Changes in urinary bladder function and somatic sensation may be mediated, in part, by inflammatory changes in the urinary bladder including the expression of
chemokines. Male and female C57BL/6 mice were treated with
cyclophosphamide (CYP; 75 mg/kg, 200 mg/kg, i.p.) to induce bladder
inflammation (4 h, 48 h, chronic). We characterized the expression of
CXC chemokines (CXCL9, CXCL10 and CXCL11) in the urinary bladder and determined the effects of blockade of their common
receptor, CXCR3, at the level urinary bladder on bladder function and somatic (hindpaw and pelvic) sensation. qRT-PCR and
Enzyme-Linked Immunoassays (ELISAs) were used to determine
mRNA and
protein expression of CXCL9, CXCL10 and CXCL11 in urothelium and detrusor. In urothelium of female mice treated with CYP, CXCL9 and CXCL10
mRNA significantly (p ≤ 0.01) increased with CYP treatment whereas CXC
mRNA expression in the detrusor exhibited both increases and decreases in expression with CYP treatment. CXC
mRNA expression urothelium and detrusor of male mice was more variable with both significant (p ≤ 0.01) increases and decreases in expression depending on the specific
CXC chemokine and CYP treatment. CXCL9 and CXCL10
protein expression was significantly (p ≤ 0.01) increased in the urinary bladder with 4 h CYP treatment in female mice whereas CXC
protein expression in the urinary bladder of male mice did not exhibit an overall change in expression. CXCR3 blockade with
intravesical instillation of
AMG487 (5 mg/kg) significantly (p ≤ 0.01) increased bladder capacity, reduced voiding frequency and reduced non-voiding contractions in female mice treated with CYP (4 h, 48 h). CXCR3 blockade also reduced (p ≤ 0.01) hindpaw and pelvic sensitivity in female mice treated with CYP (4 h, 48 h).
CXC chemokines may be novel targets for treating urinary bladder dysfunction and somatic sensitization resulting from urinary bladder
inflammation.