Absence of prostacyclin greatly relieves cyclophosphamide‐induced cystitis and bladder pain in mice

Abstract

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.

Prostacyclin synthase deficiency exacerbates inflammatory reactions in lipopolysaccharide-induced sepsis in vivo

“…Male 8-to 10-week-old C57BL/6 mice were used. PGIS KO mice were described previously [11]. Mice were bred in climate-controlled rooms (23°C) under speci c pathogen-free conditions on a 12-h light/dark cycle at the Institute of Laboratory Animals of Showa University (Tokyo, Japan).…”

“…Samples were prepared according to a previously described methodology with minor modi cation [11]. Brie y, to prepare samples, 750 µL of 0.03% formic acid containing ultrapure water and an internal standard (25 pg of leukotriene (LT) B 4 -d 4 , Cayman (Ann Arbor, MI, USA)) were added to the each 250 µL aliquot of the sample.…”

“…COX-2/PGIS-derived PGI 2 has been shown to be crucial for the regulation of platelet aggregation and vascular tone [10]. In addition, we previously demonstrated that PGIS has a proin ammatory function in several disease models using PGIS gene knockout (KO) mice [11,12]. On the other hand, other research groups have reported that PGIS-derived PGI 2 has an anti-in ammatory function [13].…”

Prostacyclin Synthase as an Ambivalent Regulator of Inflammatory Reactions

“…Moreover, we recently reported the involvement of PGISderived PGI 2 in cyclophosphamide (CP)-induced cystitis. 47) CP has been widely used in the treatment of various malignancies and autoimmune diseases, but acrolein, a byproduct of CP, is known to cause severe hemorrhagic cystitis. In the bladder tissues of CP-treated WT mice, the levels of PGE 2 , 6-keto-PGF 1α and other PGs were increased in association with hemorrhagic cystitis.…”

Sulfhydryl functionalized hyaluronic acid hydrogels attenuate cyclophosphamide-induced bladder injury

“…Cyclophosphamide (CYP), an oxazaphosphorine alkylating agent, was first successfully prepared by Norbert Brock in 1985 [1]. CYP is a prodrug that is widely used in the treatment of various malignancies and autoimmune diseases [2,3]. After administration, CYP is metabolized to 4hydroxycyclophosphamide in hepatocytes, and then enters the target cell for conversion to alkylated phosphoramide mustard, interfering with DNA replication and causing cell death [2,4].…”