembrane receptor must exist that can transduce LPS signaling across the plasma
membrane. This receptor, which has since been identified as Toll-like
receptor (Tlr)-4, is expressed in cells of monocytic lineage as well as
in non-mCD14-bearing ECs (37, 61). There has been some
controversy in the past regarding whether another member of the
Toll-like receptor family, Tlr-2, mediates LPS-induced signaling. Two
groups have reported that LPS-induced activation is mediated by Tlr-2
(121, 218). However, a subsequent study reported that
certain commercial preparations of LPS are contaminated with bacterial
lipoproteins and that these lipoproteins, not LPS, are responsible for
Tlr-2 activation (90). The genetic evidence clearly
establishes Tlr-4 as a true LPS receptor (166). C3H/HeJ and C57BL/10ScCr mice, which contain a missense mutation in or a null
mutation for the Tlr-4 gene, respectively, are resistant to
LPS (166). Furthermore, transfection of Tlr-4 into
LPS-insensitive HEK-293 cells confers sensitivity to LPS-induced
NF-B activation (37). Finally, anti-Tlr-4 antibodies
abrogate LPS-induced EC NF-
B activation, whereas anti-Tlr-2
antibodies have no inhibitory effect (61).
![]() |
TLR-4 SIGNALING LEADING TO NF-![]() |
---|
Tlr-4 is integrally involved in LPS signaling and has a requisite
role in the activation of the transcription factor NF-B. The
extracellular domain of Tlr-4 contains repeating leucine-rich motifs
characteristic of innate immune response pattern recognition receptors
(Fig. 1) (48). The
cytoplasmic domain contains regions that are homologous to the
intracellular signaling domain of the type 1 IL-1 receptor. Although
the exact mechanism by which LPS is recognized by Tlr-4 remains
unclear, cell activation is dependent on the cell surface assembly of a
multiprotein recognition complex consisting of CD14, MD-2, and Tlr-4
(3) (Fig. 2). After
activation of the Tlr-4 receptor complex, the adapter protein
myeloid differentiation factor 88 (MyD88) is recruited to the
cytoplasmic domain of Tlr-4 through homotypic binding of respective
Toll receptor-IL-1 receptor (TIR) domains (146, 154).
MyD88 contains an additional protein-binding domain, the death domain
(DD) (Fig. 1), which facilitates its association with another
DD-containing signaling molecule, IL-1 receptor-associated kinase-1
(IRAK-1) (48). After autophosphorylation, IRAK-1
dissociates from MyD88 and interacts with TNF receptor-associated factor-6 (TRAF-6) (137, 194), resulting in the activation
of a downstream kinase cascade involving NF-
B-inducing kinase
(NIK) and I
B kinase (IKK) (Fig. 2). The IKK-mediated phosphorylation of I
B, an inhibitor of NF-
B, leads to I
B degradation through the proteasome pathway and enables NF-
B to translocate to the nucleus where it promotes new gene expression (48).
|
|
![]() |
TLR-4 SIGNALING LEADING TO APOPTOSIS |
---|
Several of the upstream signaling molecules involved in LPS
activation of NF-B are similarly involved in promoting LPS-induced apoptosis. Macrophages derived from C3H/HeJ mice, which have a missense mutation in the third exon of Tlr-4 (166), are
resistant to LPS-induced apoptosis (110).
Furthermore, neutralization of the lipid A moiety of LPS, which is the
domain of LPS recognized by Tlr-4 (139), protects against
LPS-induced EC apoptosis (18, 19). Downstream of
Tlr-4, MyD88 and IRAK-1 have been implicated in mediating LPS-elicited
cell death signaling. Expression of either MyD88 or IRAK-1
dominant-negative (D/N) constructs, which inhibit LPS-induced NF-
B
activation (19, 222), protects against LPS-induced EC
apoptosis (19). MyD88 has similarly been shown to
mediate Tlr-2 activation of NF-
B and proapoptotic signaling (5). Downstream of MyD88 and IRAK-1, TRAF-6 has been
implicated in promoting LPS-induced EC apoptosis
(100). TRAF-6 participation in LPS-induced
apoptosis involves c-jun NH2-terminal
kinase, the activation of which lies upstream of caspase activation.
Together, these data indicate that Tlr-4 can serve as a death receptor
for LPS and that the signaling molecules involved in LPS-induced
NF-
B activation serve a dual role in promoting LPS-induced
apoptosis (Fig. 2).
There is evidence suggesting that Tlr-4 activation of NF-B can occur
through a MyD88- and IRAK-1-independent pathway. The LPS-induced
DNA-binding activity of NF-
B in macrophages derived from either
MyD88 or IRAK-1 knockout mice is delayed, but not inhibited, indicating
that cellular activation by LPS can occur in the absence of these
signaling molecules (115, 194). Recently, an MyD88-like
protein has been identified by two independent groups, MyD88
adapter-like protein (MAL) or TIR domain-containing adapter protein
(TIRAP), which promote LPS-induced NF-
B signaling through IRAK-2
(62, 91). MAL/TIRAP contains a COOH terminus TIR domain but lacks the NH2 terminus DD present in MyD88 (Fig. 1).
Similar to MyD88, MAL/TIRAP has an additional role in promoting
LPS-induced EC apoptosis (15). These studies
demonstrate the presence of an MyD88-independent pathway that serves a
redundant signaling role in promoting both LPS-induced NF-
B
activation and apoptosis in ECs (Fig. 2).
Although Tlr-4 and its respective intracellular binding partners MyD88
and MAL/TIRAP have been shown to mediate LPS-induced apoptosis,
questions remain as to how this signaling pathway activates the
effector proteases of apoptosis, the caspases. The
Fas-associated death domain (FADD) is a proapoptotic adapter
protein that couples death receptors to initiator caspases (24,
35, 96, 126). Its role in mediating apoptosis has been
well elucidated in death signaling initiated by the Fas and TNF-
receptors. FADD recruitment, either directly to Fas or through the
intermediary TNF receptor-associated DD protein in the case of the
TNF-
receptor, is mediated through binding between the two highly
conserved DDs found on these proteins. Similarly, FADD and procaspase-8
interact through the death effector domains (DED) contained by each
protein (Fig. 1). Procaspase-8 contains partial proteolytic activity
that enables it to cleave other procaspase-8 molecules brought into
close proximity after recruitment to FADD (155).
Activation of caspase-8 initiates a proteolytic cascade resulting in
the activation of downstream effector caspases, including caspase-3
(89). Although a role for FADD in mediating TNF-
- and
Fas-induced apoptosis has been well established, there are
conflicting reports as to whether this molecule is involved in LPS
proapoptotic signaling. Choi et al. (36) reported that
expression of a FADD D/N protected against LPS-induced EC
apoptosis, whereas another group showed that the same FADD D/N
had no effect (19). It is difficult to reconcile these
differences because both studies utilized the same EC type and a
comparable retrovirus-based system to stably express identical FADD D/N
constructs. Furthermore, both studies were able to demonstrate the
efficacy of the FADD D/N construct in protecting against
TNF-
-elicited apoptosis. One major difference between the
studies was in the assay used to measure cell death. In the study by
Choi et al. (36), mitochondrial activity was used as a
measure of cell viability. This method of viability, however,
does not discriminate between necrotic and apoptotic cell death. In
the contrasting report, a more selective assay for determining
apoptotic cell death, which involved measuring caspase
activity, was used (19). One explanation for these
differences may be that LPS induces both apoptotic
(caspase-dependent) and nonapoptotic (caspase-independent) cell
death and that FADD plays a role in mediating the latter.
Tlr-4 is one member of a larger family of pattern recognition receptors
involved in the innate immune response. Another member of the Tlr
family, Tlr-2, recognizes the cell wall components peptidoglycan and
bacterial lipoproteins found in both gram-positive and -negative
bacteria as well as gram-positive-restricted lipoteichoic acid
(4, 186). Several of the intracellular signal transduction molecules involved in Tlr-4-mediated activation of NF-B, including MyD88, IRAK, TRAF-6, NIK, and IKK, are similarly involved in Tlr-2 signaling. Interestingly, bacterial lipoprotein-elicited Tlr-2 proapoptotic signaling is reportedly mediated by MyD88 and FADD, two molecules similarly involved in LPS/Tlr-4-induced apoptosis (5). In contrast, Tlr-2-mediated apoptosis occurs
independently of TRAF-6 involvement (5), a signaling
molecule recently established to participate in LPS/Tlr-4
proapoptotic signaling (100). Thus divergence in the
apoptotic signaling pathways mediated by Tlr-2 and Tlr-4 occurs
downstream of MyD88.
![]() |
ROLE OF NF-![]() |
---|
LPS-induced activation of NF-B is a key signaling event that
mediates an array of EC responses, including increased 1)
IL-6 (109), IL-8 (7, 223), and IL-1
(138) production, 2) E-selectin, ICAM-1, and
VCAM-1 surface expression (34, 108), and 3)
tissue factor activity (42, 75). In addition to its role
in promoting the expression of proinflammatory gene products, NF-
B
has been implicated in both pro- (86, 178) and
antiapoptotic signaling (128, 203). In ECs, inhibition
of NF-
B activation sensitizes human ECs to direct TNF-
-induced
apoptosis in the absence of cycloheximide, suggesting an
antiapoptotic role for NF-
B (221). Evidence exists
that this sensitization is conferred by inhibition of NF-
B-dependent
expression of members of the inhibitors of apoptosis (IAP) gene
family (190). In contrast to TNF-
, inhibition of
NF-
B does not sensitize human ECs to direct LPS-induced
apoptosis (221). These data, therefore, preclude
an antiapoptotic role for NF-
B in conferring protection against
LPS-elicited apoptosis.
There are reports that NF-B signaling has a role in proapoptotic
signaling (86, 178). On the basis of the predominant role
of NF-
B in mediating LPS-elicited EC responses and the finding that
MyD88, MAL/TIRAP, and IRAK-1 promote both LPS-induced NF-
B activation and apoptosis (Fig. 2), there has been speculation that these events are coupled. Several lines of evidence, however, suggest that these events occur independently of one another. First,
the presumed mechanism of the proapoptotic properties of NF-
B
reported by Ryan et al. (178) is through the promotion of
new gene expression, similar to its antiapoptotic role and the
induction of antiapoptotic proteins. The finding that LPS elicits
EC apoptosis in the absence of new protein synthesis argues against a proapoptotic role for NF-
B that involves new gene
expression (21). Second, inhibition of NF-
B activation
by overexpression of an I
B
superrepressor fails to block
LPS-induced EC apoptosis (19, 21). This latter
finding also demonstrates a bifurcation in the NF-
B and
apoptotic pathways that mediate LPS signaling upstream of I
B
degradation. Finally, complete inhibition of apoptosis with the
caspase inhibitor zVAD-FMK does not inhibit the ability of LPS to
activate NF-
B (19). Thus despite a commonality among upstream signaling molecules, LPS/Tlr-4-induced NF-
B activation and
apoptosis are mutually independent events (Fig. 2).
![]() |
ROLE OF CASPASES |
---|
A hallmark of apoptosis is the activation of highly specific effector proteases of the caspase family. Caspases exist as inactive zymogens (proenzymes) that are activated by proteolytic processing of the procaspase molecule in one of three ways: 1) autoactivation due to low levels of intrinsic catalytic activity, 2) transactivation by other caspases within close proximity, or 3) activation by noncaspase proteases (198). Once activated, caspases cleave and activate other members of the caspase family leading to amplification of a proteolytic cascade. The end result is a series of proteolytic events that lead to the cleavage of intracellular substrates, chromatin condensation, DNA fragmentation, and eventual cell death.
