42 IL-1 Decreases The Production of Cellular Retinoic Acid Binding Protein-I (Crabp-I) in The Lungs of Transgenic Mice: A Possible Link Between Inflammation and The Retinoic Acid Pathway in The Pathogenesis of Bronchopulmonary Dysplasia (BPD)

Abstract

Background: Pulmonary inflammation, increased production of the inflammatory cytokine IL-1, and vitamin A deficiency are associated with the development of BPD. In order to determine the mechanisms by which IL-1 influences lung development, we have developed a transgenic mouse overexpressing IL-1 in the lung epithelium in an externally regulatable manner. Lung histology of these mice after perinatal induction of IL-1 production shows impaired alveolar and 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. We hypothesized that a mechanism by which IL-1 decreases septation, is inhibition of RA action. Cellular retinoic acid binding protein I (CRABP-I) is an intracellular protein that binds RA with high affinity. Lack of CRABP-I results in decreased intracellular RA concentrations when the extracellular RA level is low. OBJECTIVE: To study CRABP-I mRNA expression and protein production in the lungs of fetal and newborn IL-1 overexpressing mice and their wild-type littermates.

Methods: IL-1 expression was induced in transgenic fetuses and newborns. Nontransgenic littermates were used as controls. CRABP-I mRNA expression was studied with real-time RT-PCR on Ed 18, and postnatal days 0, 5 and 9. Immunohistochemistry for CRABP-I was performed using a monoclonal antibody (Abcam).

Results: In control mice, CRABP-I mRNA expression and protein production increased at the beginning of alveolarization, reaching a maximum on postnatal day 9 (Table, arbitrary units). In contrast, in IL-1 overexpressing mice, the CRABP-I mRNA levels remained low. Immunohistochemistry for CRABP-I showed presence of CRABP-I protein in alveolar septae. Immunostaining was weaker in IL-1-overexpressing mice than in controls.

Table 1

Conclusion: During alveolarization, CRABP-I production increases in the lungs of wild-type mice. This increase fails to occur in mice overexpressing IL-1. Decreased production of CRABP-I may be a mechanism by which inflammation inhibits alveolar septation. Lack of CRABP-I limits intracellular availability of RA when extracellular RA levels are low. Thus, inhibition of CRABP-I by IL-1 may be of particular importance in vitamin A deficiency, which is common in premature newborns. The present results suggest a possible link between inflammation and the RA pathway in the pathogenesis of BPD. Whether RA treatment improves alveolar development in the inflamed lung remains to be studied.

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