Effects Of Inhaled Corticosteroids On Lung Morphogenesis, IGFBP-2and IGF-1/PI3K Pathway In Neonatal Rats

ObjectiveTo explore the impact of long-term postnatal inhaled corticosteroids (ICSs) onearly lung development. To investigate the effects of ICSs on lung morphogenesis,the expression of insulin-like growth factor binding protein2(IGFBP-2), andIGF-1/PI3K cell signal pathway in lung tissue.Methods64neonatal rats were randomly assigned4groups: control group (nebulizedsaline), low-dose budesonide group, medium-dose budesonide group, high-dosebudesonide group (nebulized budesonide). Treatment began at5day of age andcontinued for1-wk/2-wk period. At the end of treatment, body weight and lungindex were investigated. Alveolar counts, alveolar septum thickness and alveolarspace as morphologic markers were used to evaluate alveolar development. Realtime Quantitative PCR was used to detect the mRNA level of IGF-1in the lungtissue. The expression of IGFBP-2and downstream proteins of IGF-1/PI3K cellsignal pathway was detected by western blot (WB).Results1) effects of glucocorticoids exposure on lung index: lung index was significantlydecreased in high-dose BUD group after1-wk exposure (P<0.01), and it was alsodecreased in medium-dose/high-dose groups after2-wk treatment (P<0.05, P<0.01respectively).2) effects of glucocorticoids exposure on postnatal lung development: The total number of alveoli was dramatically reduced in high-dose BUD groups after1-wktreatment (p<0.01), medium-dose/high-dose groups after2-wk treatment(p<0.01), and low-dose group after2-wk treatment (p<0.05) when comparedwith control. Alveolar space increased in those groups (P<0.05). The alveolar wallof high-dose BUD groups after1-wk treatment was thinner than CONT group(P<0.01); However, no significant differences about the thickness of alveolar wallwere investigated in the four groups after2-wk exposure (P>0.05).3) IGF-1: The mRNA level of IGF-1in lung tissue of high-dose BUD groupsincreased after1-wk or2-wk treatment when compared with CONT group(P<0.01). After2-wk treatment, IGF-1significantly increased in medium-doseBUD group (P<0.01).4) IGFBP-2: The expression of IGFBP-2in lung tissue of the two high-dose BUDgroups significantly increased compared with CONT group detected by WB(P<0.05). After2-wk treatment, IGFBP-2overexpressed in medium-dose BUDgroup (P<0.05).5) AKT/m-TOR: The downstream proteins of IGF-1/PI3K pathway weresignificantly increased in the high-dose BUD groups for1-wk/2-wk treatment(P<0.01). After2-wk exposure, IGF-1/PI3K pathway was enhanced in themedium-dose BUD groups. No significant differences about downstream proteinsof IGF-1/PI3K pathway were investigated in low-dose groups (P>0.05).Conclusion1) Long-term inhaled budesonide had no significantly adverse effect on the wholebody growth on neonatal rats, except for retardation on lung growth.2) Because of failure forming of secondary septa, long-term inhaled budesonideaffected postnatal lung development and led to a simple structural of lung.3) Long-term inhaled higher dose BUD induced the overexpression of IGFBP-2and IGF-1in lung tissue, and the upregulated activities of PI3K/AKT/mTOR in lungtissue. Those changes were likely to associate with the altered parenchymalstructure.