BPD is a lung disease that causes dependence on oxygen supplementation for an extended period
of time, which is a common respiratory disease with a high mortality rate that affects premature infants. Survivors often leave behind repeated lower respiratory tract infections and growth retardation, which makes it a critical factor affecting the quality of life of premature infants. The risk factors for BPD suggested by previous studies include low gestational age, small birth weight, oxygen, respiratory support, nutrition and infection[13]. Recently, studies have also shown a close association between various cytokines and the occurrence and development of BPD in preterm infants.
In premature infants born at < 32 gestational weeks, alveoli formation begins and is incomplete, Tissue apoptosis and the accumulation and activation of inflammatory cells in the lungs due to various inflammatory cytokines are possible contributors to BPD[14].Results provided by the scarce studies carried out in infants support the evidence from previous animal experiments. IL-1β, IL-6, TNF-α, and IL-10 cytokine levels were altered in the amniotic fluid[15], core blood[16] and serum[6]were observed in BPD infants. In addition, studies showed pro-inflammatory cytokine (such as IL-6) activity in cord blood positively correlates with gestational age, whereas anti-inflammatory cytokine (such as IL-10 ) does not [17]. On the basis of previous studies[7], compared to non-BPD infants, some particular cytokine levels were upregulated in the first 28 days of life in BPD infants. In the study presented here, we further explored the correlation between the cytokine profile and FiO2 on day 28. Our results confirm the fact that during the first week of life, infants with BPD had significantly lower IL-10 levels. However, this inflammation is transient and no longer present on days 14–28. Instead, IL-4, IL-6, and IL-8 were increased in the BPD group on days 14–28. Which means Persistent lung inflammation, with an imbalance of pro-inflammatory versus anti-inflammatory mediators, plays a central role in the pathogenesis of BPD along with an arrest of lung growth.IL-6 and IL-8 are pro-inflammatory cytokines. IL-6 is secreted by macrophages, T cells and endothelial cells to stimulate the immune response, leading to the synthesis of a variety of inflammatory mediators, including neutrophils, and secreting a variety of inflammatory mediators to promote inflammation, thus causing airway remodeling. which is an independent risk factor for BPD in premature infants[18]. The biological function of IL-8 is to mediate neutrophil migration, development and aggravation of inflammatory responses. It has been hypothesized that elevated cord blood IL-8 is associated with death or moderate/severe BPD[16].
IL-10 is a potent anti-inflammatory cytokine, and an increasing number of studies have shown that IL-10 could be a protective factor against the development of BPD by reducing acute lung injury caused by mechanical stretching [19]. In addition, inhibiting the activation of nuclear transcription factor-κB (NF-κB) is secondary to hyperoxia injury [20]. In our research, the non-BPD group had higher IL-10 on days 2–7, and the difference between the two groups disappeared on days 14–28. This result may suggest that the protective effect of IL-10 decreased over time.
At the same time, the results of our study showed lower IL-13 on days 14–28 and higher IL-4 in the BPD group than in the non-BPD control group, which suggested that the increased expression of IL-4 may be involved in abnormal lung development and maturation in neonates with BPD and that IL-13 may play a protective role in the development of BPD. Even though IL-13 is associated with the development of bronchial hyperreactivity[21], but it also inhibits inflammatory cytokine production in macrophages andepithelial cells such as TNF-α, IL-6, IL-8 and IL-1β [22, 23] and upregulates the anti-inflammatory cytokine[24]. At the same time, the action of IL-4 was two-sided effects of lung inflammation, it may inhibits to some aspects of lung inflammation, furthermore, it may induces collagen production and proliferation of subsets of lung fibroblasts[25]. It has been clearly demonstrated that nutrition status influences immune cell function in previous research and that immune cell function determines the cellular metabolic state, and the role of cytokines as mediators of weight loss and anorexia or chronic liver disease has been previously proven in studies concerning malignancies, showing an apparent relationship between the levels of IL-6, IL-1 and TNF and neoplastic cachexia [26, 27]. Is it possible that nutritional status promotes the development of BPD by affecting cytokines? How do it contribute to bpd? Given the above, we attempted to assess the mediation effect of serum cytokines in the development of BPD from nutrition to explore the mechanism of BPD.
