Bone Marrow Cell Recruitment Mediated by Inducible Nitric Oxide Synthase/Stromal Cell-Derived Factor-1α Signaling Repairs the Acoustically Damaged Cochlear Blood-Labyrinth Barrier

Using a mouse model with noise induced cochlear blood labyrinth barrier (CBLB) injury we examined the effects of inducible nitric oxide synthase (iNOS) on the recruitment of bone marrow derived cells (BMDCs) to the CBLB after acoustic injury Lethally Irradiated C57BL/6J and B6 129P2 Nos(tm1Lau)/J mice were transplanted with GFP(+) BMDCs from C57B1/6 Tg (UBC GFP) mice Four weeks after transplantation we assessed the population of GFP(+) BMDCs in the CBLB Only small numbers of GFP(+) BMDCs were found to infiltrate the area of the CBLB in the control recipient mice However robust GFP(+) BMDC migration occurred in the area of the CBLB within the Injured cochlea during the first week following acoustic trauma and further BMDC accumulation was seen by 2 weeks posttrauma After 4 weeks the BMDCs were integrated into vessels Local iNOS from perivascular resident macrophages was found to be important for BMDC infiltration since mice deficient in iNOS (Inos(-/-)) and mice with iNOS that had been inhibited by 1400W displayed reduced BMDC infiltration Stromal cell derived factor 1 alpha (SDF 1 alpha) and its chemokine receptor 4 (CXCR4) were required for the iNOS triggered recruitment BMDC recruitment was significantly reduced by the inhibition of SDF 1 alpha activity Inhibition of the iNOS/SDF 1 alpha signaling path way reduced vascular repair as observed by reduced vascular density Our study revealed an intrinsic signaling pathway of iNOS that mediates SDF 1 alpha to promote GFP(+) BMDC infiltration/targeting in cochlear vascular repair (Am J Pathol 2010 177 3089-3099 DOI 10 2353/ajpath 2010 100340)