Of the 14 known caspases expressed in mammalian cells, LPS has been
reported to activate caspase-1 (152, 185), caspase-3 (15, 49, 100, 111, 152), caspase-6 (111), and
caspase-8 (100, 111). Activation of caspase-1
(interleukin-1 converting enzyme) is primarily responsible for IL-1
processing and has limited involvement in apoptosis
(43). In contrast, caspase-3, -6, and -8 all have been
established to prominently participate in apoptosis. Caspase-8,
also known as FADD-like interleukin converting enzyme protease (FLICE),
is classically described as an initiator caspase that is recruited to
such death receptors as TNFR and Fas. Procaspase-8 has
intrinsically low levels of proteolytic activity that enables it
to cleave other procaspase-8 molecules brought into close proximity
after recruitment to the receptor (155). Activation of
caspase-8 initiates a proteolytic cascade resulting in the activation
of downstream effector caspases and the onset of apoptosis
(89). A key target of caspase-8 is procaspase-3. Proteolytic processing of procaspase-3 results in an active caspase-3 molecule that serves as a key effector caspase responsible for much of
the proteolysis associated with apoptosis (89,
107). The effects of LPS-induced caspase activation on ECs are
quite dramatic, resulting in the cleavage of nuclear proteins as well as structural proteins that mediate cell-cell and cell-substrate adhesion (18, 21). In vivo studies support a role for
caspases in mediating LPS-induced EC apoptosis (49,
116). Liver ECs derived from mice administered intravenous LPS
display enhanced capase-3 activity (49). Furthermore,
inhibition of caspase activation with the cell-permeable, pan-caspase
inhibitor peptide zVAD protects against EC apoptosis elicited
by LPS in a murine model of endotoxin shock (116).
The mechanism by which LPS/Tlr-4 signaling activates caspases remains unknown. A proximal event in LPS signaling is MyD88 recruitment of IRAK through reciprocal binding of the DD regions on each of these molecules (48). One possibility is that FADD or a FADD-like protein may bind either MyD88 and/or IRAK-1 through homophilic DD-DD interactions (Fig. 2). By a mechanism similar to that reported for other death receptor signaling pathways, including those involving Fas and TNFR1 (11), FADD, which contains an additional DED binding domain, may recruit procaspase-8 via DED-DED interactions to the Tlr-4 signaling complex. The induced proximity of procaspase-8 molecules could lead to respective activation and the onset of apoptosis. In support of this hypothesis, overexpressed MyD88 has been reported to bind FADD via DD-mediated interactions (5, 92). Whether this interaction occurs when these proteins are expressed at physiological levels remains unknown.
![]() |
ANTIAPOPTOTIC SIGNALING AND ROLE OF FLICE-LIKE INHIBITOR PROTEIN |
---|
FLICE-like inhibitor protein (FLIP) is an antiapoptotic protein with significant homology to caspase-8 (FLICE) (106). In FLIP, a substitution of two amino acids that corresponds to the caspase-8 catalytic site renders it catalytically inactive. The role of FLIP in the inhibition of Fas death signaling has been well elucidated. On Fas ligand binding, the adapter protein FADD is recruited to the Fas receptor via an interaction between the DD of each protein (199). FLIP and procaspase-8 are, in turn, recruited to FADD via DED protein-protein interactions contained within all three proteins (Fig. 1). It has been proposed that FLIP can inhibit activation of upstream initiator caspases, including caspase-8, by competitively binding to FADD and blocking assembly of a functional death signaling complex (188). Alternatively, FADD recruitment of FLIP, which lacks intrinsic proteolytic activity, may prevent transactivation of procaspase-8 (182). A role for FLIP in inhibiting TNFR1-elicited apoptosis through a similar mechanism has been reported (97).
Recent studies indicate that FLIP protects against LPS-induced apoptosis. First, decreased expression of FLIP parallels in both a dose- and time-dependent manner with EC sensitization to LPS-induced apoptosis (21, 60). Second, inhibition of proteasome-mediated FLIP degradation protects against LPS-induced apoptosis (21). Third, specific inhibition of FLIP expression with antisense oligonucleotides sensitizes ECs to LPS-induced apoptosis (21). Finally, overexpression of FLIP protects against LPS-evoked apoptosis (60). Together, these data indicate that FLIP confers protection against LPS-induced apoptosis. The mechanism of protection remains unknown. A previous report has implicated a role for FADD in mediating LPS-induced apoptosis (36). One may speculate that Tlr-4 recruitment of FADD or a FADD-like molecule leads to the recruitment of upstream initiator caspases and subsequent caspase activation. In a manner analogous to the Fas and TNFR1 pathways, FLIP recruitment to FADD would be expected to prevent caspase recruitment and/or activation and block the onset of apoptosis (Fig. 2).
Both LPS and TNF- directly induce EC apoptosis in bovine
ECs. Human EC sensitization to apoptosis elicited by either of
these agents is dependent on the absence of de novo gene expression (164). EC sensitization is conferred by either
cycloheximide or actinomycin D, protein or mRNA synthesis inhibitors,
respectively. The requisite inhibition of gene expression required for
sensitization suggests that either a constitutively expressed protein
with a relatively short half-life or an inducible protein confers EC resistance to LPS- and TNF-
-induced apoptosis. LPS and
TNF-
each upregulate the expression of several antiapoptotic
proteins, including A1 (99, 112, 113), A20 (58, 99,
220), and cellular inhibitor of apoptosis proteins
(cIAPs) (190) in an NF-
B-dependent manner.
Blocking NF-
B activation sensitizes ECs to direct TNF-
-induced apoptosis and correlates with the inhibition of expression of these NF-
B-inducible antiapoptotic proteins (221).
In contrast, inhibition of NF-
B activation fails to sensitize ECs to
direct LPS-induced apoptosis, suggesting a distinct mechanism
by which inhibition of new gene expression sensitizes ECs to LPS- and
TNF-
-induced apoptosis. Recently, inhibition of
proteasome-mediated protein degradation was shown to protect against
LPS-induced apoptosis in the presence of cycloheximide
(21). That LPS-evoked apoptosis was prevented in
the absence of new gene expression precludes a role for an inducible
gene product. Interestingly, inhibition of de novo protein synthesis
leads to a marked decrease in the expression of FLIP, a constitutively
expressed protein implicated in conferring resistance to LPS-induced
apoptosis (21, 60). This suggests that
cycloheximide sensitization of human ECs to LPS-induced
apoptosis is mediated by both the inhibition of de novo
synthesis of FLIP and the rapid degradation of preexisting FLIP
molecules via the proteasome (Fig. 3).
|
Although cycloheximide or actinomycin D have been used as tools to
investigate sensitization to LPS-induced apoptosis by
inhibiting de novo gene expression, it is difficult to imagine a
scenario in which these agents would be present in vivo with LPS.
However, naturally occurring agents that inhibit protein synthesis may be expected to confer similar sensitivity. Shiga toxin and Shiga-like toxin-1 (SLT-1), produced by Shigella dysenteriae serotype 1 and certain strains of E. coli, respectively, inhibit
protein synthesis (141, 162, 213). Both of these toxins
have been implicated in the pathogenesis of hemolytic uremic syndrome
and its attendant EC injury (158, 167, 170). Shiga toxin
and SLT-1 inhibit protein synthesis by cleaving a specific bond in the
28S rRNA component of the 60S ribosomal subunit, resulting in the
release of a single adenine base and the inhibition of aminoacyl tRNA
binding to the ribosome (79, 158). Recent findings suggest
that SLT-1 sensitizes human ECs to LPS-induced apoptosis by
virtue of its protein synthesis inhibitory properties (60)
(Fig. 3). SLT-1 inhibition of FLIP expression sensitizes ECs to
LPS-induced apoptosis in both a dose- and time-dependent
manner. Furthermore, sustained expression of FLIP in the presence of
SLT-1 abrogates SLT-induced sensitization of human ECs to LPS-induced
apoptosis. Thus strains of E. coli that produce
SLT-1 have all the necessary components to elicit EC apoptosis,
namely a sensitizing agent, SLT-1, and an inducer of apoptosis,
LPS. Other naturally occurring agents reported to have protein
synthesis inhibitory properties include Pseudomonas aeruginosa toxin (101), interferons
(39), and TNF- (129). The role of these
agents in sensitizing ECs to LPS-induced apoptosis during mixed
infection and inflammation should be considered. Furthermore, patients
in severe sepsis often are in a profound catabolic state
(85). Whether this influences the ability of cells to
maintain adequate levels of antiapoptotic proteins while being
exposed to LPS and/or apoptotic-inducing cytokines remains unknown.
![]() |
ROLE OF BCL-2 FAMILY MEMBERS |
---|
Cell commitment to apoptosis is governed by both pro- and antiapoptotic signaling pathways. The Bcl-2 family of proteins plays a central role in mediating these two opposed pathways (2, 8). The Bcl-2 family is composed of both pro- and antiapoptotic members. A key mechanism by which these proteins mediate apoptosis is through the regulation of cytochrome c release from the mitochondrion (2, 8). Cytochrome c is a cofactor in the activation of caspase-9, the latter of which activates downstream effector caspases, including caspase-3. Proapoptotic and antiapoptotic members of the Bcl-2 family facilitate and restrict, respectively, cytochrome c release from the mitochondrion. The various Bcl-2 family members are characterized by the presence of one or more of four distinct Bcl-2 homology (BH) domains that facilitate protein-protein interactions. Antiapoptotic Bcl-2 family members exert their effect by forming heterodimers via these BH domains with the proapoptotic members, thereby impairing the ability of the proapoptotic members to induce cytochrome c release.
Several lines of evidence suggest that members of the Bcl-2 family mediate sepsis- and LPS-induced apoptosis. First, in a murine model of sepsis induced by cecal ligation and puncture, enhanced endothelial apoptosis parallels a decrement in the expression of the antiapoptotic protein Bcl-2 (217). Second, LPS upregulates EC expression of the proapoptotic Bcl-2 family members Bax (81, 118, 152), Bad (147), and Bak (147). LPS has also been reported to upregulate expression of A1 (99) and to downregulate levels of Bcl-2 (81, 118) and Bcl-xL (147), all of which are antiapoptotic members of the Bcl-2 family. Third, vascular endothelial growth factor (VEGF) (152) and other agents (81, 118) that inhibit LPS-induced upregulation of proapoptotic Bcl-2 family members protect against LPS-induced EC apoptosis. Inhibition of LPS-induced downregulation of antiapoptotic Bcl-2 homologs similarly confers protection (81, 118). Finally, overexpression of A1 or Bcl-xL protects against LPS-induced EC apoptosis (99). Together, these data implicate a role for Bcl-2 homologs in determining EC fate after LPS exposure.
![]() |
ROLE OF NITRIC OXIDE |
---|
Nitric oxide (NO) is a biological messenger molecule with profound
influence on the vasculature. NO has been implicated in the regulation
of vasomotor tone, inhibition of platelet aggregation and leukocyte
adhesion to ECs, activation of transcription factors leading to new
gene expression, and the regulation of apoptosis (140). In ECs, NO is generated by both a constitutive
nitric oxide synthase and an inducible nitric oxide synthase (iNOS)
(168). LPS upregulates the expression of iNOS and the
production of NO in ECs (130, 156, 175, 179). These EC
responses are further potentiated by LPS coadministration with other
proinflammatory cytokines, including interferon- (70,
208).