For very low birth weight (VLBW) and extremely low birth weight (ELBW) infants whose alveolar maturity mostly or completely occurs after birth, nutrition supply in the early postnatal period plays a crucial role in respiratory development[28, 29]. Regarding the association of nutritional support with the development of BPD described by our research, the BPD group had a significantly lower total energy and total protein intake than the non-BPD group within the first week after birth. Malnutrition interferes with pulmonary defenses against volutrauma and infection, all of which are harmful to lung repair, development and maturation. Early sufficient protein supply in premature infants can lower protein breakdown, promote improved protein balance, and increase protein synthesis[3, 30]. In a retrospective cohort study of BPD infants, it was found that an energy intake in the range of 120–150 kcal/kg/day and a minimum protein intake of at least 3.5 g/kg/day are needed in BPD infants[31].
Moreover, our results show that infants who survived without BPD had a significantly higher intake of enteral feed (including each ingredient and energy) and a lower parenteral intake than infants who developed BPD. In a prospective study, the same association identified that enteral nutrition can reduce the incidence of growth retardation in premature infants with BPD[32]. The start of enteral nutrition was delayed by the presence of hemodynamic or respiratory instability, which means that such infants may suffer from inflammation of the storm caused by infection, the lungs of shunt caused by PDA, or mechanical stretch caused by mechanical ventilation.
Our results showed dynamic changes in cytokines at different time points. Some cytokines (e.g.IL-4, IL-6, IL-8 and IL-13) showed no significant changes in the early stages but exhibited significant changes in the late stages in premature infants who received insufficient nutrition in the first week of life and subsequently developed BPD. From a comprehensive perspective of the results of the correlation study between cytokines and nutritional support, we supposed that early nutritional support influenced the development of BPD though IL-4, IL-6, IL-8 and IL-13. Then the role of inflammatory mediating effect in nutrition and BPD was further explored in our study. The results show that there is an intermediary relationship between total protein, enteral nutrition (including carbohydrates, energy and proteins) and FiO2 on day 28, which supports the idea that early protein and enteral nutrition deficiency can improve oxygen dependence on day 28 after birth and promote BPD by increasing proinflammatory mediators on days 14–28.
As shown in Table 1, the occurrence and development of BPD was involving various factors, such as birth weight and gestational age, and these characteristics make difference of complications, such as infections, PDA, mechanical Ventilation time and NRDS etc. (which can in turn affect the inflammatory status) in two group. These clinical complications of premature birth were complex processes involving multiple factors, and multi-stage interactions, in addition, some maternal factors could also affect the inflammatory state of the newborn (e.g. intrauterine infection), nutritional support was only accounts for a part of it. At that same time, nutrition support also affects the occurrence of BPD through various ways, our findings illustrate that serum cytokines mediated a partial association between nutrition support and BPD, which implies that for premature infants, BPD may result from cytokine changes caused by other factors (such as hyperoxia injury and gut microbiota), apart from the mediating role of the change in serum cytokines in nutritional support, which is worthy of further investigation.
Our results provide evidence for BPD control measures in early nutrition and provide hints for exploring the potential mechanisms of these risk factors. Based on these facts, the efforts of clinicians have been focused on effective nutritional treatment strategies. We must note that the sample in our study was very small, and this observation needs to be verified in a larger cohort.
We are aware of the limitations of our study, as it is a single-center retrospective cohort, and the present study is a cross-sectional study, which could only provide association and by nature could not provide causality. Future longitudinal studies may further verify the serum cytokine mediation effect of nutrition and BPD. Certainly, the design of retrospective data collection and analysis does allow us to generate a hypothesis by identifying significant associations between several variables and the outcomes and it should be well tested by a prospective, randomized clinical trial in future researches. What’s more, cytokine was partly intermediate between nutritional factors and BPD, and we are looking forward more researches to explore other intermediary factors.
However, we believe that our data can help support future meta-analysis studies on this hypothesis. Strong evidence indicates that energy and protein intake in the first weeks of life is important in the lung development of premature infants.