Inhibition of nitric oxide synthase (NOS) aggravates Staphylococcus aureus septicaemia and septic arthritis

The aim of this study was to assess the role of NO and its metabolites in bacterial arthritis. The murine model of haematogenously acquired septic arthritis was used. Swiss mice treated with NOS inhibitors (N(G)-monomethyl-L-arginine or N(omega)-nitro-L-arginine methyl ester) were injected intravenously with toxic shock syndrome toxin-1 (TSST-1) producing Staphylococcus aureus LS-1. Arthritis was evaluated clinically and histopathologically. Serum cytokine levels, bacterial isolates and intracellular capacity of macrophages to kill bacteria were also analysed. The frequency of arthritis in mice treated with NOS inhibitors was three to four-fold higher than that in non-treated controls (75% versus 20%). The severity of arthritis, expressed as mean arthritic index, was 1.4 and 0.4, respectively. Cartilage and/or bone destruction occurred in 63% of NOS inhibitor-treated mice, but only in 10% of controls. Also, the cumulative septicaemia-induced mortality was clearly higher in mice treated with NOS inhibitors compared with non-treated controls. Intracellular killing capacity of the peritoneal macrophages, treated in vitro with NOS inhibitors, was decreased. Thus, 24 h after bacterial inoculation peritoneal macrophages pretreated with NOS inhibitors killed more than 10 times less bacteria than the control ones (P<0.01). We conclude that NOS inhibitors aggravate S. aureus arthritis, possibly by inducing impairment of the intracellular killing capacity of macrophages.