Presentation Authors: Evaristus Mbanefo*, Loc Le, Rockville, MD, Rebecca Zee, Washington DC, DC, Nirad Banskota, Rockville , MD, Kenji Ishida, Rockville, MD, Luke Pennington, Stanford, CA, Justin Odegaard, Redwood, CA, Theodore Jardetzky, Stanford, CA, Abdulaziz Alouffi, Franco Falcone, Nottingham, United Kingdom, Michael Hsieh, Washington DC, DC
Introduction: Ifosfamide and other oxazaphosphorines can result in hemorrhagic cystitis, a constellation of complications caused by acrolein metabolites. We previously showed that a single dose of IPSE, a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the exact mechanisms underlying this urotoxic effect and its prevention are not fully understood.
Methods: To provide insights into IPSEâ€™s protective mechanism, we undertook transcriptional profiling of bladders from ifosfamide-treated mice, with or without pretreatment with IPSE or IPSE NLS mutant
Results: The pro-inflammatory pathway involving the IL-1Î²-TNFÎ±-IL-6 triad via NF&[kappa]B and STAT3 signaling pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates both Hmox1-mediated heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory and cellular proliferation cascades implicated in tissue repair, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE administration before ifosfamide injection resulted in significant downregulation of major proinflammatory pathways including the triad of IL-1β-TNFÎ±-IL-6 pathways, the interferon signaling pathway, in addition to notable reduction in oxidative stress responses. IPSE NLS mutant reduced inflammation with no effect on oxidative stress.
Conclusions: Taken together, we have identified signatures of acute phase inflammation and oxidative stress responses in the ifosfamide-injured bladder, which are reversed by pretreatment with IPSE, a parasite-derived anti-inflammatory molecule. In addition to providing new insights into the underlying mechanism of IPSEâ€™s therapeutic effects, this work has revealed several pathways that could be therapeutically targeted to prevent and treat ifosfamide-induced hemorrhagic cystitis.
Source of Funding: NIDDK R01DK113504 (MH), NIAID R56AI119168 (MH), Urology Care Foundation Research Scholar Award (EM)