NO has been reported to inhibit LPS-induced EC apoptosis. ECs exposed to the NO donors S-nitroso-N-acetylpenicillamine or (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate demonstrate reduced sensitivity to LPS-induced apoptosis (51, 196). Enhanced production of endogenous NO after overexpression of iNOS has been similarly shown to block LPS-elicited EC apoptosis (31, 200). The mechanism by which NO inhibits LPS-induced EC apoptosis remains unclear. Increased levels of NO have been reported to suppress LPS-induced activation of caspase-3 in ECs (31, 200). In vitro studies using purified human recombinant caspases have shown that NO reversibly inhibits seven distinct members of the caspase family, including caspase-3, through direct S-nitrosylation of a cysteine residue required for caspase catalytic activity (55, 119, 136). Thus the protective effect of NO on LPS-exposed ECs may be mediated by NO inactivation of caspases.
In contrast to a cytoprotective role for NO, other studies have reported that suppression of iNOS induction and inhibitors of NOS activity protect against LPS-elicited EC injury (87, 160, 180), suggesting that NO promotes LPS-induced apoptosis. The differential effects of NO on mediating LPS-induced EC apoptosis appear to be dose dependent. DeMeester et al. (51) have reported that moderate levels of NO confer protection, whereas higher concentrations of NO enhance LPS-induced EC apoptosis. Although the mechanism by which NO potentiates LPS-elicited apoptosis remains unknown, high concentrations of NO can inhibit protein synthesis (214). Because protein synthesis inhibition has been established to sensitize human ECs to LPS-induced apoptosis by inhibiting the expression of the antiapoptotic protein FLIP (21), one may speculate that high levels of NO may result in decreased expression of this cytoprotective protein. Alternatively, increased production of NO after LPS induction of iNOS may result in NO reaction with superoxide anion to form peroxynitrite. EC injury resulting from the generation of peroxynitrite, a potent oxidizer, may synergistically enhance the EC apoptosis elicited by LPS. Further studies are needed to clarify the potential proapoptotic role of NO in mediating LPS-induced EC apoptosis.
![]() |
ROLE OF REACTIVE OXYGEN SPECIES |
---|
In response to stress and/or injury, ECs generate reactive oxygen species (ROS) and nitrogen intermediates (165). Generation of these free radicals can lead to an alteration in the balance of the pro- and antioxidant states, resulting in oxidative stress and potential cell injury (32). Increases in ROS or depletion of antioxidants can lead to apoptosis in a variety of cell types, including ECs (54, 68, 125, 134, 135). LPS elicits an increase in the generation of EC ROS (28, 117, 118, 177, 216). Interestingly, LPS-induced generation of ROS correlates with the onset of apoptosis, and agents that inhibit the formation of ROS confer protection against LPS-evoked EC apoptosis (1, 28, 117, 118, 150). Although the mechanism by which ROS contribute to LPS-induced EC apoptosis remains unknown, ROS have been shown to increase mitochondrial membrane permeability, resulting in the release of proapoptotic factors (10, 29, 63, 195, 224). One of these factors is cytochrome c, a cofactor that drives the assembly of the caspase-9-activating apoptosome (169). Furthermore, ROS have been reported to increase both the expression and activation of caspase-8 (151, 224) as well as the activation of caspase-3 (10, 224).
In addition to the generation of ROS, LPS induces the upregulation of manganese superoxide dismutase (MnSOD) (150, 206) and copper, zinc superoxide dismutase (Cu,Zn-SOD) (123). SODs serve as an important component of the EC antioxidant defense system by accelerating the conversion of superoxide to H2O2. Although both superoxide and H2O2 are potent oxidants, the latter reacts much more slowly with cellular substrates (165). LPS-induced upregulation of MnSOD is mediated, in part, by increased generation of ROS, thus SOD may act to counterbalance the proapoptotic effects of ROS (150). Consistent with this hypothesis, upregulation of SOD has been reported to inhibit apoptosis in a variety of cell types, including ECs (56, 120, 215). Furthermore, overexpression of Cu,Zn-SOD protects against reactive oxygen intermediates (ROI)-elicited induction of caspase-8, activation of caspase-3, and mitochondrial release of cytochrome c after ischemia (151, 191). Finally, overexpression of MnSOD decreases the sensitivity of ECs to LPS-induced apoptosis (31). Clearly, one possible mechanism by which SOD confers protection is by restricting the accumulation of potent oxidizing molecules that may promote apoptosis. Another mechanism may be through SOD's role in accelerating the conversion of superoxide to H2O2. Although H2O2 has been reported to induce apoptosis in some systems, others have reported that high levels of H2O2 inhibit caspase activation and apoptosis (25, 83, 131). Whether LPS-induced upregulation of SODs generates H2O2 at a level that will promote or inhibit LPS-evoked EC apoptosis remains unknown.
The role of ROS in mediating apoptosis is further complicated
by ROS activation of signal transduction pathways that inhibit EC
apoptosis (105, 165). ROS-activated pathways
include: 1) the mitogen-activated protein kinases, which
have been implicated in VEGF-induced EC survival (78),
2) Akt, a kinase involved in phosphoinositide 3-kinase
signaling that is linked to shear stress and VEGF-induced survival
(53, 66, 71), and 3) NF-B, a transcription
factor that upregulates the antiapoptotic proteins A1, A20, and
IAPs (44, 99, 113, 183, 190, 209, 221). Whether
LPS-induced generation of ROS activates these pathways resulting in
resistance to LPS proapoptotic signaling remains unknown.
![]() |
ROLE OF APOPTOTIC SIGNALING MOLECULES IN MEDIATING LPS-INDUCED EC ACTIVATION |
---|
A key marker of EC activation is NF-B activation and nuclear
translocation, a requisite event for many EC responses, including increased expression of cytokines and adhesion molecules. Recent studies demonstrate that several signaling molecules originally described as mediators of apoptosis also contribute to the
regulation of NF-
B activation (33, 98, 102, 103, 114, 184,
207). Evidence supporting this dual function for apoptotic
signaling molecules includes: 1) enhanced caspase activation
inhibits TNF-
-induced EC NF-
B nuclear translocation and VCAM-1
expression (157), 2) transient overexpression
of FADD, FLIP, or caspase-8 augments basal levels of NF-
B activation
(33, 98, 114), 3) overexpression of FADD
upregulates monocyte chemotactic protein-1 and IL-8 expression, the
transcription of which is mediated by NF-
B (184), and
4) FADD-deficient Jurkat cells display impaired
activation of NF-
B after exposure to TNF-
, TNF-related
apoptosis-inducing ligand (TRAIL), or Fas (207).
Similarly, evidence exists that apoptotic signaling molecules also
influence the ability of LPS to induce NF-B activation. LPS-insensitive human embryonic kidney 293T cells are sensitized to
LPS-induced NF-
B activation on induced expression of Nod1, a
cytoplasmic protein with structural homology to the apoptosis regulator, Apaf-1 (104). Furthermore, overexpression of
Bcl-2 and Bcl-xL inhibits LPS-induced NF-
B activation
and NF-
B-dependent gene expression in ECs (13). This
inhibition of NF-
B activation corresponds with Bcl-2-mediated
inhibition of I
B
degradation. The mechanism by which Bcl family
members inhibit LPS-induced NF-
B activation remains unknown.
Identification of a caspase consensus site within I
B
has led to
speculation that caspases may be involved in its proteolysis
(13). Thus Bcl-mediated inhibition of caspase activation
may be expected to block I
B
degradation and subsequent activation
of NF-
B.
Further evidence for cross talk between apoptotic signaling
molecules and LPS-induced NF-B activation was provided in a recent report demonstrating that the proapoptotic adapter protein FADD downregulates LPS-induced NF-
B activation (20). In that
study, overexpression of either full-length FADD or the DD of FADD in ECs blocked LPS-induced NF-
B activation. Furthermore, mouse embryo fibroblasts (MEF) derived from FADD
/
mice embryos displayed enhanced NF-
B activity relative to FADD+/+ MEF after LPS treatment. The production of IL-6 and KC, two NF-
B-dependent gene
products, were similarly enhanced in FADD
/
MEF after LPS exposure
relative to FADD+/+ MEF. Reconstitution of FADD in FADD
/
MEF
abrogated the enhanced NF-
B activation and IL-6 and KC production
elicited by LPS. Together, these data suggest that changes in FADD
expression can affect LPS-induced activation of NF-
B. The role of
FADD in inhibiting this event under basal conditions remains unclear as LPS activates EC NF-
B in the presence of physiological levels of FADD.
The mechanism by which FADD downregulates NF-B-dependent gene
expression remains unknown. However, the enhanced NF-
B activity in
the FADD
/
MEF after LPS stimulation correlated with enhanced degradation of the inhibitor of NF-
B, I
B, suggesting that FADD exerts its effect upstream of I
B degradation. Interestingly, NF-
B
activation by IL-1
, a proinflammatory cytokine that shares the same
intracellular signaling pathway leading to NF-
B activation as that
of LPS, is similarly downregulated by FADD (20).
The data that FADD inhibition of LPS and IL-1-induced NF-
B
activation occurs upstream of I
B degradation and that FADD inhibits a signaling pathway shared by these two distinct stimuli suggests that
FADD may exert its effect through inhibiting and/or sequestering signaling molecules involved in both LPS and IL-1
-induced NF-
B activation. A proximal event in LPS and IL-1
signaling is MyD88 recruitment of IRAK through reciprocal binding of the DD regions on
each of these molecules (48, 194, 212) (Fig.
4). One possibility is that FADD, another
DD-containing protein, may bind and/or sequester MyD88 and/or IRAK-1
through homophilic DD-DD interactions. In fact, overexpressed MyD88
reportedly binds FADD via DD-mediated interactions (5,
92). Whether this interaction occurs when these proteins are
expressed at physiological levels is not known. It has been well
established that both MyD88 and IRAK are required for optimal
LPS-induced NF-
B activation and NF-
B-dependent gene expression
(115, 194, 222). Thus any protein that can interfere with
the recruitment of these molecules to the Tlr-4 receptor-signaling complex, perhaps through DD-DD interactions, would be expected to
disrupt LPS-induced NF-
B signaling. FADD contains an additional protein-binding domain, the DED (Fig. 1), which facilitates recruitment of FLIP and caspase-8 (Fig. 4). FLIP and caspase-8 have been
demonstrated to bind NIK and IKK in a DED-dependent manner
(33). This raises another possibility that FADD itself
may, through its DED, associate with and/or sequester NIK and IKK, two
proteins involved in LPS activation of NF-
B. Alternatively, both
FLIP and caspase-8 have been demonstrated to potentiate NF-
B
activation, whereas caspase-8 D/N constructs inhibit NF-
B activation
induced by a variety of death receptors, including TNFR1, Fas, DR3,
DR4, and DR5 (33). These data suggest a role for these
proteins in promoting NF-
B activation. Therefore, another mechanism
by which FADD may inhibit LPS-induced NF-
B activation is through the
sequestering of FLIP and/or caspase-8 (Fig. 4). Further studies are
required to define the role(s) of these DED-containing molecules in
mediating LPS signaling.
|
![]() |
FUTURE DIRECTIONS |
---|
The unique position of the endothelium at the blood-extravascular
tissue interface exposes ECs to an array of circulating mediators that
may be injurious. EC injury and/or dysfunction contribute to the
development of complications that often accompany gram-negative sepsis,
including ARDS. The pathophysiological implications of EC involvement
warrant investigation into the mechanisms of EC injury and/or death.
