An article by Kobayashi et al. (2010) in a recent issue of The Journal of Physiology presents exciting new data demonstrating that inflammatory mediators weaken the amniotic membrane barrier through disruption of tight junctions. The authors used pregnant mice treated with either intraperitoneal lipopolysaccharide (LPS) or intraamniotic interleukin-6 (IL-6) or tumour necrosis factor-α (TNFα). In addition, amniotic membrane organ culture responses were studied following exposure to pro-inflammatory cytokines. Using a variety of methods, the authors demonstrated that the amniotic barrier is weakened in response to the inflammatory milieu. Transepithelial resistance decreased and fluorescein transport increased across the amniotic membranes following intraperitoneal LPS or intra-amniotic IL6 and TNFα injection. When examining the mechanisms for reduced barrier function, the authors quantified decreases in claudin-3 and claudin-4 levels as well as the localization of claudin at the critical apical junction. In addition, the authors demonstrated that TNFα induced apoptosis of the amniotic epithelial cells, itself representing a mechanism for markedly reduced barrier function.
The findings of this paper have important implications from clinical and research perspectives. The amniochorion is recognized as a leaky structure with extremely low transepithelial potential and high conductance. However, there are marked differences between the amniotic layer, which appears to be a more effective diffusional barrier, and the overlying chorionic membrane. Nevertheless, the properties of both membranes are critical for the maintenance of the amniotic fluid environment. A reduction in chorioamniotic membrane barrier function may potentially predispose to bacterial invasion, exposure to vaginal ligands, or gross rupture of the amniotic fluid. Under clinical conditions, presumed inflammation of the chorion may result in a collection of fluid between the presenting amnionic and chorionic membranes. Spontaneous or induced rupture of the chorionic membrane may result in the impression of ruptured membranes, though the amnion may remain intact for a period of time. This clinical scenario may be explained in part by the authors’ results. Vaginal bacteria-induced inflammation of the chorion and ultimately the amnion may result in a loss of amnion barrier function and fluid extravasation into the chorioamniotic space. Ultimately, chorioamnion apoptosis may predispose to both amnion and chorion rupture.
The authors’ results suggest that maternal systemic inflammation (induced by LPS) may reduce amniotic barrier function through a process similar to that induced by direct intraamniotic cytokine injection. Studies by our laboratory and others (Gayle et al. 2004; Beloosesky et al. 2006) demonstrate that intraperitoneal LPS induces an increase in amniotic fluid cytokine concentrations. Together these results suggest that maternal systemic inflammation may predispose to weakened chorioamniotic membranes and premature ruptured membranes via mechanisms other than stimulated preterm uterine contractions. These findings may provide further impetus to the use of anti-inflammatory agents (Beloosesky et al. 2006) for maternal systemic inflammation during pregnancy.
As the authors examined only amniotic membrane, it would be of additional value to compare the results of amnion vs. chorion, as well as to correlate intraperitoneal LPS responses with measures of intraamniotic cytokines. The roles of claudin and induced apoptosis offer the opportunity for additional prophylactic or therapeutic modalities to assure an intact chorioamniotic membrane until the parturition.