Antiinflammatory Effects of Budesonide in Human Fetal Lung

Abstract

Lung inflammation in premature infants contributes to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease with long-term sequelae. Pilot studies administering budesonide suspended in surfactant have found reduced BPD without the apparent adverse effects that occur with systemic dexamethasone therapy. Our objective was to determine budesonide potency, stability, and antiinflammatory effects in human fetal lung. We cultured explants of second-trimester fetal lung with budesonide or dexamethasone and used microscopy, immunoassays, RNA sequencing, liquid chromatography/tandem mass spectrometry, and pulsating bubble surfactometry. Budesonide suppressed secreted chemokines IL-8 and CCL2 (MCP-1) within 4 hours, reaching a 90% decrease at 12 hours, which was fully reversed 72 hours after removal of the steroid. Half-maximal effects occurred at 0.04-0.05 nM, representing a fivefold greater potency than for dexamethasone. Budesonide significantly induced 3.6% and repressed 2.8% of 14,500 sequenced mRNAs by 1.6-to 95-fold, including 119 genes that contribute to the glucocorticoid inflammatory transcriptome; some are known targets of nuclear factor-kB. By global proteomics, 22 secreted inflammatory proteins were hormonally regulated. Two glucocorticoid-regulated genes of interest because of their association with lung disease are CHI3L1 and IL1RL1. Budesonide retained activity in the presence of surfactant and did not alter its surface properties. There was some formation of palmitate-budesonide in lung tissue but no detectable metabolism to inactive 16a-hydroxy prednisolone. We concluded that budesonide is a potent and stable antiinflammatory glucocorticoid in human fetal lung in vitro, supporting a beneficial antiinflammatory response to lung-targeted budesonide:surfactant treatment of infants for the prevention of BPD.

Ancestry and Genetic Associations with Bronchopulmonary Dysplasia in Preterm Infants

“…Pathway analysis using Ingenuity Pathway Analysis (IPA) of 181 genes with gene-based p-values < 0.01 of 209 canonical pathways identified two with a significant enrichment of genes following a Bonferroni correction: agranulocyte adhesion and diapedesis (p=3.06x10 −5 ) and granulocyte adhesion and diapedesis (p=1.22x10 −4 ); genes in these two pathways are identical except for MYL9 (Table 7). With the exception of CLDN17 , all genes identified in these pathways are expressed in human fetal lung (12).…”

“…Lastly, in addition to ligand inhibition of BMP, DAN family members are known to modulate wnt and VEGF signaling pathways that have a role in lung development and injury/repair (48). Overall, there is strong biological plausibility for a role of genetic variation in NBL1 and respiratory outcome in iNO-treated infants based on 1) the critical role of BMP signaling in lung development and disease, 2) the mediation of BMP action via NO, 3) the expression of NBL1 and BMPs in human fetal lung (35), and 4) the racial differences in BPD and NO metabolism (12).…”

“…We found a significant association with genetic variation in a single gene - CCL18 , a cytokine involved in the immune response that promotes collagen production in lung fibroblasts (43) and is associated with pulmonary fibrosis and interstitial lung diseases in adults (51, 66). Inflammation is known to be important in the pathogenesis of BPD, and anti-inflammatory therapy (dexamethasone) suppresses a variety of inflammatory mediators, including CCL18, and reduces BPD (12, 26). Second, because all infants in the study received iNO, we hypothesized that variation in genes in the NO pathway may contribute to differential response to iNO treatment as indicated by survival without BPD.…”

“…For selected genes of interest, mRNA expression levels were obtained from a previous study that performed RNAseq on 3 specimens of human fetal lung of 23 wk gestational age (Gene Expression Omnibus, accession number GSE83888) (12).…”

Actividad anti-inflamatoria de compuestos sesquiterpénicos aislados de Psacalium decompositum (Gray) Rob. and Brett. en modelo de TPA y en la línea celular de macrófagos RAW 264.7

“…El sistema inmunológico de los vertebrados consiste en una serie de órganos y tejidos constituido por diferentes tipos celulares que tienen como función específica reconocer agentes externos y eliminarlos (Barrette AM1 2016).…”