LPS is a key proinflammatory mediator that contributes, at least in
part, to the deleterious effects of gram-negative bacteremia and its
attendant endotoxemia. LPS is a potent activator of the vascular
endothelium and elicits an array of EC responses, including
apoptosis. Key areas of future study include: 1)
identifying the adapter proteins that link the Tlr-4 signaling
molecules to the recruitment and activation of caspases (Fig. 2),
2) determining whether FLIP and Bcl-2 homologs participate
in redundant cytoprotective pathways and identifying the mechanism by
which these molecules confer EC protection against LPS-induced
apoptosis, 3) evaluating the cross talk between
apoptotic signaling molecules and NF-B activation with the goal
of devising a common therapeutic intervention that could dampen an
excessive host inflammatory response and simultaneously protect against host tissue injury (Fig. 4), 4) investigating the
synergistic effect that endogenous proinflammatory mediators may have
with LPS and one another on promoting EC apoptosis, and
5) extending the promising though limited research
evaluating the efficacy of caspase inhibitors in sepsis models.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: D. D. Bannerman, Immunology and Disease Resistance Laboratory, United States Dept. of Agriculture-Agricultural Research Service/ANRI, BARC-East, Bldg. 1040, Rm. #2, Beltsville, MD 20705-2350 (E-mail: dbanner{at}anri.barc.usda.gov).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajplung.00338.2002
![]() |
REFERENCES |
---|
1.
Abello, PA,
Fidler SA,
Bulkley GB,
and
Buchman TG.
Antioxidants modulate induction of programmed endothelial cell death (apoptosis) by endotoxin.
Arch Surg
129:
134-140,
1994[Abstract].
2.
Adams, JM,
and
Cory S.
The Bcl-2 protein family: arbiters of cell survival.
Science
281:
1322-1326,
1998
3.
Akashi, S,
Ogata H,
Kirikae F,
Kirikae T,
Kawasaki K,
Nishijima M,
Shimazu R,
Nagai Y,
Fukudome K,
Kimoto M,
and
Miyake K.
Regulatory roles for CD14 and phosphatidylinositol in the signaling via Toll-like receptor 4-MD-2.
Biochem Biophys Res Commun
268:
172-177,
2000[ISI][Medline].
4.
Aliprantis, AO,
Yang RB,
Mark MR,
Suggett S,
Devaux B,
Radolf JD,
Klimpel GR,
Godowski P,
and
Zychlinsky A.
Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2.
Science
285:
736-739,
1999
5.
Aliprantis, AO,
Yang RB,
Weiss DS,
Godowski P,
and
Zychlinsky A.
The apoptotic signaling pathway activated by Toll-like receptor-2.
EMBO J
19:
3325-3336,
2000
6.
Alpert, G,
Baldwin G,
Thompson C,
Wainwright N,
Novitsky TJ,
Gillis Z,
Parsonnet J,
Fleisher GR,
and
Siber GR.
Limulus antilipopolysaccharide factor protects rabbits from meningococcal endotoxin shock.
J Infect Dis
165:
494-500,
1992[ISI][Medline].
7.
Anrather, J,
Csizmadia V,
Brostjan C,
Soares MP,
Bach FH,
and
Winkler H.
Inhibition of bovine endothelial cell activation in vitro by regulated expression of a transdominant inhibitor of NF-B.
J Clin Invest
99:
763-772,
1997
8.
Antonsson, B,
and
Martinou JC.
The Bcl-2 protein family.
Exp Cell Res
256:
50-57,
2000[ISI][Medline].
9.
Arditi, M,
Zhou J,
Dorio R,
Rong GW,
Goyert SM,
and
Kim KS.
Endotoxin-mediated endothelial cell injury and activation: role of soluble CD14.
Infect Immun
61:
3149-3156,
1993[Abstract].
10.
Armstrong, JS,
Steinauer KK,
Hornung B,
Irish JM,
Lecane P,
Birrell GW,
Peehl DM,
and
Knox SJ.
Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line.
Cell Death Differ
9:
252-263,
2002[ISI][Medline].
11.
Ashkenazi, A,
and
Dixit VM.
Death receptors: signaling and modulation.
Science
281:
1305-1308,
1998
12.
Assaly, R,
Olson D,
Hammersley J,
Fan PS,
Liu J,
Shapiro JI,
and
Kahaleh MB.
Initial evidence of endothelial cell apoptosis as a mechanism of systemic capillary leak syndrome.
Chest
120:
1301-1308,
2001
13.
Badrichani, AZ,
Stroka DM,
Bilbao G,
Curiel DT,
Bach FH,
and
Ferran C.
Bcl-2 and Bcl-XL serve an anti-inflammatory function in endothelial cells through inhibition of NF-B.
J Clin Invest
103:
543-553,
1999
14.
Balis, JU,
Gerber LI,
Rappaport ES,
and
Neville WE.
Mechanisms of blood-vascular reactions of the primate lung to acute endotoxemia.
Exp Mol Pathol
21:
123-137,
1974[ISI][Medline].
15.
Bannerman, DD,
Erwert RD,
Winn RK,
and
Harlan JM.
TIRAP mediates endotoxin-induced NF-B activation and apoptosis in endothelial cells.
Biochem Biophys Res Commun
295:
157-162,
2002[ISI][Medline].
16.
Bannerman, DD,
Fitzpatrick MJ,
Anderson DY,
Bhattacharjee AK,
Novitsky TJ,
Hasday JD,
Cross AS,
and
Goldblum SE.
Endotoxin-neutralizing protein protects against endotoxin-induced endothelial barrier dysfunction.
Infect Immun
66:
1400-1407,
1998
17.
Bannerman, DD,
and
Goldblum SE.
Direct effects of endotoxin on the endothelium: barrier function and injury.
Lab Invest
79:
1181-1199,
1999[ISI][Medline].
18.
Bannerman, DD,
Sathyamoorthy M,
and
Goldblum SE.
Bacterial lipopolysaccharide disrupts endothelial monolayer integrity and survival signaling events through caspase cleavage of adherens junction proteins.
J Biol Chem
273:
35371-35380,
1998
19.
Bannerman, DD,
Tupper JC,
Erwert RD,
Winn RK,
and
Harlan JM.
Divergence of bacterial lipopolysaccharide pro-apoptotic signaling downstream of IRAK-1.
J Biol Chem
277:
8048-8053,
2002
20.
Bannerman, DD,
Tupper JC,
Kelly JD,
Winn RK,
and
Harlan JM.
The Fas-associated death domain protein suppresses activation of NF-B by LPS and IL-1
.
J Clin Invest
109:
419-425,
2002
21.
Bannerman, DD,
Tupper JC,
Ricketts WA,
Bennett CF,
Winn RK,
and
Harlan JM.
A constitutive cytoprotective pathway protects endothelial cells from lipopolysaccharide-induced apoptosis.
J Biol Chem
276:
14924-14932,
2001
22.
Beal, AL,
and
Cerra FB.
Multiple organ failure syndrome in the 1990s. Systemic inflammatory response and organ dysfunction.
JAMA
271:
226-233,
1994[Abstract].
23.
Bell, RC,
Coalson JJ,
Smith JD,
and
Johanson WG, Jr.
Multiple organ system failure and infection in adult respiratory distress syndrome.
Ann Intern Med
99:
293-298,
1983[ISI][Medline].
24.
Bodmer, JL,
Holler N,
Reynard S,
Vinciguerra P,
Schneider P,
Juo P,
Blenis J,
and
Tschopp J.
TRAIL receptor-2 signals apoptosis through FADD and caspase-8.
Nat Cell Biol
2:
241-243,
2000[ISI][Medline].
25.
Borutaite, V,
and
Brown GC.
Caspases are reversibly inactivated by hydrogen peroxide.
FEBS Lett
500:
114-118,
2001[ISI][Medline].
26.
Brandtzaeg, P,
Kierulf P,
Gaustad P,
Skulberg A,
Bruun JN,
Halvorsen S,
and
Sorensen E.
Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease.
J Infect Dis
159:
195-204,
1989[ISI][Medline].
27.
Brigham, KL,
and
Meyrick B.
Endotoxin and lung injury.
Am Rev Respir Dis
133:
913-927,
1986[ISI][Medline].
28.
Brigham, KL,
Meyrick B,
Berry LC, Jr,
and
Repine JE.
Antioxidants protect cultured bovine lung endothelial cells from injury by endotoxin.
J Appl Physiol
63:
840-850,
1987
29.
Brown, GC,
and
Borutaite V.
Nitric oxide, cytochrome c and mitochondria.
Biochem Soc Symp
66:
17-25,
1999[Medline].
30.
Cai, W,
Devaux B,
Schaper W,
and
Schaper J.
The role of Fas/APO 1 and apoptosis in the development of human atherosclerotic lesions.
Atherosclerosis
131:
177-186,
1997[ISI][Medline].
31.
Ceneviva, GD,
Tzeng E,
Hoyt DG,
Yee E,
Gallagher A,
Engelhardt JF,
Kim YM,
Billiar TR,
Watkins SA,
and
Pitt BR.
Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells.
Am J Physiol Lung Cell Mol Physiol
275:
L717-L728,
1998
32.
Chandra, J,
Samali A,
and
Orrenius S.
Triggering and modulation of apoptosis by oxidative stress.
Free Radic Biol Med
29:
323-333,
2000[ISI][Medline].
33.
Chaudhary, PM,
Eby MT,
Jasmin A,
Kumar A,
Liu L,
and
Hood L.
Activation of the NF-B pathway by caspase-8 and its homologs.
Oncogene
19:
4451-4460,
2000[ISI][Medline].
34.
Chen, CC,
Rosenbloom CL,
Anderson DC,
and
Manning AM.
Selective inhibition of E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 expression by inhibitors of IB-
phosphorylation.
J Immunol
155:
3538-3545,
1995[Abstract].
35.
Chinnaiyan, AM,
Tepper CG,
Seldin MF,
O'Rourke K,
Kischkel FC,
Hellbardt S,
Krammer PH,
Peter ME,
and
Dixit VM.
FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis.
J Biol Chem
271:
4961-4965,
1996
36.
Choi, KB,
Wong F,
Harlan JM,
Chaudhary PM,
Hood L,
and
Karsan A.
Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway.
J Biol Chem
273:
20185-20188,
1998
37.
Chow, JC,
Young DW,
Golenbock DT,
Christ WJ,
and
Gusovsky F.
Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction.
J Biol Chem
274:
10689-10692,
1999
38.
Cines, DB,
Pollak ES,
Buck CA,
Loscalzo J,
Zimmerman GA,
McEver RP,
Pober JS,
Wick TM,
Konkle BA,
Schwartz BS,
Barnathan ES,
McCrae KR,
Hug BA,
Schmidt AM,
and
Stern DM.
Endothelial cells in physiology and in the pathophysiology of vascular disorders.
Blood
91:
3527-3561,
1998
39.
Clemens, MJ,
McNurlan MA,
Moore G,
and
Tilleray VJ.
Regulation of protein synthesis in lymphoblastoid cells during inhibition of cell proliferation by human interferons.
FEBS Lett
171:
111-116,
1984[ISI][Medline].
40.
Coalson, JJ,
Benjamin BA,
Archer LT,
Beller BK,
Spaet RH,
and
Hinshaw LB.
A pathologic study of Escherichia coli shock in the baboon and the response to adrenocorticosteroid treatment.
Surg Gynecol Obstet
147:
726-736,
1978[ISI][Medline].
41.
Coalson, JJ,
Hinshaw LB,
Guenter CA,
Berrell EL,
and
Greenfield LJ.
Pathophysiologic responses of the subhuman primate in experimental septic shock.
