Group Title: Critical Care
Title: Therapeutic neutralization of interferon-gamma in primates prevents lethality in Gram-negative bacteremic shock
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 Material Information
Title: Therapeutic neutralization of interferon-gamma in primates prevents lethality in Gram-negative bacteremic shock
Series Title: Critical Care
Physical Description: Archival
Creator: Lainée,P.
Publication Date: 2004
General Note: Start pageP205
General Note: M3: 10.1186/cc2672
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Bibliographic ID: UF00100042
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: Open Access:
Resource Identifier: issn - 1364-8535


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Critical Care March 2004 Vol 8 Suppl 1 24th International Symposium on Intensive Care and Emergency Medicine

P204 N-Acetylcysteine inhibits peroxynitrite-mediated damage in oleic acid-induced lung injury

0 Koksel, I Cinel, L Tamer, L Cinel, A Ozdulger, U Oral
Mersin University, Turkey
Critical Care 2004, 8(Suppl 1):P204 (DOI 10.1186/cc2671)

Since oleic acid (OA) induces morphologic and cellular changes
similar to those observed in human acute lung injury (ALl) and
acute respiratory distress syndrome (ARDS), it has become a
widely used model to investigate the effects of several agents on
pathogenesis of lung injury. The antioxidant, anti-inflammatory and
antiapoptotic properties of N-acetylcysteine (NAC) have been
documented in many lung injury models [1]. In this study, we
evaluated the role of NAC in an OA-induced lung injury model by
measuring myeloperoxidase (MPO) activity, malondialdehyde
(MDA) and 3-nitrotyrosine (3-NT) levels in lung tissue.

Five groups (sham, NAC, OA, pre-OA-NAC and post-OA-NAC)
were determined. ALI/ARDS was induced by intravenous (IV)
administration of OA. The pre-OA-NAC group received IV NAC
15 min before OA infusion and the post-OA-NAC group received
IV NAC 2 hours after OA infusion. In both of the NAC treatment
groups, blood and tissue samples were collected 4 hours after OA
infusion, independent of the time of NAC infusion.

The MPO activity, MDA and 3-NT levels in lung homogenates were
found to be increased in the OA group, and the administration of
NAC significantly reduced tissue MPO, MDA and 3-NT levels
(P= 0.0001). Lung histopathology was also protected by NAC in
this OA-induced experimental lung injury model.
In conclusion, the present study demonstrates that oleic acid
induces myeloperoxydase activation and consequently increases
3-NT and MDA levels in lung tissue. Our data suggest that elevated
3-NT levels in lung tissue represent the role of excessive formation of
peroxynitrite and the efficacy of NAC treatment in the prevention of
peroxynitrite-mediated OA-induced lung injury. Due to its antioxidant
and antiinflammatory properties, NAC seems to be a promising
agent in treatment of critically ill patients with lung injury states.
1. Ozdulger A, Cinel I, Koksel 0, et al.: The protective effect of N-
acetylecysteine on apoptotic lung injury in CLP-induced
sepsis model. Shock 2003, 19:366-372.

P205 Therapeutic neutralization of interferon-gamma in primates prevents lethality in Gram-negative bacteremic shock

P Lainee1, P Efron2, K Lorre3, L Moldawer2
'CIT, Evreux, France; 2University of Florida College of Medicine, Gainesville, Florida, USA; 31nnogenetics, Gent, Belgium
Critical Care 2004, 8(Suppl 1):P205 (DOI 10.1186/cc2672)

Background The treatment of severe sepsis and septic shock with
anticytokine therapies remains a dilemma. Although a number of
preclinical studies have shown efficacy in primate models of
bacteremic shock when administered prophylactically, these same
therapies have a much diminished effectiveness when
administered therapeutically.

Aim This study investigated whether therapeutic administration of
a novel antihuman interferon-gamma (anti-IFNy) monoclonal
antibody (mAb) could improve outcome in a lethal model of Gram-
negative bacteremic shock.

Methods Gram-negative bacteremic shock was induced in
14 anesthetized Cynomolgus monkeys by intravenous injection of
approximately 10 (10) cfu live Escherichia coli. Treatment was
administered only after the animals developed symptoms of shock
meeting at least two of the predefined criteria: 30% reduction in
blood pressure, 30% increase in heart rate and oliguria (urine output
<1 ml/kg body weight/hour). Six of the animals received placebo
while eight were treated with 10 mg/kg humanized anti-IFNy mAb.
Invasive hemodynamic monitoring under anesthesia was continued
for 1 2 hours, after which the animals were returned to their cages,
and were followed daily for clinical signs during 14 days.

Results Five out of the six placebo-treated Cynomolgus monkeys
died or required euthanasia within 24-72 hours after E. coli
challenge, while one animal survived for 5 days. In contrast, six of
the eight animals treated with the humanized anti-IFNy mAb
survived for 7-14 days (P= 0.013 vs placebo). More specifically
within the treated group, two animals died early of sepsis (day 3
and day 4, respectively), two animals were euthanized on day 7
because of limb necrosis (caused by catheter-related thrombosis)
and not directly because of the sepsis symptoms, one animal was
euthanized on day 9 due to sepsis symptoms, and three animals
survived 14 days and appeared to be in good health. Treatment
with the anti-IFNy mAb decreased the systemic TNF-c, IL-6 and
IL-1 P response to E. coli. Furthermore, renal dysfunction,
evidenced by increased creatinine, was significantly decreased by
treatment with the anti-IFNy mAb.

Conclusions This study demonstrates that, in a primate model of
E. coli-induced septic shock, the neutralization of IFNy with a mAb,
administered after the onset of clinical signs of sepsis, improves
survival and attenuates the pathological changes associated with
the development of multiple organ dysfunction. This suggests that
IFNy blockade potentially represents an effective mode of
intervention in lethal septic shock.

P206 Predicting the response to therapy from a mathematical model

G Clermont1, R Kumar2, J Bartels3, Y Vodovotz2, S Chang3, C Chow2
1UPMC, Pittsburgh, Pennsylvania, USA; 2University of Pittsburgh, Pennsylvania, USA; 31mmunetrics, Inc., Pittsburgh, Pennsylvania,
Critical Care 2004, 8(Suppl 1):P206 (DOI 10.1186/cc2673)

Objectives To determine the feasibility and usefulness of Methods We simulated an interventional trial of a neutralizing body
computer simulations in evaluating therapeutic strategies and against tissue necrosis factor (anti-TNF) in sepsis based on a
patient selection in clinical trials of sepsis. mechanistic mathematical model that includes a bacterial infection,

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