Theophylline improves lipopolysaccharide-induced alveolarization arrest through inflammatory regulation

Abstract

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‑α, macrophage inflammatory protein (MIP)-1α and MIP-2, and markedly elevated the production of tumor growth factor (TGF)-β family members TGF-β1, TGF-β2 and TGF-β3, 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.

A new target for caffeine in the developing lung: endoplasmic reticulum stress?

“…Among the reports from the "pro-caffeine lobby" are observations that caffeine administration to neonatal rats blunted the lung inflammation that was provoked by hyperoxia (38) and that caffeine administration to preterm rabbits limited the damaging effects of hyperoxia on lung alveolarization, ostensibly also by blunting hyperoxia-provoked inflammation (23). When intra-amniotic bacterial lipopolysaccharide (LPS) was used to mimic chorioamnionitis in pregnant rats, leading to arrested lung alveolarization in offspring, the administration of caffeine (20) or the related methylxanthine theophylline (17,26), appreciably attenuated the blunted alveolarization, most likely by limiting inflammation. The utility of theophylline to attenuate arrested lung alveolarization in rats caused by hyperoxia exposure has also been demonstrated, also by limiting inflammation (40).…”

“…Numbers in parenthesis indicate the relevant citations. Asterisk indicates citation group (8,17,20,26,35,38,40). AEC, alveolar epithelial cell; TGF, transforming growth factor.…”

Neurodevelopmental Outcomes in Very Low Birth Weight Infants Using Aminophylline for the Treatment of Apnea

“…25 He H et al have also proposed that theophylline may protect against BPD by regulating the balance between pro-and anti-inflammatory cytokine expression. 24 Our results showed that the rate of BPD was significantly higher in the M A N U S C R I P T…”

“…The pathologic changes in BPD result in increased airway resistance, 23 decreased number of alveoli, and increased airspace. 24 Anthony et al have suggested that theophylline may play a role in decreasing airway resistance, increasing dynamics compliance and shortening duration of ventilator weaning of infants less than 30 days old age with BPD. 25 He H et al have also proposed that theophylline may protect against BPD by regulating the balance between pro-and anti-inflammatory cytokine expression.…”

“…Aminophylline treatment is thought to be a therapeutic strategy for AOP and BPD. 23,24,26 Considering this, we speculated that the high percentage of BPD in the aminophylline group was because these infants had more severe and longer AOP, and consequently they needed longer NCPAP support combined with aminophylline treatment to prevent hypoxic insult to the brain. According to our NICU policy, NCPAP and aminophylline for the treatment of AOP are preferable to a high oxygen concentration supplement.…”