Periostin downregulation is an early marker of inhibited neonatal murine lung alveolar septation

Abstract

BACKGROUND Extreme preterm birth exposes the saccular lung to multiple teratogens, which ultimately retard alveolar development. Specifically, therapeutic high level oxygen supplementation adversely affects the premature lungs and results in blunted alveolarization. Prolonged hyperoxic lung injury has previously been shown to upregulate the matricellular protein Periostin (Postn) and stimulate ectopic accumulation of alpha smooth muscle actin (αSMA) myofibroblasts. Therapies that promote lung septation are lacking largely due to a lack of reliable early biomarkers of injury. Thus, we determined if Postn expression correlated with the initial appearance of myofibroblasts in the saccular lung and was required for early alveolar development. METHODS Lung development in C57BL/6J mice following room-air (RA, 21%-O2) or continu ous hyperoxia (85%-O2) from birth (P0) through postnatal day P14 was correlated with Postn and αSMA expression. Alveolarization in Postn knockout mice exposed to room-air, 60%-, and 85%-O2 was also examined. RESULTS Postn was widely expressed in distal lung septa through P2 to P4 and peak expression coincided with accumulation of saccular myofibroblasts. Initially, 85%-O2 prematurely downregulated Postn and αSMA expression and suppressed proliferation before the first evidence of distal lung simplification at P4. By P14, chronic 85%-O2 resulted in secondary upregulation of Postn and αSMA in blunted septa. Myofibroblast differentiation and alveolar development was unaffected in Postn null mice and acute 85%-O2 exposure equally inhibited septal formation in Postn null and wild-type littermates. CONCLUSION Postn expression is tightly correlated with the presence of αSMA-myofibroblasts and is a novel early biomarker of acutely inhibited alveolar septation during a crucial window of lung development.

Temporal, spatial, and phenotypical changes of PDGFRα expressing fibroblasts during late lung development

“…6K, Data in Brief Table 4). Persistence and overabundance of myofibroblasts in the alveolar interstitium, because of premature birth or perinatal hyperoxia exposure, is found in association with arrested alveolar septation in bronchopulmonary dysplasia (BPD) (Ahlfeld et al, 2013; Bozyk et al, 2012; Toti et al, 1997). Further analysis of Profile #18, which contains 66 genes that are uniquely upregulated on PN7, in combination with gene expression studies from BPD samples and other septation defects will provide valuable insight into the regulatory networks that result in fibroblast differentiation to smooth muscle cells or transient myofibroblasts.…”

Fetal lung transcriptome patterns in an ex vivo compression model of diaphragmatic hernia

“…Recently, investigators have shown that POSTN is widely expressed by mesenchymal cells during the saccular stage of lung development and is coincident with the accumulation of a-SMA myofibroblasts. 33 Studies have shown that POSTN may play an important role in normal alveolar septation and can function as a ligand for a v b 3 and a v b 5 integrins, thereby having pleiotropic effects in supporting adhesion and migration of epithelial cells. 34,35 Others have demonstrated that POSTN potentiates the effects of the TGF-b family of peptides, which are known to exert inhibitory effects on lung epithelial cell proliferation and to cause epithelial-tomesenchymal transition during terminal bud morphogenesis.…”

Increased Cardiac Output and Preserved Gas Exchange Despite Decreased Alveolar Surface Area in Rats Exposed to Neonatal Hyperoxia and Adult Hypoxia

“…After determination of DF CO , lungs were immediately inflation fixed. The left lung volume was determined by fluid displacement and then processed and stained for determination of mean linear intercept (Lm) and alveolar surface area (estimated as 4V/Lm), as previously described (17,22).…”