ORIGINAL ARTICLE
The Effect of Lornoxicam on TLR2 and TLR4 Messenger RNA
Expression and Tumor Necrosis Factor-α, Interleukin-6,
and Interleukin-8 Secretion in Patients With Systemic
Complications of Acute Pancreatitis
Victor Aleksandrovitch Gorsky, MD, PhD,* Mikhail Adnreevitch Agapov, MD, PhD,*
Marina Victorovna Khoreva, MD, PhD,† and Igor Valentinovitch Leonenko, MD, PhD‡
Objectives: To assess the effects of the cyclooxygenase-1/cyclooxygenase-2
inhibitor lornoxicam on systemic complications in patients with acute pan-
creatitis, Toll-like receptor (TLR)2 and TLR4 messenger RNA expression,
and cytokine secretion (IL-6, IL-8, tumor necrosis factor-α).
Methods: Adult patients with acute pancreatitis were randomized to
standard therapy or standard therapy plus lornoxicam. Standard therapy in-
cluded analgesics, spasmolytics, octreotide, pantoprazole, and intravenous fluids.
The TLR2 and TLR4 expression levels and TLR2- and TLR4-mediated cytokine
production in peripheral blood mononuclear cells were assessed in patients
with severe complications and in healthy volunteers (n = 15).
Results: A total of 334 patients received standard therapy (n = 246) or
standard therapy plus lornoxicam (n = 88), 172 (51.5%) of whom devel-
oped systemic complications. Occurrence of complications was higher
with standard therapy compared with lornoxicam (57.3% versus 35.2%;
P = 0.00034), as was mortality (19.1% versus 6.8%; P = 0.006). The
TLR2 and TLR4 expression and TLR2 and TLR4-mediated cytokine pro-
duction were significantly higher in patients with systemic complications
of acute pancreatitis compared with healthy volunteers. Relative TLR2 ex-
pression and cytokine production were significantly reduced in patients re-
ceiving lornoxicam versus standard therapy.
Conclusions: The use of lornoxicam at the onset of acute pancreatitis
decreased TLR2 and TLR4 expression and the production of proinflam-
matory cytokines, thereby reducing the risk of systemic complications
and mortality.
Key Words: acute pancreatitis, lornoxicam, COX inhibition, toll-like
receptors, proinflammatory cytokines
(Pancreas 2015;44: 824–830)
T oll-like receptors (TLRs) are a family of pattern recognition
receptors of innate immunity that play a key role in the recog-
nition of pathogen-associated molecular structures by the immune
system. Several studies have shown that TLRs can also be acti-
vated by endogenous ligands, with the production of proinflam-
matory cytokines triggering aseptic inflammation in response to
trauma, ischemia, and massive tissue damage, even in the absence
of pathogen-triggered infection.1–4 Such ligands are known as
From the *Division of Experimental and Clinical Surgery, Department of Med-
icine and Biology, †Division of Immunology, and ‡Division of General Pathol-
ogy, Department of Medicine and Biology, N.I. Pirogov Russian National
Research Medical University, Moscow, Russia.
Received for publication March 7, 2014; accepted December 29, 2014.
Reprints: Mikhail Adnreevitch Agapov, MD, PhD, Division of Experimental
and Clinical Surgery, Department of Medicine and Biology, N.I. Pirogov
Russian National Research Medical University, Moscow, Russia
(e‐mail: getinfo911@mail.ru).
This study was supported by the Division of Experimental and Clinical Surgery,
Department of Medicine and Biology, N.I. Pirogov Russian National
Research Medical University.
The authors declare no conflict of interest.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
824 www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
“danger signals” or damage-associated molecular patterns
(DAMP) and include heat-shock proteins (eg, HSP60, HSP70), fi-
bronectin, hyaluronic acid, and many others. These substances are
released as a result of cell necrosis, massive tissue destruction, and
the breakdown of extracellular matrix molecules.5,6 In physiolog-
ical concentrations, endogenous ligands facilitate the process of
tissue regeneration and healing, whereas their excessive release
may be associated with tissue damage.
