Intravesical immune suppression by liposomal tacrolimus in cyclophosphamide-induced inflammatory cystitis.
OBJECTIVE
Potent immunosuppressive effect of tacrolimus has encouraged its topical application for achieving local anti-inflammatory effect. However, its poor aqueous solubility presents challenges in formulating biocompatible instillations to justify the investigation of liposomes as vehicle for tacrolimus.


METHODS
Adult female Sprague-Dawley rats (N=52) divided into 4 groups were injected with cyclophosphamide (CYP) (200 mg/kg, ip) except for sham (saline injection, ip). Other three groups were instilled with either saline (1 cc, retained for 1 hr), liposome (LP- 1 cc) or liposomal encapsulated tacrolimus (LFK- 0.2 mg tacrolimus/1 ml LP). Baseline cystometrogram was performed on day 1 and day 3 prior to bladder harvest for histological staining (N=24) in all groups except sham. In addition, 4-hr baseline urine on day 1 and day 3 was collected from all groups for urine PGE2 assay and bladder harvested for PGE2 and IL2 assay on day 3 (N=28).


RESULTS
Rats treated with LFK demonstrated suppression of CYP induced inflammatory reaction with reduced EP4 staining and bladder overactivity (intercontraction interval 61.0% decrease in untreated animals) as well as normalized the several fold elevation of IL 2 and PGE2 levels in tissue and urine. CYP induced effects were not suppressed in rats left untreated with tacrolimus.


CONCLUSIONS
This is the first report of immunosuppression in bladder by intravesical delivery of tacrolimus using liposomes. LFK significantly inhibited CYP induced inflammatory cystitis through the modulation of IL2, PGE2, and EP4 function. These findings support investigation of local tacrolimus in cases of inflammatory cystitis refractory to conventional therapy.
Chuang
Yao-Chi
YC
Department of Urology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. chuang82@ms26.hinet.net
Tyagi
Pradeep
P
Huang
Hsuan-Ying
HY
Yoshimura
Naoki
N
Wu
Moya
M
Kaufman
Jonathan
J
Chancellor
Michael B
MB
D000283:Administration, Intravesical; D000818:Animals; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D015232:Dinoprostone / Q000378:metabolism / Q000652:urine; D004195:Disease Models, Animal; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood; D007376:Interleukin-2 / Q000378:metabolism / Q000652:urine; D008081:Liposomes; D051381:Rats; D017207:Rats, Sprague-Dawley; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage* / Q000097:blood; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014554:Urination / Q000187:drug effects
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008081:Liposomes; C545652:Ptger4 protein, rat; D058309:Receptors, Prostaglandin E, EP4 Subtype; D003520:Cyclophosphamide; D015232:Dinoprostone; D016559:Tacrolimus