Oral spermine administration inhibits nitric oxide-mediated intestinal damage and levels of systemic inflammatory mediators in a mouse endotoxin model

Enhanced intestinal nitric oxide production observed during sepsis is thoug ht to play a central role in lipopolysaccharide-induced intestinal damage. In contrast intestinal polyamines, both from endogenous and exogenous origi n, are essential for the maintenance of mucosal integrity. Polyamines have been shown to inhibit lipopolysaccharide-induced nitric oxide release in vi tro and have been claimed to exert additional antiinflammatory actions. In this study, the effect of the polyamine spermine on the release of the proi nflammatory mediators nitric oxide and tumor necrosis factor-alpha by a mur ine macrophage cell line was investigated. Furthermore, we investigated whe ther oral spermine administration inhibits lipopolysaccharide-induced intes tinal inducible nitric oxide synthase and nitrotyrosine expression and modu lates the release of inflammatory mediators. Our results show that although spermine inhibited lipopolysaccharide-induced nitric oxide release in a mu rine macrophage cell line, no effect on tumor necrosis factor-alpha or rele ase was observed. In addition, oral spermine administration inhibited intes tinal inducible nitric oxide synthase and nitrotyrosine expression suggesti ng a protective effect of spermine on lipopolysaccharide-induced intestinal damage. In parallel a decrease in serum levels of the proinflammatory medi ators nitrate, nitrite, and interferon-gamma and an increase in the antiinf lammatory cytokine interleukin-10 was observed, although tumor necrosis fac tor-alpha levels were unaffected. These results indicate that spermine inhi bits lipopolysaccharide-induced nitric oxide release in vitro as well as in vivo. Further, intraluminally derived polyamines modulate the systemic imm une response. It is concluded that oral spermine administration might have therapeutic perspectives for several disorders characterized by systemic in flammation and intestinal damage.