One out of every eight babies in the United States is born prematurely, yet very little is known about the causes of preterm labor.1 One clue is that labor, both at term and preterm, is associated with an inflammatory response. Amniotic fluid (AF) levels of IL-1ß, IL-6, and TNF-a, as well as numerous other pro-inflammatory cytokines and chemokines, are elevated during labor.2 Further, it appears that in approximately one out of every three cases, preterm labor may be initiated by the development of a mild infection that induces an exaggerated inflammatory response.1,2 A second clue is that the initiating signal appears to come from the fetus.3-5 For example, it has been suggested that an amniotic fluid factor of fetal origin, perhaps surfactant, stimulates the amnion to release prostaglandin, which in turn elevates uterine contractility.3,4
A recent study by Condon et al. implicates surfactant protein A (SP-A) as the fetal factor that initiates labor.6 SP-A was first described over three decades ago as a major component of pulmonary surfactant. SP-A is a member of the collectin (collagenous C-type lectin) family and is composed of a carboxy-terminal C-type lectin domain, a collagen-like domain, and an amino-terminal domain. Individual monomers form trimers via a-helical coiled-coils and six trimers further assemble into octadecameric complexes via disulfide bonding between amino-terminal domain cysteine residues. SP-A also exhibits extensive post-translational modification including acetylation, glycosylation, hydroxylation, and sulfation.7 While SP-A participates in surfactant function and homeostasis, its major role is in host defense. SP-A binds a number of allergens as well as a variety of viruses, bacteria, fungi, and their components. SP-A then stimulates macrophages and neutrophils via toll-like receptors (TLRs) to initiate an inflammatory response.7
|Figure 1. Fetal lung surfactant protein A (SP-A) is first detectable in the amniotic fluid (AF) after approximately 80% of gestation is completed. Beginning at that time, levels rise dramatically until labor. SP-A binds toll-like receptors (TLRs) on AF macrophages and, via NF-?B, elicits an inflammatory response. Further, SP-A-stimulated AF macrophages migrate to the uterus and increase uterine contractility.|
During development, surfactant production does not begin until after approximately 80% of gestation is completed. However, accumulation of sufficient surfactant in the fetal lung is absolutely critical to neonatal survival, as respiratory distress syndrome is a primary cause of death among premature infants.8 Thus it is not surprising that a surfactant component may be involved in the mechanism of parturition. Condon et al. have described SP-A as a link between lung development and the timing of labor resulting from the ability of SP-A to initiate inflammation and promote uterine infiltration by AF macrophages. First, the researchers were able to induce preterm labor in 15 dpc mice by giving intraamniotic (i.a.) injections of SP-A. Next, they successfully elicited NF-?B and IL-1ß expression in SP-A-treated AF macrophages isolated from 15, 17, and 19 dpc mice. Further, Condon and coworkers were capable of significantly delaying the onset of labor by giving i.a. injections of SN50, an NF-k B peptide inhibitor. Finally, they observed a significant increase in the numbers of macrophages present in uterine tissue after i.a. SP-A injections, with at least some being of fetal origin.7 These data suggest a model (Figure 1) in which fetal lung SP-A reaches some critical threshold in the AF, stimulates AF macrophages via TLRs, and causes pro-inflammatory cytokine release and macrophage migration to the uterus. Further examination of this mechanism may lead to the development of better methods for prediction and prevention of preterm labor.