Abstract
BackgroundA precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization. The mechanisms controlling this balance are largely unknown, but recent evidence suggests that midkine (MK), a retinoic acid-regulated, pro-angiogenic growth factor, may function as a critical regulator. The purpose of this study was to examine regulation of MK by GC and RA during postnatal alveolar formation in rats.MethodsNewborn rats were treated with dexamethasone (DEX) and/or all-trans-retinoic acid (RA) during the first two weeks of life. Lung morphology was assessed by light microscopy and radial alveolar counts. MK mRNA and protein expression in response to different treatment were determined by Northern and Western blots. In addition, MK protein expression in cultured human alveolar type 2-like cells treated with DEX and RA was also determined.ResultsLung histology confirmed that DEX treatment inhibited and RA treatment stimulated alveolar formation, whereas concurrent administration of RA with DEX prevented the DEX effects. During normal development, MK expression was maximal during the period of alveolarization from postnatal day 5 (PN5) to PN15. DEX treatment of rat pups decreased, and RA treatment increased lung MK expression, whereas concurrent DEX+RA treatment prevented the DEX-induced decrease in MK expression. Using human alveolar type 2 (AT2)-like cells differentiated in culture, we confirmed that DEX and cAMP decreased, and RA increased MK expression.ConclusionWe conclude that MK is expressed by AT2 cells, and is differentially regulated by corticosteroid and retinoid treatment in a manner consistent with hormonal effects on alveolarization during postnatal lung development.
Highlights
A precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization
Dexamethasone and 8-bromo-cAMP were purchased from Sigma Chemical Company and 35S-methionine was purchased from Perkin-Elmer Inc. (Boston, MA)
Resolution of corticosteroid-induced changes in architecture was seen between PN10 and 15 in pups treated with concomitant DEX and retinoic acid (RA), such that, at PN15, the lungs displayed architecture similar to that of controls and Radial alveolar counts (RAC) were the same as controls (# p < 0.05 vs. DEX)
Summary
A precise balance exists between the actions of endogenous glucocorticoids (GC) and retinoids to promote normal lung development, in particular during alveolarization The mechanisms controlling this balance are largely unknown, but recent evidence suggests that midkine (MK), a retinoic acid-regulated, pro-angiogenic growth factor, may function as a critical regulator. The formation of alveoli involves mesenchymal thinning and the development of crests, or secondary septae, at precise sites of the saccular wall. These crests protrude into the saccular air space, include the inner layer of the capillary bilayer, and further subdivide the saccule into subsaccules that later become mature alveoli. DEXinduced changes are ameliorated in animals that receive concomitant DEX+RA administration [6]
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