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 (PGI₂) is produced in bladder tissues, and PGI₂ has been shown to play a critical role in bladder homeostasis. PGI₂ is biosynthesized from prostaglandin (PG) H₂, the common precursor of PGs, by PGI₂ synthase (PTGIS) and is known to also be involved in inflammatory responses. However, little is known about the roles of PTGIS-derived PGI₂ in bladder inflammation including CP-induced hemorrhagic cystitis. Using both genetic and pharmacological approaches, we here revealed that PTGIS-derived PGI₂-IP (PGI₂ 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.

中文翻译：

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前列环素的缺失极大地缓解了环磷酰胺引起的小鼠膀胱炎和膀胱疼痛

环磷酰胺 (CP) 已广泛用于治疗各种恶性肿瘤和自身免疫性疾病，但 CP 的副产物丙烯醛作为 CP 的主要副作用会导致严重的出血性膀胱炎。另一方面，膀胱组织中会产生大量的前列环素 (PGI ₂ )，并且 PGI ₂已被证明在膀胱稳态中起着关键作用。PGI ₂由前列腺素 (PG) H ₂，即前列腺素的常见前体，通过 PGI ₂合酶 (PTGIS)生物合成，并且已知也参与炎症反应。然而，对 PTGIS 衍生的 PGI ₂的作用知之甚少在膀胱炎症中，包括 CP 引起的出血性膀胱炎。使用遗传和药理学方法，我们在这里揭示了 PTGIS 衍生的 PGI ₂ -IP（PGI ₂受体）信号加剧了 CP 诱导的膀胱炎症反应。Ptgis缺乏减弱了 CP 诱导的血管通透性和趋化因子介导的中性粒细胞迁移到膀胱组织，然后抑制了出血性膀胱炎。用 RO1138452（一种 IP 选择性拮抗剂）治疗也抑制了 CP 诱导的膀胱炎。我们进一步发现膀胱炎相关的伤害性行为在两个Ptgis ^{-/- 中}也得到缓解小鼠和 RO1138452 处理的小鼠。我们的发现可能为 CP 诱导的出血性膀胱炎中的膀胱炎症和炎症性疼痛提供新的药物靶点。