Inhibition of Cxcr 1 and 2 Delays Preterm Delivery and Reduces Neonatal Mortality in a Mouse Model of Chorioamnionitis

Abstract

Intrauterine infection is one of the main etiologies associated with preterm delivery. Cytokines involved in chorioamnionitis, including IL-1, TNF-α, IL-6, IL-8, and MCP1, activate different pathways that lead to preterm delivery. Antileukinate (AL) is a potent selective IL-8 inhibitor that binds to CXC receptors 1&2 on neutrophils, thereby inhibiting IL-8-induced neutrophil chemotaxis and degranulation. Since CXC receptors 1&2 are critically involved in the pathology of chorioamnionitis, their inhibition with AL may have therapeutic potential. Four timed-pregnant C57BL6 mice groups were studied. LPS group received LPS intraperitoneally on gestational day (GD) 15. The AL group received LPS on GD15 followed immediately by intraperitoneal AL injection and repeated on GD16, and 17. Control groups received either saline, or no injections. In the LPS group, 90% delivered within 24 hours after LPS administration compared to 20% in the AL group. The LPS group had 85% stillborn compared to 15% in the AL group. Uterine histopathology AL group showed evidence of less inflammatory reaction compared to the LPS group. Uterine tissue and serum from the AL group had a significant reduction of inflammatory cytokines compared with the LPS group. Cytokine levels in brain and lung tissues from surviving pups were not significantly different between the AL and control groups. Our data show that antileukinate significantly delays preterm delivery in a mouse model of chorioamnionitis, and reduces neonatal mortality and morbidity.