Abstract:

Objective To investigate the role of theophylline on amelioration of chorioamnionitis-induced alveolar arrest, and explore the potential mechanism. Methods Chorioamnionitis was induced by intra-amniotic injection of lipopolysaccharides (LPS) in SD rats (E16.5), and the same amount of normal saline was intra-amniotically injected in control SD pregnant mice (E16.5). Pups of same litter with intra-amniotic injection of LPS were randomly divided into LPS+theo group and LPS+saline group. In LPS+theo group, pups were injected subcutaneously in the neck with theophylline once a day until the seventh day, and the same amount of normal saline instead in LPS+saline group. Pups with intra-amniotic injection of normal saline obtained identical postnatal treatment as LPS+saline group, which was defined as control group. Seven days after treatment, the lungs of neonatal rats were harvested, sections with HE staining and cytokine antibody arrays were prepared, the pathological changes of lung tissues were observed, and the expression of inflammatory cytokines was determined. Results Histopathological examination revealed that the alveolar counts and secondary septa counts in LPS+saline group were significantly smaller than those in control group (P<0.05), and the alveolar counts and secondary septa counts in LPS +theo group were significantly larger than those in LPS+saline group (P<0.05). The detection of antibody arrays indicated that the expression of inflammatory cytokines such as interferon γ (IFN-γ), interleukin (IL)-α, IL-6 and chemokine receptor type 4 (CXCR4) in lung tissues of neonatal rats in LPS+saline group was higher than that in control group, the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), macrophage inflammatory protein (MIP)-1α and MIP-2 in LPS+theo group was significantly lower than that in LPS+saline group (decreased by 37.4 times, 12.5 times and 8.6 times respectively), and the expression of anti-inflammatory cytokines such as transforming growth factor (TGF)-β1, TGF-β2 and TGF-β3 in LPS+theo group was significantly higher than that in LPS+saline group (increased by 2.4 times, 56.9 times and 17.8 times respectively). Conclusion Theophylline can inhibit the expression of pro-inflammatory cytokines, increase the expression of anti-inflammatory cytokines, and relieve alveolar arrest through regulating the balance between pro- and anti-inflammatory cytokines. Theophylline may play a role in the amelioration of chorioamnionitis-induced bronchopulmonary dysplasia.

Key words: bronchopulmonary dysplasia, theophylline, chorioamnionitis, inflammation