Immune system disorders, both acquired and inborn, play an
important role in the pathogenesis of acute pancreatitis. Proin-
flammatory cytokines, such as tumor necrosis factor (TNF)-α,
interleukin (IL)-1, IL-6, IL-8, and cyclooxygenase (COX), are
involved in the inflammatory response seen in acute pancreatitis.7–10
The TLRs also appear to have a role in the inflammatory cascade in
acute pancreatitis. Endogenous ligands, such as heparan sulfate or
pancreatic elastase released during cell destruction, have been shown
to activate TLRs, facilitate formation of NLRP3 inflammasome, and
induce the release of inflammatory cytokines in a murine model of
acute pancreatitis.11 It is also known that the majority of endogenous
ligands interact with TLR2 and TLR4 receptors12 and that pancreatic
expression of TLR4 messenger RNA (mRNA) is increased during
the early stages of acute pancreatitis.13
In experimental models of acute pancreatitis, TLR4 knock-
out animals have less profound damage to the pancreas and the
kidneys.14,15 Lipopolysaccharide and bacteria in the serum or
the pancreas were not detected in these models, suggesting that
DAMPs are endogenous TLR4 ligands. The TLR4 is expressed
by epithelial cells of pancreatic ducts, endothelial cells, and tissue
macrophages but is absent on the surface of acinar cells.16 Thus,
the expression and activation of TLRs, associated with the synthe-
sis of inflammatory cytokines, is viewed as one of the main factors
in aseptic inflammation that can progress to systemic inflamma-
tory response syndrome (SIRS).
Increased understanding of the pathogenesis of acute pancre-
atitis has resulted in the development of new strategies for thera-
peutic intervention. In experimental models, inhibition of high-
mobility group protein B1 through the use of anti–high-mobility
group protein B1 neutralizing antibodies decreased damage to the
pancreas and kidneys.17 Similarly, the use of TLR7 and TLR9 an-
tagonists reduced pancreatic acinar cell necrosis and lung dam-
age,18 whereas the use of chloroquine decreased the severity of
pancreatic damage and mortality by inhibiting the endosomal oxi-
dation necessary for activation of some TLRs.19,20
In this prospective, randomized study, we assessed the effects
of the COX-1/COX-2 inhibitor lornoxicam on the occurrence
of systemic complications in patients with acute pancreatitis.
We also analyzed the influence of lornoxicam on the expression
of TLR2 and TLR4 mRNA in peripheral blood mononuclear
cells (PBMCs) and cytokine secretion (IL-6, IL-8, TNF-α) from
PBMCs in patients with complications.
Pancreas • Volume 44, Number 5, July 2015
Pancreas • Volume 44, Number 5, July 2015
MATERIALS AND METHODS
Adult patients (aged 18–60 years) with acute pancreatitis
(computed tomography severity index [Balthazar score] ≥2 and
Ranson score ≥2) were enrolled if time from onset of disease to
hospitalization was less than 48 hours. Patients with expected mor-
tality within 24 hours or with decompensated liver cirrhosis and
portal hypertension, cardiac failure (New York Heart Association
stage III-IV), bronchial asthma, chronic viral hepatitis, autoimmune
disease, tuberculosis infection, human immunodeficiency virus
infection, or who were pregnant were excluded. Patients were ran-
domized to receive either standard conservative therapy (n = 246)
or standard therapy plus lornoxicam (n = 88). Standard therapy in-
cluded analgesics, spasmolytics, suppression of exocrine func-
tion of the pancreas by octreotide 100 to 300 μg 3 times daily,
proton pump inhibition with pantoprazole 40 mg intravenous
(IV) twice daily (consistent with the Russian recommendations
for prevention of acute gastric lesions) and IV fluids. Nonsteroidal
anti-inflammatory drugs (other than lornoxicam in the lornoxicam
group) were not administered to any patient. Lornoxicam was ad-
ministered as an IV infusion for 5 days starting on the day of admis-
sion with daily doses of 32 mg (days 1 and 2), 24 mg (day 3), and
16 mg (days 4 and 5), given as twice daily divided doses. All patients
received both enteral (balanced enteral formulas via nasogastric
tube) and parenteral nutrition from the day of admission. All patients
provided informed consent for participation in this trial.