Lab Invest
32:
561-569,
1975[Medline].
42.
Colucci, M,
Balconi G,
Lorenzet R,
Pietra A,
Locati D,
Donati MB,
and
Semeraro N.
Cultured human endothelial cells generate tissue factor in response to endotoxin.
J Clin Invest
71:
1893-1896,
1983[ISI][Medline].
43.
Colussi, PA,
and
Kumar S.
Targeted disruption of caspase genes in mice: what they tell us about the functions of individual caspases in apoptosis.
Immunol Cell Biol
77:
58-63,
1999[ISI][Medline].
44.
Cooper, JT,
Stroka DM,
Brostjan C,
Palmetshofer A,
Bach FH,
and
Ferran C.
A20 blocks endothelial cell activation through a NF-B-dependent mechanism.
J Biol Chem
271:
18068-18073,
1996
45.
Cox, G,
Crossley J,
and
Xing Z.
Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in vivo.
Am J Respir Cell Mol Biol
12:
232-237,
1995[Abstract].
46.
Curzen, NP,
Griffiths MJ,
and
Evans TW.
Role of the endothelium in modulating the vascular response to sepsis.
Clin Sci (Lond)
86:
359-374,
1994[ISI][Medline].
47.
Cybulsky, MI,
Chan MK,
and
Movat HZ.
Acute inflammation and microthrombosis induced by endotoxin, interleukin-1, and tumor necrosis factor and their implication in gram-negative infection.
Lab Invest
58:
365-378,
1988[ISI][Medline].
48.
Daun, JM,
and
Fenton MJ.
Interleukin-1/Toll receptor family members: receptor structure and signal transduction pathways.
J Interferon Cytokine Res
20:
843-855,
2000[ISI][Medline].
49.
Deaciuc, IV,
Fortunato F,
D'Souza NB,
Hill DB,
Schmidt J,
Lee EY,
and
McClain CJ.
Modulation of caspase-3 activity and Fas ligand mRNA expression in rat liver cells in vivo by alcohol and lipopolysaccharide.
Alcohol Clin Exp Res
23:
349-356,
1999[ISI][Medline].
50.
Delvos, U,
Janssen B,
and
Muller-Berghaus G.
Effect of lipopolysaccharides on cultured human endothelial cells. Relationship between tissue factor activity and prostacyclin release.
Blut
55:
101-108,
1987[ISI][Medline].
51.
DeMeester, SL,
Qiu Y,
Buchman TG,
Hotchkiss RS,
Dunnigan K,
Karl IE,
and
Cobb JP.
Nitric oxide inhibits stress-induced endothelial cell apoptosis.
Crit Care Med
26:
1500-1509,
1998[ISI][Medline].
52.
Desch, CE,
O'Hara P,
and
Harlan JM.
Antilipopolysaccharide factor from horseshoe crab, Tachypleus tridentatus, inhibits lipopolysaccharide activation of cultured human endothelial cells.
Infect Immun
57:
1612-1614,
1989[ISI][Medline].
53.
Dimmeler, S,
Assmus B,
Hermann C,
Haendeler J,
and
Zeiher AM.
Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: involvement in suppression of apoptosis.
Circ Res
83:
334-341,
1998
54.
Dimmeler, S,
Haendeler J,
Galle J,
and
Zeiher AM.
Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases. A mechanistic clue to the 'response to injury' hypothesis.
Circulation
95:
1760-1763,
1997
55.
Dimmeler, S,
Haendeler J,
Nehls M,
and
Zeiher AM.
Suppression of apoptosis by nitric oxide via inhibition of interleukin-1-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases.
J Exp Med
185:
601-607,
1997
56.
Dimmeler, S,
Hermann C,
Galle J,
and
Zeiher AM.
Upregulation of superoxide dismutase and nitric oxide synthase mediates the apoptosis-suppressive effects of shear stress on endothelial cells.
Arterioscler Thromb Vasc Biol
19:
656-664,
1999
57.
Dinarello, CA.
Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock.
Chest
112:
321S-329S,
1997
58.
Dixit, VM,
Green S,
Sarma V,
Holzman LB,
Wolf FW,
O'Rourke K,
Ward PA,
Prochownik EV,
and
Marks RM.
Tumor necrosis factor- induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin.
J Biol Chem
265:
2973-2978,
1990
59.
Engelberts, I,
van Hoof SC,
Samyo SK,
Buurman WA,
and
van der Linden CJ.
Generalized inflammation during peritonitis evidenced by intracutaneous E-selectin expression.
Clin Immunol Immunopathol
65:
330-334,
1992[ISI][Medline].
60.
Erwert, RD,
Winn RK,
Harlan JM,
and
Bannerman DD.
Shiga-like toxin inhibition of FLICE-like inhibitory protein expression sensitizes endothelial cells to bacterial lipopolysaccharide-induced apoptosis.
J Biol Chem
277:
40567-40574,
2002
61.
Faure, E,
Equils O,
Sieling PA,
Thomas L,
Zhang FX,
Kirschning CJ,
Polentarutti N,
Muzio M,
and
Arditi M.
Bacterial lipopolysaccharide activates NF-B through Toll-like receptor-4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of tlr-4 and tlr-2 in endothelial cells.
J Biol Chem
275:
11058-11063,
2000
62.
Fitzgerald, KA,
Palsson-McDermott EM,
Bowie AG,
Jefferies CA,
Mansell AS,
Brady G,
Brint E,
Dunne A,
Gray P,
Harte MT,
McMurray D,
Smith DE,
Sims JE,
Bird TA,
and
O'Neill LA.
Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.
Nature
413:
78-83,
2001[ISI][Medline].
63.
Fleury, C,
Mignotte B,
and
Vayssiere JL.
Mitochondrial reactive oxygen species in cell death signaling.
Biochimie
84:
131-141,
2002[ISI][Medline].
64.
Frey, EA,
and
Finlay BB.
Lipopolysaccharide induces apoptosis in a bovine endothelial cell line via a soluble CD14-dependent pathway.
Microb Pathog
24:
101-109,
1998[ISI][Medline].
65.
Fry, DE,
Pearlstein L,
Fulton RL,
and
Polk HC, Jr.
Multiple system organ failure. The role of uncontrolled infection.
Arch Surg
115:
136-140,
1980[Abstract].
66.
Fujio, Y,
and
Walsh K.
Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner.
J Biol Chem
274:
16349-16354,
1999
67.
Fujita, M,
Kuwano K,
Kunitake R,
Hagimoto N,
Miyazaki H,
Kaneko Y,
Kawasaki M,
Maeyama T,
and
Hara N.
Endothelial cell apoptosis in lipopolysaccharide-induced lung injury in mice.
Int Arch Allergy Immunol
117:
202-208,
1998[ISI][Medline].
68.
Galle, J,
Heermeier K,
and
Wanner C.
Atherogenic lipoproteins, oxidative stress, and cell death.
Kidney Int Suppl
71:
S62-S65,
1999[Medline].
69.
Gaynor, E,
Bouvier C,
and
Spaet TH.
Vascular lesions: possible pathogenetic basis of the generalized Shwartzman reaction.
Science
170:
986-988,
1970[ISI][Medline].
70.
Geiger, M,
Stone A,
Mason SN,
Oldham KT,
and
Guice KS.
Differential nitric oxide production by microvascular and macrovascular endothelial cells.
Am J Physiol Lung Cell Mol Physiol
273:
L275-L281,
1997
71.
Gerber, HP,
McMurtrey A,
Kowalski J,
Yan M,
Keyt BA,
Dixit V,
and
Ferrara N.
Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation.
J Biol Chem
273:
30336-30343,
1998
72.
Gerrity, RG,
Richardson M,
Caplan BA,
Cade JF,
Hirsh J,
and
Schwartz CJ.
Endotoxin-induced vascular endothelial injury and repair. II. Focal injury, en face morphology, [3H]thymidine uptake and circulating endothelial cells in the dog.
Exp Mol Pathol
24:
59-69,
1976[ISI][Medline].
73.
Gobe, G,
Browning J,
Howard T,
Hogg N,
Winterford C,
and
Cross R.
Apoptosis occurs in endothelial cells during hypertension-induced microvascular rarefaction.
J Struct Biol
118:
63-72,
1997[ISI][Medline].
74.
Goldblum, SE,
Brann TW,
Ding X,
Pugin J,
and
Tobias PS.
Lipopolysaccharide (LPS)-binding protein and soluble CD14 function as accessory molecules for LPS-induced changes in endothelial barrier function, in vitro.
J Clin Invest
93:
692-702,
1994[ISI][Medline].
75.
Golenbock, DT,
Bach RR,
Lichenstein H,
Juan TS,
Tadavarthy A,
and
Moldow CF.
Soluble CD14 promotes LPS activation of CD14-deficient PNH monocytes and endothelial cells.
J Lab Clin Med
125:
662-671,
1995[ISI][Medline].
76.
Granville, DJ,
Carthy CM,
Hunt DW,
and
McManus BM.
Apoptosis: molecular aspects of cell death and disease.
Lab Invest
78:
893-913,
1998[ISI][Medline].
77.
Grau, GE,
Mili N,
Lou JN,
Morel DR,
Ricou B,
Lucas R,
and
Suter PM.
Phenotypic and functional analysis of pulmonary microvascular endothelial cells from patients with acute respiratory distress syndrome.
Lab Invest
74:
761-770,
1996[ISI][Medline].
78.
Gupta, K,
Kshirsagar S,
Li W,
Gui L,
Ramakrishnan S,
Gupta P,
Law PY,
and
Hebbel RP.
VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling.
Exp Cell Res
247:
495-504,
1999[ISI][Medline].
79.
Gyles, CL.
Escherichia coli cytotoxins and enterotoxins.
Can J Microbiol
38:
734-746,
1992[ISI][Medline].
80.
Hack, CE,
and
Zeerleder S.
The endothelium in sepsis: source of and a target for inflammation.
Crit Care Med
29:
S21-S27,
2001[ISI][Medline].
81.
Haendeler, J,
Zeiher AM,
and
Dimmeler S.
Vitamin C and E prevent lipopolysaccharide-induced apoptosis in human endothelial cells by modulation of Bcl-2 and Bax.
Eur J Pharmacol
317:
407-411,
1996[ISI][Medline].
82.
Haimovitz-Friedman, A,
Cordon-Cardo C,
Bayoumy S,
Garzotto M,
McLoughlin M,
Gallily R,
Edwards CK, III,
Schuchman EH,
Fuks Z,
and
Kolesnick R.
Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation.
J Exp Med
186:
1831-1841,
1997
83.
Hampton, MB,
and
Orrenius S.
Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis.
FEBS Lett
414:
552-556,
1997[ISI][Medline].
84.
Harlan, JM,
Harker LA,
Reidy MA,
Gajdusek CM,
Schwartz SM,
and
Striker GE.
Lipopolysaccharide-mediated bovine endothelial cell injury in vitro.
Lab Invest
48:
269-274,
1983[ISI][Medline].
85.
Hawker, FH.
How to feed patients with sepsis.
Curr Opin Crit Care
6:
247-252,
2000[Medline].
86.
Heimberg, H,
Heremans Y,
Jobin C,
Leemans R,
Cardozo AK,
Darville M,
and
Eizirik DL.
Inhibition of cytokine-induced NF-B activation by adenovirus-mediated expression of a NF-
B super-repressor prevents
-cell apoptosis.
Diabetes
50:
2219-2224,
2001
87.
Higaki, A,
Ninomiya H,
Saji M,
Maki H,
Koike T,
and
Ohno K.
