Abstract
Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and voiding dysfunction caused by hemorrhage and inflammation. Novel therapeutic options to treat hemorrhagic cystitis are needed. We previously reported that systemic administration of the
-derived protein H-IPSE
(IL-4-inducing principle from
eggs) is superior to three doses of MESNA in alleviating hemorrhagic cystitis (Mbanefo EC, Le L, Pennington LF, Odegaard JI, Jardetzky TS, Alouffi A, Falcone FH, Hsieh MH.
32: 4408-4419, 2018). Based on prior reports by others on
IPSE (M-IPSE) and additional work by our group, we reasoned that H-IPSE mediates its effects on hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, promoting urothelial proliferation, and translocating to the nucleus to modulate expression of genes implicated in relieving bladder dysfunction. We speculated that local bladder injection of the
IPSE ortholog IPSE
, hereafter called H-IPSE
, might be more efficacious in preventing hemorrhagic cystitis compared with systemic administration of IPSE
. We report that H-IPSE
, like M-IPSE and H-IPSE
, activates IgE-bearing basophils in a nuclear factor of activated T-cells reporter assay, indicating activation of the cytokine pathway. Furthermore, H-IPSE
attenuates ifosfamide-induced increases in bladder wet weight in an IL-4-dependent fashion. H-IPSE
relieves hemorrhagic cystitis-associated allodynia and modulates voiding patterns in mice. Finally, H-IPSE
drives increased urothelial cell proliferation, suggesting that IPSE induces bladder repair mechanisms. Taken together, H-IPSE
may be a potential novel therapeutic to treat hemorrhagic cystitis by basophil activation, attenuation of allodynia, and promotion of urothelial cell proliferation.