The anti-inflammatory effects of therapy with and without
lornoxicam were assessed by the occurrence of systemic compli-
cations of severe acute pancreatitis and mortality related to these
complications. The effects of lornoxicam were also compared by
analyzing TLR2 and TLR4 mRNA expression levels in PBMCs,
and TLR2- and TLR4-mediated cytokine (TNF-α IL-6 and
IL-8) production by PBMCs in patients with acute pancreatitis
as well as in a control group of 15 healthy volunteers.
Blood from patients was taken on admission day 1 (before
initiation of treatment), day 3, day 7, and day 12. The PBMCs
were extracted by gradient centrifugation using Ficoll media and
were incubated at a concentration of 10  6/mL for 24 hours in
RPMI-1640 media containing antibiotic (100 μg/mL), glutamine,
and 5% fetal bovine serum.
The RNA from PBMCs was extracted using commercial kits
(RNeasy Plus Mini Kit, Qiagen, Hilden, Germany). Equal amounts
of RNA from patients with acute pancreatitis, and healthy donors
TABLE 1. Systemic Complications in Patients With Acute Pancreatitis
Type of Complication Standard Therapy (n = 246)
Pancreatogenic shock 30 (12.2%)
Acute cardiovascular insufficiency 49 (19.9%)
Acute renal failure 99 (40.2%)
Altered mental status due to intoxication 42 (17.1%)
Gastrointestinal dysfunction 116 (47.2%)
Acute respiratory failure 28 (11.4%)
Acute liver failure* 61 (24.8%)
Overall 141 (57.3%)
Mortality 47 (19.1%)
Data in bold face are statistically significant values, P < 0.05.
*Based on corresponding clinical and laboratory criteria: thrombocytopenia (by complete blood count); prothrombin time and INR; elevated AST, ALT,
and ALP; elevated serum bilirubin; elevated serum ammonia (arterial > venous); low blood glucose; elevated serum lactate; hypoxemia; elevated serum cre-
atinine; low serum phosphate.
INR indicates international normalized ratio; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Lornoxicam in Acute Pancreatitis
were analyzed. Reverse transcription polymerase chain reaction
was performed using the high-capacity RNA-to-cDNA Master Mix
kit (Applied Biosystems/Life Technologies, Moscow, Russia). Gene
expression assays used in real-time quantitative polymerase chain
reaction were Hs01014511_m1 (TLR2) and Hs00152939_m1
(TLR4), with β-actin human ACTB endogenous control (FAM/
MGB Probe) (all Applied Biosystems/Life Technologies). The re-
action mixture contained 12.5 μL of Taqman Gene Expression
Master Mix, 1.25 μL of assay mix (primers) and 2.5 μL of cDNA
in a total volume of 25 μL. The Applied Biosystems 7500 device
was used for analysis. Data were analyzed by the ΔΔСt method.
The first step was normalization to the endogenous control
(ΔCt = Ct [target, TLR] − Ct [endogenous control]), and the
second step was normalization to the calibrator (ΔΔCt = ΔCt
(sample) − ΔCt [calibrator]). The β-actin was used as endoge-
nous control, whereas cDNA from healthy donors was used as
the calibrator. Expression of TLR mRNA in PBMCs of patients
with acute pancreatitis was measured in relative units, or relative
quantity in comparison with the healthy volunteer control group,
calculated as relative quantity = 2-ΔΔCt.
Cytokine production was induced using the TLR2 ligand
peptidoglycan from S. aureus at a concentration of 2.5 μg/mL
and the TLR4 ligand lipopolysaccharide from E. coli 0127: B8
(both Sigma-Aldrich, Moscow, Russia) at a concentration of
0.1 μg/mL. The PBMC supernatants were collected and stored
at −70 °C, and the concentration of cytokines (TNF-α, IL-6 and
IL-8) were determined by enzyme-linked immunosorbent assay
using commercial kits (eBioscience Inc., San Diego, CA).
