Theophylline improves lipopolysaccharide-induced alveolarization arrest through inflammatory regulation

Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased numbers of alveoli and increased airspace. BPD, frequently suffered by very low birth weight infants, has been closely associated with intrauterine infection. However, the underlying mechanisms of BPD remain unclear. In the present study, it was identified that administration of intra-amniotic lipopolysaccharide (LPS) to pregnant rats on embryonal day 16.5 (E16.5) induced significant alveolarization arrest similar to that of BPD in neonatal pups, and theophylline injected subcutaneously into the newborns improved the pathological changes. To further investigate the underlying mechanism of the morphogenesis amelioration of theophylline, cytokine antibody arrays were performed with the lung lysates of neonatal rats. The results indicated that LPS upregulated a series of pro-inflammatory cytokines and theophylline significantly attenuated the expression levels of pro-inflammatory cytokines tumor necrosis factor-a, macrophage inflammatory protein (MIP)-1 alpha and MIP-2, and markedly elevated the production of tumor growth factor (TGF)-beta family members TGF-beta 1, TGF-beta 2 and TGF-beta 3, which are anti-inflammatory cytokines. Accordingly, it was hypothesized that theophylline may protect against BPD and improve chorioamnionitis-induced alveolar arrest by regulating the balance between pro-and anti-inflammatory cytokine expression.