Pathogenesis of Bronchopulmonary Dysplasia: The Role of Interleuken 1β in the Regulation of Inflammation-Mediated Pulmonary Retinoic Acid Pathways in Transgenic Mice

Background

Pulmonary inflammation, increased production of the inflammatory cytokine interleukin-1β (IL-1β), and vitamin A deficiency are risk factors for the development of bronchopulmonary dysplasia (BPD) in premature infants. To determine the mechanisms by which IL-1β influences lung development, we have generated transgenic mice in which human IL-1β is expressed in the lung epithelium with a doxycycline-inducible system controlled by the Clara cell secretory protein promoter. Perinatal IL-1β production in these mice causes a phenotype that is strikingly similar to BPD. Pulmonary pathology in the mice shows inflammation, lack of alveolar septation, and impaired vascular development of the lung, similar to the histological characteristics of BPD. Retinoic acid (RA), one of the most biologically active derivatives of vitamin A, increases septation. Proteins involved in mediating the cellular responses to RA include the cellular retinoic acid binding proteins CRABP-I and CRABP-II and the nuclear retinoic acid receptors RAR-α, RAR-β, and RAR-γ.

Objective

To test the hypothesis that IL-1β inhibits the expression of proteins involved in mediating the cellular response to RA.

Methods

The mRNA expression of CRABP-I, CRABP-II, RAR-α1, RAR-β2, RAR-β4, and RAR-γ2 was studied with real-time RT-PCR on gestational day 18, and postnatal days 0, 1, 5, and 7 in IL-1β-expressing mice and their control littermates. In addition, immunohistochemistry for CRABP-I was performed.

Results

IL-1β decreased the mRNA expression and protein production of CRABP-I as well as the mRNA expression of RAR-γ2. In contrast, no differences between IL-1β-expressing and control mice were detected in the expression of CRABP-II, RAR-α1, RAR-β2, or RAR-β4.

Conclusion

The present study demonstrates for the first time a link between inflammation and the retinoic acid pathway. Inhibition of CRABP-I and RAR-γ2 expression may be one mechanism by which inflammation prevents alveolar septation. The therapeutic potential of RA in promoting septation in the setting of perinatal lung inflammation deserves further investigation.

Keywords:  cytokine , inflammation , retinoic acid , lung development , interleukin-1 , bronchopulmonary dysplasia