Major complications during pregnancy include preterm birth (PTB) and preeclampsia. PTB affects more than 15 million babies worldwide and results in more than 1 million newborn deaths and complications of survivors. Despite vast improvement in the care of preterm infants in recent decades, an effective drug for prevention and treatment of PTB has yet to be identified.

PTB is a multifactorial condition with a number of risk factors including previous PTB, uteroplacental ischemia, uterine overdistension, cervical disorders, and maternal stress. However, intrauterine infection and inflammation have been established as major risk factors of PTB and in a number of adverse neonatal outcomes such as neonatal brain injury.

Cytokines and chemokines are known to be involved in both the physiological and the pathological processes of inflammation. Cytokines have also been shown to be involved in the physiology or pathophysiology of ovulation, implantation, placental function, parturition, and cervical ripening. Many studies of cytokine expression have used lipopolysaccharide (LPS), an endotoxin of Gram-negative bacterial cell walls, treatments to demonstrate inflammatory systems associated with preterm birth or preeclampsia.

Administration of LPS activates the maternal innate immune system by binding to pattern recognition receptors such as Toll-like receptors (TLRs). Activation of TLRs by LPS increases the production of arrays of proinflammatory cytokines and chemokines. These cytokines and chemokines recruit neutrophils and macrophages to the maternal-fetal interface and increase the production of downstream mediators in the uterus, placenta, and fetal tissues. The most important mediators of the effects of cytokines are prostaglandins and matrix metalloproteases, which result in uterine contraction, cervical ripening, rupture of membrane, and detachment of the placenta, leading to a normal physiological birth. Excessive inflammatory responses produced by LPS application or infection result in PTB or affect fetal perfusion and maternal problems associated with preeclampsia and contribute to various other short- and long-term fetal morbidities.

Recently the concept of a cholinergic or nicotinic antiinflammatory pathway has emerged as a system that contributes both to physiological and pathological regulation of cytokines. The key features of this pathway are that acetylcholine from the nervous system, principally the vagus nerve or other nonneural systems, inhibits cytokine release from immune cells, primarily macrophages, and thereby control inflammatory responses. Similarly, LPS or products of infection stimulate the cytokine cascade, and this activation is suppressed by acetylcholine or nicotine.

Acetylcholine and nicotine are thought to bind to specific acetylcholine receptors on macrophages to suppress cytokine production. Because cytokines are known to be involved in almost all steps in female reproduction including ovulation, implantation, placentation, placental blood flow, fetal development, cervical ripening, and parturition, this pathway is of particular importance to the physiological regulation of these steps. In addition, because infection and inflammation are thought to involve cytokine activation and synthesis during premature birth and preeclampsia, the presence of this pathway is very significant to an understanding of these conditions during pregnancy.

Nicotine, a constituent of cigarettes, which are a major health concern, interacts with a specific nicotinic receptor (α7 nicotinic acetylcholine receptor [α7 nAChR]) to exert systemic antiinflammatory effects. Nicotine has been demonstrated to attenuate the inflammatory response during experimental endotoxemia in rodents by decreasing proinflammatory cytokines release and leukocyte migration and recruitment. Many studies have shown that the cholinergic antiinflammatory pathway may be involved in a variety of medical conditions. Other studies have shown that treatment with nicotine initiated after the onset of sepsis showed decreased serum high-mobility group box 1 levels and better survival in an experimental mouse model of sepsis.

The antiinflammatory pathway has also been targeted in clinical trials for the treatments of inflammatory disorders such as Crohn’s disease and ulcerative colitis, but the pathway and effects of nicotine have not been studied in relationship to physiological or pathological steps involved in female reproduction.

Recently, we observed that nicotine treatment partially blocked cervical ripening, a process known to involve inflammatory pathways and marginally prolonged gestation in pregnant rats, but nicotine had no effect on fetal numbers or pup birthweights. We attributed this to the antiinflammatory effects of nicotine. Based on the observations that nicotine attenuates inflammatory disease and has a key role in inhibition of inflammation, it is reasonable to anticipate that nicotine or other α7 nAChR agonists may have some therapeutic benefits for complications of pregnancy including PTB. To test this hypothesis, we investigated the effects on the inflammatory responses induced by LPS administration in rats during pregnancy.