Absence Of Prostacyclin Greatly Relieves Cyclophosphamide-Induced Cystitis And Bladder Pain In Mice

Cyclophosphamide (CP) has been widely used in the treatment of various malignancies and autoimmune diseases. but acrolein, a byproduct of CP, causes severe hemorrhagic cystitis as the major side effect of CP. On the other hand, a large amount of prostacyclin (PGI(2)) is produced in bladder tissues, and PGI(2) has been shown to play a critical role in bladder homeostasis. PGI(2) is biosynthesized from prostaglandin (PG) H-2, the common precursor of PGs, by PGI(2) synthase (PTGIS) and is known to also be involved in inflammatory responses. However, little is known about the roles of PTGIS-derived PGI(2) in bladder inflammation including CP-induced hemorrhagic cystitis. Using both genetic and pharmacological approaches, we here revealed that PTGIS-derived PGI(2)-IP (PGI(2) receptor) signaling exacerbated CP-induced bladder inflammatory reactions. Ptgis deficiency attenuated CP-induced vascular permeability and chemokine-mediated neutrophil migration into bladder tissues and then suppressed hemorrhagic cystitis. Treatment with RO1138452, an IP selective antagonist, also suppressed CP-induced cystitis. We further found that cystitis-related nociceptive behavior was also relieved in both Ptgis(-/-) mice and RO1138452-treated mice. Our findings may provide new drug targets for bladder inflammation and inflammatory pain in CP-induced hemorrhagic cystitis.