Statistical analysis of the study results was performed using
nonparametric tests with the help of the StatSoft Statistica 6.0 ap-
plication. Quantitative variables were compared between groups
using the Mann-Whitney U test and Wilcoxon test. Differences
between groups were considered statistically significant if P is less
than 0.05.
RESULTS
A total of 334 patients with acute pancreatitis were enrolled
in this study. Patients were aged between 25 and 68 years, and al-
most two thirds were men (men, n = 211 [63.2%]; women, n = 123
[36.8%]). The most frequent cause of acute pancreatitis was ex-
cessive alcohol intake (44.3% of patients in both groups), whereas
biliary pancreatitis accounted for 17.7% of cases (lornoxicam
Standard Therapy Plus Lornoxicam
(n = 88) Р Total (n = 334)
6 (6.8%) 0.276 36 (10.8%)
12 (13.6%) 0.191 61 (18.3%)
28 (31.8%) 0.163 127 (38%)
9 (10.2%) 0.126 51 (15.3%)
30 (34.1%) 0.034 146 (43.7%)
9 (10.2%) 0.767 37 (11.1%)
19 (21.6%) 0.546 80 (24%)
31 (35.2%) 0.00034 172 (51.5%)
6 (6.8%) 0.006 53 (15.9%)
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Gorsky et al Pancreas • Volume 44, Number 5, July 2015

FIGURE 1. Expression of TLR2 and TLR4 mRNA in peripheral blood mononuclear cells of patients with systemic complications of acute
pancreatitis; *P = 0.001 for patients with complications of acute pancreatitis versus healthy volunteers; **P < 0.05 for standard therapy versus
standard therapy with lornoxicam.

FIGURE 2. (A) LPS- and (B) PG-induced production of TNF-α by peripheral blood mononuclear cells of patients with acute pancreatitis and
healthy volunteers; *P = 0.038 (LPS) and P = 0.034 (PG) for patients with complications of acute pancreatitis versus healthy volunteers;
**P < 0.05 for standard therapy versus standard therapy with lornoxicam. LPS indicates lipopolysaccharide; PG, peptidoglycan.

826 www.pancreasjournal.com © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pancreas • Volume 44, Number 5, July 2015
group, 24%; standard group, 16%), and trauma was the cause in
1 patient in the lornoxicam group. No cause could be determined
in the remaining 37.7% of patients (lornoxicam group, 31%; stan-
dard group, 40%).
Systemic Complications of Acute Pancreatitis
Of the 334 randomized patients, 172 (51.5%) developed sys-
temic complications of acute pancreatitis (Table 1). Complications
were significantly more frequent in the group who received stan-
dard therapy compared with those who also received lornoxicam
(57.3% versus 35.2%; P = 0.00034). The most frequent complica-
tions were gastrointestinal dysfunction manifesting as paralytic
ileus, which occurred in 43.7% of patients overall and was signif-
icantly more frequent in the standard therapy group (47.2% versus
34.1%; P = 0.034), acute renal failure (38.0% of patients overall;
no significant between-group difference), and acute liver failure
(24.0% of patients overall; no significant between-group differ-
ence). Most patients who developed systemic complications had
a combination of several different conditions. Mortality related to
the development of systemic complications of acute pancreatitis
(ie, multiorgan failure) was also significantly lower in the group
that received lornoxicam compared with standard therapy alone
(6.8% versus 19.1%; P = 0.006). No adverse drug reactions related
to lornoxicam were reported.
