Pathogenesis of bronchopulmonary dysplasia: the role of interleukin 1beta in the regulation of inflammation-mediated pulmonary retinoic acid pathways in transgenic mice.
BACKGROUND
Pulmonary inflammation, increased production of the inflammatory cytokine interleukin-1beta (IL-1beta), and vitamin A deficiency are risk factors for the development of bronchopulmonary dysplasia (BPD) in premature infants. To determine the mechanisms by which IL-1beta influences lung development, we have generated transgenic mice in which human IL-1beta is expressed in the lung epithelium with a doxycycline-inducible system controlled by the Clara cell secretory protein promoter. Perinatal IL-1beta 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-alpha, RAR-beta, and RAR-gamma.


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


METHODS
The mRNA expression of CRABP-I, CRABP-II, RAR-alpha1, RAR-beta2, RAR-beta4, and RAR-gamma2 was studied with real-time RT-PCR on gestational day 18, and postnatal days 0, 1, 5, and 7 in IL-1beta-expressing mice and their control littermates. In addition, immunohistochemistry for CRABP-I was performed.


RESULTS
IL-1beta decreased the mRNA expression and protein production of CRABP-I as well as the mRNA expression of RAR-gamma2. In contrast, no differences between IL-1beta-expressing and control mice were detected in the expression of CRABP-II, RAR-alpha1, RAR-beta2, or RAR-beta4.


CONCLUSIONS
The present study demonstrates for the first time a link between inflammation and the retinoic acid pathway. Inhibition of CRABP-I and RAR-gamma2 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.
Bry
Kristina
K
Department of Pediatrics, Göteborg University, The Queen Silvia Children's Hospital, 41685 Göteborg, Sweden. kristina.bry@pediat.gu.se
Lappalainen
Urpo
U
D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000378:metabolism*
D007375:Interleukin-1; D014212:Tretinoin