Mice Deficient in Surfactant Protein A (SP-A) and SP-D or in TLR2 Manifest Delayed Parturition and Decreased Expression of Inflammatory and Contractile Genes

Previously we obtained compelling evidence that the fetus provides a critical signal for the initiation of term labor through developmental induction of surfactant protein (SP)-A expression by the fetal lung and secretion into amniotic fluid (AF). We proposed that interactions of AF macrophage( M phi) Toll-like receptors (TLRs) with SP-A, at term, or bacterial components, at preterm, result in their activation and migration to the pregnant uterus. Herein the timing of labor in wild-type (WT) C57BL/6 mice was compared with mice homozygous null for TLR2, SP-A, SP-D, or doubly deficient in SP-A and SP-D. Interestingly, TLR2(-/-) females manifested a significant (P < 0.001) delay in timing of labor compared with WT as well as reduced expression of the myometrial contraction associated protein (CAP) gene, connexin-43, and M phi marker, F4/80, at 18.5 d postcoitum (dpc). Whereas in first pregnancies, SP-A(-/-), SP-D-/-, and SP-A/D-/- females delivered at term (similar to 19.5 dpc), in second pregnancies, parturition was delayed by approximately 12 h in SP-A(-/-) (P = 0.07) and in SP-A/D-/- (P <0.001) females. Myometrium of SP-A/D-/- females expressed significantly lower levels of IL-1 beta, IL-6, and CAP genes, connexin-43, and oxytocin receptor at 18.5 dpc compared with WT. F4/80(+) AF M phi s from TLR2(-/-) and SP-A/D-/- mice expressed significantly lower levels of both proinflammatory and antiinflammatory activation markers (e. g. IL-1 beta, IL-6, ARG1, YM1) compared with gestation-matched WT AF M phi s. These novel findings suggest that the pulmonary collectins acting via TLR2 serve a modulatory role in the timing of labor; their relative impact may be dependent on parity. (Endocrinology 154: 483-498, 2013)