This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Villa, P. Articles by Ghezzi, P. Search for Related Content PubMed Articles by Villa, P. Articles by Ghezzi, P. Social Bookmarking                   What's this?

Protection against lethal polymicrobial sepsis by CNI-1493, an inhibitor of pro-inflammatory cytokine synthesis

Mario Negri Institute for Pharmacological Research, Milan, Italy, CNR Cellular and Molecular Pharmacology Center, Milan, Italy

C. Meazza

Mario Negri Institute for Pharmacological Research, Milan, Italy

M. Sironi

Mario Negri Institute for Pharmacological Research, Milan, Italy

M. Bianchi

The Picower Institute for Medical Research, Manhasset, New York, USA

P. Ulrich

The Picower Institute for Medical Research, Manhasset, New York, USA

G. Botchkina

The Picower Institute for Medical Research, Manhasset, New York, USA

K.J. Tracey

The Picower Institute for Medical Research, Manhasset, New York, USA, ktracey{at}picower.edu, Department of Surgery, North Shore University Hospital, Manhasset, New York, USA

P. Ghezzi

Mario Negri Institute for Pharmacological Research, Milan, Italy

Polymicrobial sepsis caused by cecal ligation and puncture (CLP) in mice produces the inflammatory and pathological sequelae of lung neutrophil infiltration, adult respiratory distress syndrome (ARDS) and death. These sequelae are dependent upon the synergistic interaction between several inflammatory mediators, including tumor necrosis factor (TNF), interleukin 1 (IL-1 ), and nitric oxide (NO). The overlapping spectrum of multiple mediator toxicity has hampered efforts to develop therapies for sepsis based on selective inhibition of a single mediator. Therefore, we tested the hypothesis that inhibition of multiple pro-inflammatory mediators would abrogate lethality. Our results show that administration of a tetravalent guanylhydrazone compound (CNI-1493) protected mice against 10 day mortality in CLP. Evidence of suppression of the cytokine cascade was given by decreased serum levels of TNF and IL-6 in CNI-1493 treated animals (TNF reduced 60% as compared to controls; IL-6 reduced 90% compared to controls; P < 0.05), and decreased levels of the acute-phase protein serum amyloid A response measured 24 h after CLP. Serum nitrites/nitrates, which give an index of NO production, were also significantly reduced (50%). Protection against CLP induced lung damage was observed as attenuation of edema and alveolar neutrophil infiltration, suppression of pulmonary TNF levels, and reduction of TUNEL-positive staining in lung. We conclude that CNI-1493 effectively inhibits the synthesis of multiple pro-inflammatory mediators and protects against death during polymicrobial sepsis.

Journal of Endotoxin Research, Vol. 4, No. 3, 197-204 (1997)
DOI: 10.1177/096805199700400305


CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				X. Lin, H. Yang, T. Sakuragi, M. Hu, L. L. Mantell, S. Hayashi, Y. Al-Abed, K. J. Tracey, L. Ulloa, and E. J. Miller {alpha}-Chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis Am J Physiol Lung Cell Mol Physiol, October 1, 2005; 289(4): L583 - L590. [Abstract] [Full Text] [PDF]

				C. Granert, H. Abdalla, L. Lindquist, A. Diab, M. Bakhiet, K. J. Tracey, and J. Andersson Suppression of Macrophage Activation with CNI-1493 Increases Survival in Infant Rats with Systemic Haemophilus influenzae Infection Infect. Immun., September 1, 2000; 68(9): 5329 - 5334. [Abstract] [Full Text] [PDF]

				C. A. Salkowski, G. Detore, A. Franks, M. C. Falk, and S. N. Vogel Pulmonary and Hepatic Gene Expression following Cecal Ligation and Puncture: Monophosphoryl Lipid A Prophylaxis Attenuates Sepsis-Induced Cytokine and Chemokine Expression and Neutrophil Infiltration Infect. Immun., August 1, 1998; 66(8): 3569 - 3578. [Abstract] [Full Text] [PDF]

				M. M. Kemeny, G. I. Botchkina, M. Ochani, M. Bianchi, C. Urmacher, and K. J. Tracey The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy PNAS, April 14, 1998; 95(8): 4561 - 4566. [Abstract] [Full Text] [PDF]