TLR2 and TLR4 mRNA Expression in Patients With
Systemic Complications of Acute Pancreatitis
The TLR2 mRNA expression in PBMCs from patients
with systemic complications of acute pancreatitis (n = 172)
FIGURE 3. (A) LPS- and (B) PG-induced production of IL-6 by peripheral blood mononuclear cells of patients with acute pancreatitis and
healthy volunteers; *P = 0.002 (LPS and PG) for patients with complications of acute pancreatitis versus healthy volunteers; **P < 0.05
standard therapy versus standard therapy with lornoxicam.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Lornoxicam in Acute Pancreatitis
was significantly higher (P = 0.001) than that in the healthy vol-
unteer control group (Fig. 1A) on day 1. In patients who were re-
ceiving standard therapy (n = 141), an increase in TLR2 mRNA
expression was observed from day 1 to day 3 before declining at
days 7 and 12. However, in patients receiving lornoxicam
(n = 31), no increased expression of TLR2 mRNA was observed
on day 3. Instead, a gradual decrease was observed from day 1
to day 12. Relative TLR2 mRNA expression in the lornoxicam
group was significantly lower than that in the standard therapy
group on days 7 (р = 0.007) and 12 (р = 0.013).
Similarly, expression of TLR4 mRNAwas significantly higher
(P = 0.001) in PBMCs from patients with complications of acute
pancreatitis at day 1 compared with healthy donors (Fig. 1B). The
TLR4 mRNA expression decreased in both groups from day 1 to
day 12 with no significant differences between groups at any
time point.
TLR2- and TLR4-Mediated Release of Cytokines in
Patients With Systemic Complications of
Acute Pancreatitis
Compared with healthy donors, patients with complications
of acute pancreatitis had significantly higher TLR2 and
TLR4-mediated proinflammatory cytokine release (TNF-α,
IL-6, and IL-8) from PBMCs on day 1. At day 3, TLR2- and
TLR4-mediated cytokine production had increased from day
1 in standard therapy patients but decreased in lornoxicam-
treated patients (Figs. 2–4). These differences were statisti-
cally significant between-groups. Some increase in cytokine
production was observed in the lornoxicam-treated group 2
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Gorsky et al
FIGURE 4. (A) LPS- and (b) PG-induced production of IL-8 by peripheral blood mononuclear cells of patients with acute pancreatitis and
healthy volunteers; *P = 0.034 (LPS and PG) for patients with complications of acute pancreatitis versus healthy volunteers.
from day 3 to day 7, which might be attributable to the discon-
tinuation of lornoxicam therapy after 5 days.
DISCUSSION
The main underlying mechanism for systemic manifestations
of acute pancreatitis, such as respiratory, cardiovascular, renal and
liver failure, is the massive release and circulation of inflamma-
tory mediators, of which TNF-α, IL-6, and IL-8 are the most im-
portant.21 Massive necrosis of pancreatic and retroperitoneal
tissue is associated with the release of a large amount of tissue
degradation products into the blood. These substances are the
endogenous ligands for TLR2 and TLR4. Excessive activation
of TLRs may lead to an uncontrolled snowballing release of pro-
inflammatory cytokines, potentially resulting in SIRS, multiple
organ dysfunction syndrome and death.
The PBMCs have been shown to play an important role in
the development of systemic complications of acute pancreatitis
and organ dysfunction21–23 and so represent a valid target for the
development of a therapeutic strategy. The increased TLR2 and
TLR4 mRNA expression that we observed in PBMCs of patients
with acute pancreatitis provides further evidence to suggest that
TLRs are involved in the pathogenesis of this condition. Acute
pancreatitis is associated with massive cellular destruction and a
release of TLR activators of endothelial origin into extracellular
space, which creates the conditions for the activation of the TLR
signal pathway and increased expression of TLR2 and TLR4
genes. Enzymes released from the pancreas, such as elastase and
heparin sulfate, can activate TLR4 and act as DAMP molecules.24
The TLR2 and TLR4 mRNA expression was higher in pa-
tients with systemic complications of acute pancreatitis than that
in the healthy controls, suggesting that they are a risk factor for
828 www.pancreasjournal.com
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Pancreas • Volume 44, Number 5, July 2015
the development of pancreatogenic toxemia. This is supported
by the decrease in TLR2 expression observed seen in patients with
a more favorable course of acute pancreatitis. Sharif and col-
leagues14 showed that increased TLR2 and TLR4 expression
is predictive of a poor prognosis in septic patients, whereas
low expression can protect from excessive inflammation and
tissue destruction.
