Bacterial Toxin N-Formyl-Methionyl-Leucyl-Phenylalanine Acutely Contracts Human and Rabbit Detrusor Through the Release of Eicosanoids

Abstract

Uropathogenic bacteria that secrete N-formylmethionyl oligopeptides such as N-formyl-methionyl-leucyl-phenylalanine (f-MLP) are a common cause of urinary tract infections. We determined the in vitro effects of f-MLP on human and rabbit detrusor as well as its mechanism and site of action. Reverse transcriptase-polymerase chain reaction was used to investigate cyclooxygenase-2 messenger RNA within the rabbit detrusor. Standard mechanical organ bath recording techniques were used to measure contractile activity from rabbit and human detrusor muscle strips. Immunohistochemistry was performed using macrophage specific antibodies (human BerMAC3 and rabbit RAM11) on detrusor whole mount specimens. Muscle activity recorded from human and rabbit detrusor showed that f-MLP caused contracture of the detrusor, which was completely blocked by indomethacin and partially blocked by individual cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors. Exposure of the detrusor to exogenous prostaglandins indicated that f-MLP released an effective concentration of more than 1 microM. from an endogenous source. Immunohistochemical staining of the human (BerMAC3) and rabbit (RAM11) bladder demonstrated a dense network of resident macrophages lying within the detrusor muscle bundles, which are known to secrete prostaglandins during the activation of specific f-MLP receptors. Bacterial derived f-MLP contracts the detrusor through the release of eicosanoids from resident macrophages. These data suggest that bacterial activation of the resident macrophage network could participate in causing the symptoms of bacterial cystitis.