Differential regulation of Th1/Th2 in relevant tissues for sepsis pathogenesis with a Limulus anti-LPS factor-derived peptide increases survival in Gram-positive sepsis

• Published in: International immunopharmacology 2004-10, Vol.4 (10-11), p.1343-1351
• Main Authors: Vallespi, Maribel G, Colas, M, Garay, H, Reyes, O, Araña, M.J
• Format: Article
• Language: English
• Subjects: Animals; Anti-Infective Agents - pharmacology; Anti-Infective Agents - therapeutic use; Antimicrobial Cationic Peptides; Antineoplastic agents; Arthropod Proteins; Biological and medical sciences; Cytokines; Cytokines - blood; Cytokines - genetics; Gene Expression Regulation; Gram-positive sepsis; Immunomodulation; Invertebrate Hormones - chemistry; Limulus; Limulus anti-LPS factor-derived peptide; Liver - pathology; Lung - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Pharmacology. Drug treatments; Prophylaxis; RNA, Messenger - blood; Sepsis - immunology; Sepsis - mortality; Sepsis - prevention & control; Staphylococcal Infections - immunology; Staphylococcal Infections - mortality; Staphylococcal Infections - prevention & control; Staphylococcus haemolyticus; Survival Rate; Th1 Cells - immunology; Th1–Th2 response; Th2 Cells - immunology; Time Factors; Tumors
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2004.05.019

Severe sepsis and septic shock are important causes of death in intensive care units. Although Gram-negative infections were predominant in the 1960s, Gram-positive infections have increased in the past two decades and now account for about half of the cases of severe sepsis. In this study, we examined the effect of a Limulus anti-LPS factor (LALF)-derived peptide on lung and liver Th1/Th2 cytokine mRNA levels during a Gram-positive sepsis. We also examined the morphopathological changes observed in these organs during the disease. Mice challenged with a high dose of Staphylococcus haemolyticus showed severe damage in lung. In contrast, the liver of challenged mice showed an accumulation of bacterial particles in the sinusoids, associated with a severe inflammatory response due to high levels of tissue mRNA proinflammatory cytokines. Treatment with the peptide LALF32–51 ameliorated the sepsis-induced effects in the lung and liver and increased the survival of mice in a dose- and time-dependent manner. Pretreatment with the peptide LALF32–51 differentially regulates TNF-α, IFN-γ, IL-12p40, IL-2 and IL-10 mRNA levels in lung and liver of peptide-treated mice, and limits the systemic inflammatory response. These findings support for the first time the effectiveness of an LALF-derived peptide in the treatment of a Gram-positive sepsis. Modulation of the Th1/Th2 pattern in tissues relevant for sepsis correlates with an improved outcome of the disease as denoted by increased survival.