We also observed increased TLR2- and TLR4-induced pro-
duction of TNF-α, IL-6, and IL-8 by PBMCs in patients with
acute pancreatitis during the first week after its onset. High levels
of proinflammatory cytokines may be associated with increased
expression and functional activity of TLR2 and TLR4 in these pa-
tients.25 The TNF-α is involved in systemic inflammation and tis-
sue destruction in several diseases. It is a key regulator of other
proinflammatory cytokines and of leukocyte adhesion molecules,
a priming activator of immune cells, and is involved in cell death
signaling. As such, it plays an important role in the systemic
progression of the inflammatory response in acute pancreatitis.
However, data on TNF-α production in acute pancreatitis are con-
flicting. Previous research has reported that levels of TNF-α pro-
duced by PBMCs from patients with acute pancreatitis did not
differ from levels in healthy controls and did not correlate with
the disease severity. Other studies have reported that elevated
levels of TNF-α produced by PBMCs of patients with acute pan-
creatitis during the first week after its onset correlate with the se-
verity of the systemic inflammatory response.26
The IL-6 and IL-8 levels are known to have an important
prognostic value in acute pancreatitis, having been shown to cor-
relate with disease severity.27,28 In our study, patients not treated
with lornoxicam had peak expression of IL-8 on day 3 after onset
of disease. It is known that IL-8 plays a key role in the pathogenesis
of tissue injury in ischemia followed by reperfusion.28 Transient
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Pancreas • Volume 44, Number 5, July 2015
ischemia is followed by tissue reperfusion due to correction of cen-
tral hemodynamics. However, restoration of blood supply to tissues
is associated with even more damage than ischemia. To a signifi-
cant extent, this phenomenon is associated with increased secretion
of IL-8, leading to activation of neutrophils, generation of free oxy-
gen radicals and tissue damage. Increased production of IL-8 on
day 3 may be considered an evidence for reperfusion tissue injury
exacerbating the course of acute pancreatitis.
It is known that during the first week after acute pancreatitis
onset, patients may experience the so-called cytokine storm,
which in turn may lead to the development of SIRS and multiple
organ dysfunction syndrome. To minimize the risk of this, strate-
gies to control production of proinflammatory cytokines during
the first week after disease onset are necessary, such as the use
of anti-inflammatory agents. The significant decrease in levels
of proinflammatory cytokines that we observed in patients receiv-
ing lornoxicam indicates its potent anti-inflammatory effect and
its ability to affect not only arachidonic acid metabolism but also
TLR-activated signal transduction pathways.
The TLR-mediated production of proinflammatory cyto-
kines occurs via signal pathways involving the transcription factor
NF-κB, which has an important role in the activation of synthesis
of many proinflammatory mediators and cytokines. It has previ-
ously been shown that COX-2 inhibitors reduced proinflamma-
tory cytokine synthesis and inhibited NF-κB activation in a rat
model of acute pancreatitis.10 In murine models, lornoxicam
effectively suppressed both NF-κB activation and synthesis of
TNF-α.29,30 It is possible that lornoxicam inhibits the produc-
tion of proinflammatory cytokines through suppression of
NF-κB activity.
CONCLUSIONS
Patients with systemic complications of acute pancreatitis
were found to have increased TLR2 and TRL4 mRNA expres-
sions and high functional activity of these receptors on PBMCs
during the first week after disease onset. The use of lornoxicam
at the onset of acute pancreatitis decreased TLR2 and TLR4
mRNA expression as well as TLR2 and TLR4-mediated produc-
tion of proinflammatory cytokines, thereby reducing the risk of
systemic complications, including SIRS. Addition of lornoxicam
to a combination of standard therapies used to treat acute pancre-
atitis was associated with a significant reduction in complications
of pancreatogenic toxemia and improved the survival of patients.
The addition of a COX inhibitor, such as lornoxicam to standard
therapy, may be beneficial in patients with acute pancreatitis
ACKNOWLEDGMENTS
The authors thank Andy Bond of Spirit Medical Communica-
tions Ltd., for the editorial assistance (editing of manuscript) pro-
vided, supported by Takeda Pharmaceuticals International GmbH.
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