Protective effect of neurotropin against lipopolysaccharide-induced hypotension and lethality linked to suppression of inducible nitric oxide synthase induction.
Jpn J Pharmacol
86:
329-335,
2001[ISI][Medline].
88.
Hinshaw, LB.
Sepsis/septic shock: participation of the microcirculation: an abbreviated review.
Crit Care Med
24:
1072-1078,
1996[ISI][Medline].
89.
Hirata, H,
Takahashi A,
Kobayashi S,
Yonehara S,
Sawai H,
Okazaki T,
Yamamoto K,
and
Sasada M.
Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis.
J Exp Med
187:
587-600,
1998
90.
Hirschfeld, M,
Ma Y,
Weis JH,
Vogel SN,
and
Weis JJ.
Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine Toll-like receptor 2.
J Immunol
165:
618-622,
2000
91.
Horng, T,
Barton GM,
and
Medzhitov R.
TIRAP: an adapter molecule in the Toll signaling pathway.
Nat Immun
2:
835-841,
2001[ISI].
92.
Horng, T,
and
Medzhitov R.
Drosophila MyD88 is an adapter in the Toll signaling pathway.
Proc Natl Acad Sci USA
98:
12654-12658,
2001
93.
Hotchkiss, RS,
Swanson PE,
Cobb JP,
Jacobson A,
Buchman TG,
and
Karl IE.
Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T- and B-cell-deficient mice.
Crit Care Med
25:
1298-1307,
1997[ISI][Medline].
94.
Hoyt, DG,
Mannix RJ,
Gerritsen ME,
Watkins SC,
Lazo JS,
and
Pitt BR.
Integrins inhibit LPS-induced DNA strand breakage in cultured lung endothelial cells.
Am J Physiol Lung Cell Mol Physiol
270:
L689-L694,
1996
95.
Hoyt, DG,
Mannix RJ,
Rusnak JM,
Pitt BR,
and
Lazo JS.
Collagen is a survival factor against LPS-induced apoptosis in cultured sheep pulmonary artery endothelial cells.
Am J Physiol Lung Cell Mol Physiol
269:
L171-L177,
1995
96.
Hsu, H,
Shu HB,
Pan MG,
and
Goeddel DV.
TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.
Cell
84:
299-308,
1996[ISI][Medline].
97.
Hu, S,
Vincenz C,
Ni J,
Gentz R,
and
Dixit VM.
I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1- and CD95-induced apoptosis.
J Biol Chem
272:
17255-17257,
1997
98.
Hu, WH,
Johnson H,
and
Shu HB.
Activation of NF-B by FADD, Casper, and caspase-8.
J Biol Chem
275:
10838-10844,
2000
99.
Hu, X,
Yee E,
Harlan JM,
Wong F,
and
Karsan A.
Lipopolysaccharide induces the antiapoptotic molecules, A1 and A20, in microvascular endothelial cells.
Blood
92:
2759-2765,
1998
100.
Hull, C,
McLean G,
Wong F,
Duriez PJ,
and
Karsan A.
Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase.
J Immunol
169:
2611-2618,
2002
101.
Iglewski, BH,
and
Kabat D.
NAD-dependent inhibition of protein synthesis by Pseudomonas aeruginosa toxin.
Proc Natl Acad Sci USA
72:
2284-2288,
1975[Abstract].
102.
Inohara, N,
Koseki T,
del Peso L,
Hu Y,
Yee C,
Chen S,
Carrio R,
Merino J,
Liu D,
Ni J,
and
Nunez G.
Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-B.
J Biol Chem
274:
14560-14567,
1999
103.
Inohara, N,
Koseki T,
Lin J,
del Peso L,
Lucas PC,
Chen FF,
Ogura Y,
and
Nunez G.
An induced proximity model for NF-B activation in the Nod1/RICK and RIP signaling pathways.
J Biol Chem
275:
27823-27831,
2000
104.
Inohara, N,
Ogura Y,
Chen FF,
Muto A,
and
Nunez G.
Human Nod1 confers responsiveness to bacterial lipopolysaccharides.
J Biol Chem
276:
2551-2554,
2001
105.
Irani, K.
Oxidant signaling in vascular cell growth, death, and survival: a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling.
Circ Res
87:
179-183,
2000
106.
Irmler, M,
Thome M,
Hahne M,
Schneider P,
Hofmann K,
Steiner V,
Bodmer JL,
Schroter M,
Burns K,
Mattmann C,
Rimoldi D,
French LE,
and
Tschopp J.
Inhibition of death receptor signals by cellular FLIP.
Nature
388:
190-195,
1997[ISI][Medline].
107.
Janicke, RU,
Sprengart ML,
Wati MR,
and
Porter AG.
Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis.
J Biol Chem
273:
9357-9360,
1998
108.
Jersmann, HP,
Hii CS,
Ferrante JV,
and
Ferrante A.
Bacterial lipopolysaccharide and tumor necrosis factor- synergistically increase expression of human endothelial adhesion molecules through activation of NF-
B and p38 mitogen-activated protein kinase signaling pathways.
Infect Immun
69:
1273-1279,
2001
109.
Jirik, FR,
Podor TJ,
Hirano T,
Kishimoto T,
Loskutoff DJ,
Carson DA,
and
Lotz M.
Bacterial lipopolysaccharide and inflammatory mediators augment IL-6 secretion by human endothelial cells.
J Immunol
142:
144-147,
1989
110.
Karahashi, H,
and
Amano F.
Lipopolysaccharide (LPS)-induced cell death of C3H mouse peritoneal macrophages in the presence of cycloheximide: different susceptibilities of C3H/HeN and C3H/HeJ mice macrophages.
J Endotoxin Res
6:
33-39,
2000[ISI][Medline].
111.
Karahashi, H,
and
Amano F.
Changes of caspase activities involved in apoptosis of a macrophage-like cell line J774.1/JA-4 treated with lipopolysaccharide (LPS) and cycloheximide.
Biol Pharm Bull
23:
140-144,
2000[ISI][Medline].
112.
Karsan, A,
Yee E,
and
Harlan JM.
Endothelial cell death induced by tumor necrosis factor- is inhibited by the Bcl-2 family member, A1.
J Biol Chem
271:
27201-27204,
1996
113.
Karsan, A,
Yee E,
Kaushansky K,
and
Harlan JM.
Cloning of human Bcl-2 homologue: inflammatory cytokines induce human A1 in cultured endothelial cells.
Blood
87:
3089-3096,
1996
114.
Kataoka, T,
Budd RC,
Holler N,
Thome M,
Martinon F,
Irmler M,
Burns K,
Hahne M,
Kennedy N,
Kovacsovics M,
and
Tschopp J.
The caspase-8 inhibitor FLIP promotes activation of NF-B and Erk signaling pathways.
Curr Biol
10:
640-648,
2000[ISI][Medline].
115.
Kawai, T,
Adachi O,
Ogawa T,
Takeda K,
and
Akira S.
Unresponsiveness of MyD88-deficient mice to endotoxin.
Immunity
11:
115-122,
1999[ISI][Medline].
116.
Kawasaki, M,
Kuwano K,
Hagimoto N,
Matsuba T,
Kunitake R,
Tanaka T,
Maeyama T,
and
Hara N.
Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor.
Am J Pathol
157:
597-603,
2000
117.
Kim, KY,
Kim BG,
Kim SO,
Yoo SE,
Kwak YG,
Chae SW,
and
Hong KW.
Prevention of lipopolysaccharide-induced apoptosis by (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine, a benzopyran analog, in endothelial cells.
J Pharmacol Exp Ther
300:
535-542,
2002
118.
Kim, KY,
Shin HK,
Choi JM,
and
Hong KW.
Inhibition of lipopolysaccharide-induced apoptosis by cilostazol in human umbilical vein endothelial cells.
J Pharmacol Exp Ther
300:
709-715,
2002
119.
Kim, YM,
Talanian RV,
and
Billiar TR.
Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms.
J Biol Chem
272:
31138-31148,
1997
120.
Kiningham, KK,
Oberley TD,
Lin S,
Mattingly CA,
and
St Clair DK.
Overexpression of manganese superoxide dismutase protects against mitochondrial-initiated poly(ADP-ribose) polymerase-mediated cell death.
FASEB J
13:
1601-1610,
1999
121.
Kirschning, CJ,
Wesche H,
Merrill Ayres T,
and
Rothe M.
Human Toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide.
J Exp Med
188:
2091-2097,
1998
122.
Koide, N,
Abe K,
Narita K,
Kato Y,
Sugiyama T,
Jiang GZ,
and
Yokochi T.
Apoptotic cell death of vascular endothelial cells and renal tubular cells in the generalized Shwartzman reaction.
FEMS Immunol Med Microbiol
16:
205-211,
1996[ISI][Medline].
123.
Kong, XJ,
and
Fanburg BL.
Regulation of Cu,Zn-superoxide dismutase in bovine pulmonary artery endothelial cells.
J Cell Physiol
153:
491-497,
1992[ISI][Medline].
124.
Koshi, R,
Mathan VI,
David S,
and
Mathan MM.
Enteric vascular endothelial response to bacterial endotoxin.
Int J Exp Pathol
74:
593-601,
1993[ISI][Medline].
125.
Kotamraju, S,
Chitambar CR,
Kalivendi SV,
Joseph J,
and
Kalyanaraman B.
Transferrin receptor-dependent iron uptake is responsible for doxorubicin-mediated apoptosis in endothelial cells: role of oxidant-induced iron signaling in apoptosis.
J Biol Chem
277:
17179-17187,
2002
126.
Kuang, AA,
Diehl GE,
Zhang J,
and
Winoto A.
FADD is required for DR4- and DR5-mediated apoptosis: lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts.
J Biol Chem
275:
25065-25068,
2000
127.
Kux, M,
Coalson JJ,
Massion WH,
and
Guenter CA.
Pulmonary effects of E. coli endotoxin: role of leukocytes and platelets.
Ann Surg
175:
26-34,
1972[ISI][Medline].
128.
LaCasse, EC,
Baird S,
Korneluk RG,
and
MacKenzie AE.
The inhibitors of apoptosis (IAPs) and their emerging role in cancer.
Oncogene
17:
3247-3259,
1998[ISI][Medline].
129.
Lang, CH,
Frost RA,
Nairn AC,
MacLean DA,
and
Vary TC.
TNF- impairs heart and skeletal muscle protein synthesis by altering translation initiation.
Am J Physiol Endocrinol Metab
282:
E336-E347,
2002
130.
Laskin, DL,
Heck DE,
Gardner CR,
Feder LS,
and
Laskin JD.
Distinct patterns of nitric oxide production in hepatic macrophages and endothelial cells following acute exposure of rats to endotoxin.
J Leukoc Biol
56:
751-758,
1994[Abstract].
131.
Lee, YJ,
and
Shacter E.
Hydrogen peroxide inhibits activation, not activity, of cellular caspase-3 in vivo.
Free Radic Biol Med
29:
684-692,
2000[ISI][Medline].
132.
Lehr, HA,
Bittinger F,
and
Kirkpatrick CJ.
Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy?
J Pathol
190:
373-386,
2000[ISI][Medline].
133.
Levi, M,
ten Cate H,
van der Poll T,
and
van Deventer SJ.
Pathogenesis of disseminated intravascular coagulation in sepsis.
JAMA
270:
975-979,
1993[Abstract].
134.
Li, AE,
Ito H,
Rovira II,
Kim KS,
Takeda K,
Yu ZY,
Ferrans VJ,
and
Finkel T.
