RESUMO
Previous studies have shown that cyclic peptides corresponding to residues 35 to 52 of the Limulus antilipopolysaccharide (anti-LPS) factor (LALF) bind and neutralize LPS-mediated in vitro and in vivo activities. Therapeutic approaches based on agents which bind and neutralize LPS activities are particularly attractive because these substances directly block the primary stimulus for the entire proinflammatory cytokine cascade. Here we describe new activities of the LALF(31-52) peptide, other than its LPS binding ability. Surprisingly, supernatants from human mononuclear cells stimulated with the LALF peptide are able to induce in vitro antiviral effects on the Hep-2 cell line mediated by gamma interferon (IFN-gamma) and IFN-alpha. Analysis of the effect of LALF(31-52) on tumor necrosis factor (TNF) and nitric oxide (NO) production by LPS-stimulated peritoneal macrophages revealed that a pretreatment with the peptide decreased LPS-induced TNF production but did not affect NO generation. This indicates that the LALF peptide modifies the LPS-induced response. In a model in mice with peritoneal fulminating sepsis, LALF(31-52) protected the mice when administered prophylactically, and this effect is related to reduced systemic TNF-alpha levels. This study demonstrates, for the first time, the anti-inflammatory properties of the LALF-derived peptide. These properties widen the spectrum of the therapeutic potential for this LALF-derived peptide and the molecules derived from it. These agents may be useful in the prophylaxis and therapy of viral and bacterial infectious diseases, as well as for septic shock.
Assuntos
Anti-Infecciosos/imunologia , Caranguejos Ferradura/imunologia , Hormônios de Invertebrado/imunologia , Lipopolissacarídeos/imunologia , Peptídeos/imunologia , Animais , Anti-Infecciosos/química , Peptídeos Catiônicos Antimicrobianos , Proteínas de Artrópodes , Humanos , Hormônios de Invertebrado/química , CamundongosRESUMO
BACKGROUND: Heparin and heparin derivatives with low anticoagulant activity exhibit a wide spectrum of biological functions affecting adhesion, activation and trafficking of leukocytes. METHODS: We investigated the in vitro effect of heparin and a low molecular weight heparin derivative (LMWH) on nitric oxide (NO) production by human polymorphonuclear leukocytes (PMN). RESULTS: N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated NO production was significantly decreased by heparin at doses of 0.5 and 5 micrograms/mL, while LMWH was only effective at doses of 50 and 200 micrograms/mL by means of a mechanism not related to NO synthase (NOS) activity. CONCLUSIONS: These results support the hypothesis that heparin and LMWH derivatives may offer therapeutic benefit for inflammatory diseases where NO plays a protagonic role.
Assuntos
Heparina de Baixo Peso Molecular/farmacologia , Heparina/farmacologia , Neutrófilos/metabolismo , Óxido Nítrico/biossíntese , Humanos , Metemoglobina/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacologiaRESUMO
BACKGROUND: Because surgery involving cardiopulmonary bypass induces a systemic inflammatory response, the effect of cardiopulmonary bypass on nitric oxide (NO) generation was investigated in human lung tissue. METHODS: Nitric oxide synthase (NOS) activity was measured by the conversion of 14C-L-arginine to 14C-L-citrulline in tissue biopsy samples obtained before and after cardiopulmonary bypass. RESULTS: The Ca(2+)-independent production of NO found before cardiopulmonary bypass was extremely low (1.5 (0.5) pmol citrulline/mg/min), but was increased after the bypass operation (23.6 (11) pmol/mg/min). CONCLUSIONS: Ca(2+)-independent NOS activity was detected in human lung after cardiopulmonary bypass. This finding may provide an important insight into the pathogenesis of the tissue damage and acute phase response observed after such surgery.