To our knowledge, this is the first study to describe an association between serum periostin levels at birth and perinatal factors in preterm and term infants and the correlation between serum periostin levels at birth and BPD. The present study revealed that higher serum periostin levels at birth in preterm infants born at less than 32 week’s gestational age are independent risk factors for BPD and reflects the severity for BPD. Although there are many studies trying to demonstrate an association between serum biomarkers and the risk of BPD, few suggest a correlation between blood periostin levels and BPD. In this study, we also demonstrated that serum periostin levels on DOL28 and corrected 36 week’s postmenstrual age could not serve as potential biomarkers for BPD. Ahlfeld et al previously suggested that early elevation of plasma periostin on DOL28 is significantly associated with chronic ventilator-dependent bronchopulmonary dysplasia (15). This may be due to the differences in the type of sample, sample size, and method of analysis. Ahlfeld’s study used plasma samples and did not include multivariate or measure periostin levels at birth. In terms of the relationship between periostin and lung disease, previous studies demonstrated that elevated serum periostin levels were associated with various lung disease such as asthma, idiopathic pulmonary fibrosis, and COPD in children and adults (5, 8, 23, 24). Furthermore, the expression of lung periostin was upregulated in patients with idiopathic lung fibrosis (8, 11). Bozyk et al. also reported that periostin expression increased in autopsy lungs of preterm neonates with BPD (14). In a murine model of BPD exposed to hyperoxia, hyperoxia upregulated periostin expression in neonatal mice lung (14). Furthermore, lung periostin levels were also increased during the saccular stage, as previously shown (25). Although the mechanism by which periostin is associated with the pathogenesis of BPD remains poorly understood, we speculate that the linkage of periostin and TGF- β might be associated with the pathogenesis of BPD. Periostin and TGF-β are known to play a critical role in the proliferation of lung fibroblasts (9). Furthermore, many studies in different animal models of BPD confirm elevated TGF-β expression levels and activation of its associated pathways as an important part of lung disease pathophysiology (22, 26, 27). Also, we previously reported that serum TGF-β levels were upregulated in BPD patients (28).
Another new finding in this study was significant correlation of serum periostin levels at birth with BW and GA. Fujitani et al. reported that periostin levels in non-allergic children from 0 years to 15 years were almost 91.9-124.8 ng/mL (29). They also suggested that serum periostin levels gradually increased after age 10 years. Anderson et al also reported that serum periostin levels at ages 2–6 years ranged from 120–150 ng/mL (16). In this study, serum periostin levels of healthy neonates were around 140 ng/mL. Furthermore, serum periostin levels at birth in neonates born at less than 32 week’s gestational age was almost 340 ng/mL. On the other hand, a previous study proposed a periostin threshold of 95 ng/mL based on values from healthy adult controls (30). Thus, serum periostin levels in infants were the highest when comparing infants, children, and adult. These developmental changes of serum periostin levels may be related to metabolic turnover and growth as periostin is a component of the extracellular matrix and regulates serum type I collagen formation, which is essential component of skin, tendon, and bone development (16, 31). Compared with term infants, the cord blood serum procollagen type I C-terminal propeptide (PICP) as bone information in preterm infants was significantly higher and influenced by fetal age (32).
Our study has several limitations. First, it was performed at a single center and the sample size of BPD patients was small. To validate our observations, a larger sample size with multiple centers and different ethnic cohorts would be invaluable. Second, we could not evaluate lung periostin. A previous study demonstrated that lung periostin in BPD infants was higher than in healthy lungs at term (9). Third, we could not detect the cellular sources of periostin. Thus, our next goal is to determine the cell types secreting periostin as well as the mechanism(s) of upregulation of periostin in BPD neonates; this will advance understanding of the pathogenesis of BPD. Lastly, in this study, we did not investigate the correlation between periostin levels and Th2 cytokines such as IL-4 and IL-13. It is noteworthy that upon stimulation by IL-4 and IL-13, periostin could be detected in lung fibroblasts (2). One of the main consequences of BPD is lung fibrosis. Although a previous study suggested that IL-4 and IL-13 levels of tracheal aspirates from premature infants were very low and did not correlate with BPD (29), premature infants born at less than 32 week’s gestational age have increased nasal airway IL-4 and IL-13 secretion during rhinovirus infections (30).
In summary, we conclude that serum periostin levels were significantly correlated with birth weight and gestational age. Furthermore, serum periostin levels at birth could serve as a biomarker for predicting BPD and severity of BPD. The mechanism by which serum periostin is upregulated in BPD infants and inversely correlated with gestational age and birth weight remains to be further elucidated.