A role for reactive oxygen species in endothelial cell anoikis.
Circ Res
85:
304-310,
1999
135.
Li, D,
Yang B,
and
Mehta JL.
Ox-LDL induces apoptosis in human coronary artery endothelial cells: role of PKC, PTK, bcl-2, and Fas.
Am J Physiol Heart Circ Physiol
275:
H568-H576,
1998
136.
Li, J,
Billiar TR,
Talanian RV,
and
Kim YM.
Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation.
Biochem Biophys Res Commun
240:
419-424,
1997[ISI][Medline].
137.
Li, L,
Cousart S,
Hu J,
and
McCall CE.
Characterization of interleukin-1 receptor-associated kinase in normal and endotoxin-tolerant cells.
J Biol Chem
275:
23340-23345,
2000
138.
Libby, P,
Ordovas JM,
Auger KR,
Robbins AH,
Birinyi LK,
and
Dinarello CA.
Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells.
Am J Pathol
124:
179-185,
1986[Abstract].
139.
Lien, E,
Means TK,
Heine H,
Yoshimura A,
Kusumoto S,
Fukase K,
Fenton MJ,
Oikawa M,
Qureshi N,
Monks B,
Finberg RW,
Ingalls RR,
and
Golenbock DT.
Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide.
J Clin Invest
105:
497-504,
2000
140.
Lopez-Farre, A,
Rodriguez-Feo JA,
Sanchez de Miguel L,
Rico L,
and
Casado S.
Role of nitric oxide in the control of apoptosis in the microvasculature.
Int J Biochem Cell Biol
30:
1095-1106,
1998[ISI][Medline].
141.
Louise, CB,
and
Obrig TG.
Shiga toxin-associated hemolytic uremic syndrome: combined cytotoxic effects of shiga toxin and lipopolysaccharide (endotoxin) on human vascular endothelial cells in vitro.
Infect Immun
60:
1536-1543,
1992[Abstract].
142.
Macnaughton, PD,
and
Evans TW.
Management of adult respiratory distress syndrome.
Lancet
339:
469-472,
1992[ISI][Medline].
143.
Maeda, K,
Abello PA,
Abraham MR,
Wetzel RC,
Robotham JL,
and
Buchman TG.
Endotoxin induces organ-specific endothelial cell injury.
Shock
3:
46-50,
1995[ISI][Medline].
144.
Martin, MA,
and
Silverman HJ.
Gram-negative sepsis and the adult respiratory distress syndrome.
Clin Infect Dis
14:
1213-1228,
1992[ISI][Medline].
145.
McCuskey, RS,
Urbaschek R,
and
Urbaschek B.
The microcirculation during endotoxemia.
Cardiovasc Res
32:
752-763,
1996[ISI][Medline].
146.
Medzhitov, R,
Preston-Hurlburt P,
Kopp E,
Stadlen A,
Chen C,
Ghosh S,
and
Janeway CA, Jr.
MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways.
Mol Cell
2:
253-258,
1998[ISI][Medline].
147.
Messmer, UK,
Briner VA,
and
Pfeilschifter J.
Tumor necrosis factor- and lipopolysaccharide induce apoptotic cell death in bovine glomerular endothelial cells.
Kidney Int
55:
2322-2337,
1999[ISI][Medline].
148.
Meyrick, B.
Pathology of the adult respiratory distress syndrome.
Crit Care Clin
2:
405-428,
1986[Medline].
149.
Meyrick, BO.
Endotoxin-mediated pulmonary endothelial cell injury.
Fed Proc
45:
19-24,
1986[ISI][Medline].
150.
Mitchell, J,
Jiang H,
Berry L,
and
Meyrick B.
Effect of antioxidants on lipopolysaccharide-stimulated induction of mangano superoxide dismutase mRNA in bovine pulmonary artery endothelial cells.
J Cell Physiol
169:
333-340,
1996[ISI][Medline].
151.
Morita-Fujimura, Y,
Fujimura M,
Yoshimoto T,
and
Chan PH.
Superoxide during reperfusion contributes to caspase-8 expression and apoptosis after transient focal stroke.
Stroke
32:
2356-2361,
2001
152.
Munshi, N,
Fernandis AZ,
Cherla RP,
Park IW,
and
Ganju RK.
Lipopolysaccharide-induced apoptosis of endothelial cells and its inhibition by vascular endothelial growth factor.
J Immunol
168:
5860-5866,
2002
153.
Mutunga, M,
Fulton B,
Bullock R,
Batchelor A,
Gascoigne A,
Gillespie JI,
and
Baudouin SV.
Circulating endothelial cells in patients with septic shock.
Am J Respir Crit Care Med
163:
195-200,
2001
154.
Muzio, M,
Natoli G,
Saccani S,
Levrero M,
and
Mantovani A.
The human Toll signaling pathway: divergence of nuclear factor-B and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6).
J Exp Med
187:
2097-2101,
1998
155.
Muzio, M,
Stockwell BR,
Stennicke HR,
Salvesen GS,
and
Dixit VM.
An induced proximity model for caspase-8 activation.
J Biol Chem
273:
2926-2930,
1998
156.
Naassila, M,
Roux F,
Beauge F,
and
Daoust M.
Ethanol potentiates lipopolysaccharide- or interleukin-1-induced nitric oxide generation in RBE4 cells.
Eur J Pharmacol
313:
273-277,
1996[ISI][Medline].
157.
Neuzil, J,
Schroder A,
von Hundelshausen P,
Zernecke A,
Weber T,
Gellert N,
and
Weber C.
Inhibition of inflammatory endothelial responses by a pathway involving caspase activation and p65 cleavage.
Biochemistry
40:
4686-4692,
2001[ISI][Medline].
158.
O'Loughlin, EV,
and
Robins-Browne RM.
Effect of Shiga toxin and Shiga-like toxins on eukaryotic cells.
Microbes Infect
3:
493-507,
2001[ISI][Medline].
159.
Olson, NC,
Hellyer PW,
and
Dodam JR.
Mediators and vascular effects in response to endotoxin.
Br Vet J
151:
489-522,
1995[ISI][Medline].
160.
Palmer, RM,
Bridge L,
Foxwell NA,
and
Moncada S.
The role of nitric oxide in endothelial cell damage and its inhibition by glucocorticoids.
Br J Pharmacol
105:
11-12,
1992[Abstract].
161.
Parsons, PE,
Worthen GS,
Moore EE,
Tate RM,
and
Henson PM.
The association of circulating endotoxin with the development of the adult respiratory distress syndrome.
Am Rev Respir Dis
140:
294-301,
1989[ISI][Medline].
162.
Pijpers, AH,
van Setten PA,
van den Heuvel LP,
Assmann KJ,
Dijkman HB,
Pennings AH,
Monnens LA,
and
van Hinsbergh VW.
Verocytotoxin-induced apoptosis of human microvascular endothelial cells.
J Am Soc Nephrol
12:
767-778,
2001
163.
Pinner, RW,
Teutsch SM,
Simonsen L,
Klug LA,
Graber JM,
Clarke MJ,
and
Berkelman RL.
Trends in infectious diseases mortality in the United States.
JAMA
275:
189-193,
1996[Abstract].
164.
Pohlman, TH,
and
Harlan JM.
Human endothelial cell response to lipopolysaccharide, interleukin-1, and tumor necrosis factor is regulated by protein synthesis.
Cell Immunol
119:
41-52,
1989[ISI][Medline].
165.
Pohlman, TH,
and
Harlan JM.
Adaptive responses of the endothelium to stress.
J Surg Res
89:
85-119,
2000[ISI][Medline].
166.
Poltorak, A,
He X,
Smirnova I,
Liu MY,
Huffel CV,
Du X,
Birdwell D,
Alejos E,
Silva M,
Galanos C,
Freudenberg M,
Ricciardi-Castagnoli P,
Layton B,
and
Beutler B.
Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
Science
282:
2085-2088,
1998
167.
Proulx, F,
Seidman EG,
and
Karpman D.
Pathogenesis of Shiga toxin-associated hemolytic uremic syndrome.
Pediatr Res
50:
163-171,
2001
168.
Radomski, MW,
Palmer RM,
and
Moncada S.
Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells.
Proc Natl Acad Sci USA
87:
10043-10047,
1990[Abstract].
169.
Ravagnan, L,
Roumier T,
and
Kroemer G.
Mitochondria, the killer organelles and their weapons.
J Cell Physiol
192:
131-137,
2002[ISI][Medline].
170.
Ray, PE,
and
Liu XH.
Pathogenesis of Shiga toxin-induced hemolytic uremic syndrome.
Pediatr Nephrol
16:
823-839,
2001[ISI][Medline].
171.
Reed, JC.
Mechanisms of apoptosis.
Am J Pathol
157:
1415-1430,
2000
172.
Reidy, MA,
and
Schwartz SM.
Endothelial injury and regeneration. IV. Endotoxin: a nondenuding injury to aortic endothelium.
Lab Invest
48:
25-34,
1983[ISI][Medline].
173.
Rietschel, ET,
Brade H,
Holst O,
Brade L,
Muller-Loennies S,
Mamat U,
Zahringer U,
Beckmann F,
Seydel U,
Brandenburg K,
Ulmer AJ,
Mattern T,
Heine H,
Schletter J,
Loppnow H,
Schonbeck U,
Flad HD,
Hauschildt S,
Schade UF,
Di Padova F,
Kusumoto S,
and
Schumann RR.
Bacterial endotoxin: chemical constitution, biological recognition, host response, and immunological detoxification.
Curr Top Microbiol Immunol
216:
39-81,
1996[ISI][Medline].
174.
Rietschel, ET,
Kirikae T,
Schade FU,
Mamat U,
Schmidt G,
Loppnow H,
Ulmer AJ,
Zahringer U,
Seydel U,
Di Padova F,
Schreier M,
and
Brade H.
Bacterial endotoxin: molecular relationships of structure to activity and function.
FASEB J
8:
217-225,
1994
175.
Rockey, DC,
and
Chung JJ.
Regulation of inducible nitric oxide synthase in hepatic sinusoidal endothelial cells.
Am J Physiol Gastrointest Liver Physiol
271:
G260-G267,
1996
176.
Rubenstein, HS,
Fine J,
and
Coons AH.
Localization of endotoxin in the walls of the peripheral vascular system during lethal endotoxemia.
Proc Soc Exp Biol Med
111:
458-467,
1962.
177.
Rubin, DB,
Reznik G,
Weiss EA,
and
Young PR.
Non-protein thiols flux to S-nitrosothiols in endothelial cells: an LPS redox signal.
Shock
14:
200-207,
2000[ISI][Medline].
178.
Ryan, KM,
Ernst MK,
Rice NR,
and
Vousden KH.
Role of NF-B in p53-mediated programmed cell death.
Nature
404:
892-897,
2000[ISI][Medline].
179.
Salvemini, D,
Korbut R,
Anggard E,
and
Vane J.
Immediate release of a nitric oxide-like factor from bovine aortic endothelial cells by Escherichia coli lipopolysaccharide.
Proc Natl Acad Sci USA
87:
2593-2597,
1990[Abstract].
180.
Sato, I,
Kaji K,
and
Murota S.
Age-related decline in cytokine-induced nitric oxide synthase activation and apoptosis in cultured endothelial cells: minimal involvement of nitric oxide in the apoptosis.
Mech Ageing Dev
81:
27-36,
1995[ISI][Medline].
181.
Savill, JS,
Wyllie AH,
Henson JE,
Walport MJ,
Henson PM,
and
Haslett C.
Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.
J Clin Invest
83:
865-875,
1989[ISI][Medline].
182.
Scaffidi, C,
Schmitz I,
Krammer PH,
and
Peter ME.
The role of c-FLIP in modulation of CD95-induced apoptosis.
J Biol Chem
274:
1541-1548,
1999
183.
Scatena, M,
Almeida M,
Chaisson ML,
Fausto N,
Nicosia RF,
and
Giachelli CM.
NF-B mediates alphavbeta3 integrin-induced endothelial cell survival.
J Cell Biol
141:
1083-1093,
1998
184.
Schaub, FJ,
Han DK,
Liles WC,
Adams LD,
Coats SA,
Ramachandran RK,
Seifert RA,
Schwartz SM,
and
Bowen-Pope DF.
Fas/FADD-mediated activation of a specific program of inflammatory gene expression in vascular smooth muscle cells.
Nat Med
6:
790-796,
2000[ISI][Medline].
185.
Schumann, RR,
Belka C,
Reuter D,
Lamping N,
Kirschning CJ,
Weber JR,
and
Pfeil D.
Lipopolysaccharide activates caspase-1 (interleukin-1-converting enzyme) in cultured monocytic and endothelial cells.
Blood
91:
577-584,
1998
186.
Schwandner, R,
Dziarski R,
Wesche H,
Rothe M,
and
Kirschning CJ.
Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2.
J Biol Chem
274:
17406-17409,
1999
187.
Sladek, Z,
and
Rysanek D.
Apoptosis of polymorphonuclear leukocytes of the juvenile bovine mammary gland during induced influx.
Vet Res
31:
553-563,
2000[ISI][Medline].
188.
Srinivasula, SM,
Ahmad M,
Ottilie S,
Bullrich F,
Banks S,
Wang Y,
Fernandes-Alnemri T,
Croce CM,
Litwack G,
Tomaselli KJ,
Armstrong RC,
and
Alnemri ES.
FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis.
J Biol Chem
272:
18542-18545,
1997
189.
Stefanec, T.
Endothelial apoptosis: could it have a role in the pathogenesis and treatment of disease?
Chest
117:
841-854,
2000
190.
Stehlik, C,
de Martin R,
Kumabashiri I,
Schmid JA,
Binder BR,
and
Lipp J.
Nuclear factor (NF)-B-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor-
-induced apoptosis.
J Exp Med
188:
211-216,
1998
191.
Sugawara, T,
Noshita N,
Lewen A,
Gasche Y,
Ferrand-Drake M,
Fujimura M,
Morita-Fujimura Y,
and
Chan PH.
Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation.
J Neurosci
22:
209-217,
2002
192.
Sutton, ET,
Zhou Z,
Baker CH,
Price JM,
and
Chen Y.
Differences in arterial and arteriolar endothelial structure during endotoxin shock.
Circ Shock
41:
71-76,
1993[ISI][Medline].
193.
Suttorp, N,
Galanos C,
and
Neuhof H.
Endotoxin alters arachidonate metabolism in pulmonary endothelial cells.
Am J Physiol Cell Physiol
253:
C384-C390,
1987
194.
Swantek, JL,
Tsen MF,
Cobb MH,
and
Thomas JA.
IL-1 receptor-associated kinase modulates host responsiveness to endotoxin.
J Immunol
164:
4301-4306,
2000
195.
Takeyama, N,
Miki S,
Hirakawa A,
and
Tanaka T.
Role of the mitochondrial permeability transition and cytochrome c release in hydrogen peroxide-induced apoptosis.
Exp Cell Res
274:
16-24,
2002[ISI][Medline].
196.
Tang, ZL,
Wasserloos KJ,
Liu X,
Stitt MS,
Reynolds IJ,
Pitt BR,
and
St. Croix CM.
Nitric oxide decreases the sensitivity of pulmonary endothelial cells to LPS-induced apoptosis in a zinc-dependent fashion.
Mol Cell Biochem
234-235:
211-217,
2002[ISI].
197.
Thijs, LG,
de Boer JP,
de Groot MC,
and
Hack CE.
Coagulation disorders in septic shock.
Intensive Care Med
19:
S8-S15,
1993[Medline].
198.
Thornberry, NA,
and
Lazebnik Y.
Caspases: enemies within.
Science
281:
1312-1316,
1998
199.
Tschopp, J,
Irmler M,
and
Thome M.
Inhibition of fas death signals by FLIPs.
Curr Opin Immunol
10:
552-558,
1998[ISI][Medline].
200.
Tzeng, E,
Kim YM,
Pitt BR,
Lizonova A,
Kovesdi I,
and
Billiar TR.
Adenoviral transfer of the inducible nitric oxide synthase gene blocks endothelial cell apoptosis.
Surgery
122:
255-263,
1997[ISI][Medline].
201.
Ulevitch, RJ,
Cochrane CG,
Henson PM,
Morrison DC,
and
Doe WF.
Mediation systems in bacterial lipopolysaccharide-induced hypotension and disseminated intravascular coagulation. I. The role of complement.
J Exp Med
142:
1570-1590,
1975[Abstract].
202.
Ulevitch, RJ,
and
Tobias PS.
Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin.
Annu Rev Immunol
13:
437-457,
1995[ISI][Medline].
203.
Van Antwerp, DJ,
Martin SJ,
Kafri T,
Green DR,
and
Verma IM.
Suppression of TNF--induced apoptosis by NF-
B.
Science
274:
787-789,
1996
204.
Vescovo, G,
Zennaro R,
Sandri M,
Carraro U,
Leprotti C,
Ceconi C,
Ambrosio GB,
and
Dalla Libera L.
Apoptosis of skeletal muscle myofibers and interstitial cells in experimental heart failure.
J Mol Cell Cardiol
30:
2449-2459,
1998[ISI][Medline].
205.
Viriyakosol, S,
and
Kirkland T.
Knowledge of cellular receptors for bacterial endotoxin.
Clin Infect Dis
21 Suppl 2:
S190-S195,
1995[ISI][Medline].
206.
Visner, GA,
Block ER,
Burr IM,
and
Nick HS.
Regulation of manganese superoxide dismutase in porcine pulmonary artery endothelial cells.
Am J Physiol Lung Cell Mol Physiol
260:
L444-L449,
1991
207.
Wajant, H,
Haas E,
Schwenzer R,
Muhlenbeck F,
Kreuz S,
Schubert G,
Grell M,
Smith C,
and
Scheurich P.
Inhibition of death receptor-mediated gene induction by a cycloheximide-sensitive factor occurs at the level of or upstream of Fas-associated death domain protein (FADD).
J Biol Chem
275:
24357-24366,
2000
208.
Walter, R,
Schaffner A,
and
Schoedon G.
Differential regulation of constitutive and inducible nitric oxide production by inflammatory stimuli in murine endothelial cells.
Biochem Biophys Res Commun
202:
450-455,
1994[ISI][Medline].
209.
Wang, CY,
Mayo MW,
Korneluk RG,
Goeddel DV,
and
Baldwin AS, Jr.
NF-B antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.
Science
281:
1680-1683,
1998
210.
Warren, HS,
Glennon ML,
Wainwright N,
Amato SF,
Black KM,
Kirsch SJ,
Riveau GR,
Whyte RI,
Zapol WM,
and
Novitsky TJ.
Binding and neutralization of endotoxin by Limulus antilipopolysaccharide factor.
Infect Immun
60:
2506-2513,
1992[Abstract].
211.
Warren, HS,
Novitsky TJ,
Bucklin A,
Kania SA,
and
Siber GR.
Endotoxin neutralization with rabbit antisera to Escherichia coli J5 and other gram-negative bacteria.
Infect Immun
55:
1668-1673,
1987[ISI][Medline].
212.
Wesche, H,
Henzel WJ,
Shillinglaw W,
Li S,
and
Cao Z.
MyD88: an adapter that recruits IRAK to the IL-1 receptor complex.
Immunity
7:
837-847,
1997[ISI][Medline].
213.
Williams, JM,
Boyd B,
Nutikka A,
Lingwood CA,
Barnett Foster DE,
Milford DV,
and
Taylor CM.
A comparison of the effects of verocytotoxin-1 on primary human renal cell cultures.
Toxicol Lett
105:
47-57,
1999[ISI][Medline].
214.
Wolkow, PP.
Involvement and dual effects of nitric oxide in septic shock.
Inflamm Res
47:
152-166,
1998[ISI][Medline].
215.
Wong, GH.
Protective roles of cytokines against radiation: induction of mitochondrial MnSOD.
Biochim Biophys Acta
1271:
205-209,
1995[ISI][Medline].
216.
Wong, HR,
Mannix RJ,
Rusnak JM,
Boota A,
Zar H,
Watkins SC,
Lazo JS,
and
Pitt BR.
The heat-shock response attenuates lipopolysaccharide-mediated apoptosis in cultured sheep pulmonary artery endothelial cells.
Am J Respir Cell Mol Biol
15:
745-751,
1996[Abstract].
217.
Wu, R,
Song X,
Xu Y,
and
Meng X.
Apoptosis of endothelial cells in alteration of microvascular permeability in lung during sepsis.
Zhonghua Wai Ke Za Zhi
38:
385-387,
2000[Medline].
218.
Yang, RB,
Mark MR,
Gray A,
Huang A,
Xie MH,
Zhang M,
Goddard A,
Wood WI,
Gurney AL,
and
Godowski PJ.
Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling.
Nature
395:
284-288,
1998[ISI][Medline].
219.
Yang, Z,
Breider MA,
Carroll RC,
Miller MS,
and
Bochsler PN.
Soluble CD14 and lipopolysaccharide-binding protein from bovine serum enable bacterial lipopolysaccharide-mediated cytotoxicity and activation of bovine vascular endothelial cells in vitro.
J Leukoc Biol
59:
241-247,
1996[Abstract].
220.
Zen, K,
Karsan A,
Eunson T,
Yee E,
and
Harlan JM.
Lipopolysaccharide-induced NF-B activation in human endothelial cells involves degradation of I
B
but not I
B
.
Exp Cell Res
243:
425-433,
1998[ISI][Medline].
221.
Zen, K,
Karsan A,
Stempien-Otero A,
Yee E,
Tupper J,
Li X,
Eunson T,
Kay MA,
Wilson CB,
Winn RK,
and
Harlan JM.
NF-B activation is required for human endothelial survival during exposure to tumor necrosis factor-
but not to interleukin-1
or lipopolysaccharide.
J Biol Chem
274:
28808-28815,
1999
222.
Zhang, FX,
Kirschning CJ,
Mancinelli R,
Xu XP,
Jin Y,
Faure E,
Mantovani A,
Rothe M,
Muzio M,
and
Arditi M.
Bacterial lipopolysaccharide activates nuclear factor-B through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes.
J Biol Chem
274:
7611-7614,
1999
223.
Zhao, B,
Bowden RA,
Stavchansky SA,
and
Bowman PD.
Human endothelial cell response to gram-negative lipopolysaccharide assessed with cDNA microarrays.
Am J Physiol Cell Physiol
281:
C1587-C1595,
2001
224.
Zhuang, S,
Lynch MC,
and
Kochevar IE.
Caspase-8 mediates caspase-3 activation and cytochrome c release during singlet oxygen-induced apoptosis of HL-60 cells.
Exp Cell Res
250:
203-212,
1999[ISI][Medline].
225.
Ziegler, EJ,
McCutchan JA,
Fierer J,
Glauser MP,
Sadoff JC,
Douglas H,
and
Braude AI.
Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli.
N Engl J Med
307:
1225-1230,
1982[Abstract].