Perinatal factors in neonatal and pediatric lung diseases

Abstract

Wheezing and asthma are significant clinical problems for infants and young children, particularly following premature birth. Recurrent wheezing in infants can progress to persistent asthma. As in adults, altered airway structure (remodeling) and function (increased bronchoconstriction) are also important in neonatal and pediatric airway diseases. Accumulating evidence suggests that airway disease in children is influenced by perinatal factors including perturbations in normal fetal lung development, postnatal interventions in the intensive care unit, and environmental and other insults in the neonatal period. Here, in addition to genetics, maternal health, environmental processes, innate immunity, and impaired lung development/function can all influence pathogenesis of airway disease in children. We summarize current understanding of how prenatal and postnatal factors can contribute to development of airway diseases in neonates and children. Understanding these mechanisms will help identify and develop novel therapies for childhood airway diseases.

Vitamin D Attenuates Cytokine‐Induced Remodeling in Human Fetal Airway Smooth Muscle Cells

“…However, the role of bioactive Vitamin D 3 metabolites in the developing airway, particularly in ASM, remains undefined. Using human fetal ASM cells as a model, we evaluated the role of calcitriol and its receptor, VDR, in cell proliferation, MMP activity, and ECM deposition following stimulation with TNFα and TGFβ: two inflammatory mediators that can contribute to airway remodeling in the context of perinatal inflammation that may occur in the setting of prenatal maternal infection, and postnatal infection and inflammation, predisposing the growing lung to diseases such as asthma (Britt et al, ). Our findings that calcitriol may have a suppressive effect on features of inflammation‐induced airway remodeling suggest the importance of calcitriol in preventing detrimental structural changes in the growing lung, and thus to the need for better understanding of Vitamin D levels in infants and children at risk for asthma.…”

“…Recurrent wheezing and asthma remain a significant clinical burden and are leading contributors to lung morbidity in children making this an important public health concern (Asher et al, ). Multiple factors contribute to the development of wheezing and asthma including genetics, in utero exposure to inflammation, environmental exposures, and maternal and neonatal nutritional status (Bush and Menzies‐Gow, ; Britt et al, ). Akin to adult patient populations (Sutherland et al, ), deficiency of Vitamin D in children is strongly associated with development of asthmatic symptoms (Freishtat et al, ; Brehm et al, ).…”

Perinatal oxygen in the developing lung

“…As the pathophysiology of BPD has changed with surfactant therapy and greater awareness of preventing barotrauma, increased airway reactivity, wheezing, and asthma have emerged as significant long term morbidities associated with premature birth (Been et al 2014; Britt et al 2013; Holditch-Davis et al 2008; Martin et al 2013; Vrijlandt et al 2013). A recent systemic meta-analysis looking at incidence of childhood wheezing disorders found a 30-90% increased risk of wheezing disorders in children born preterm compared to term infants (Been et al 2014).…”

“…The intersection of changes in oxygen tension with these infectious inflammatory processes may result in synergistic effects leading to further pulmonary injury and remodeling. Maternal infections or inflammatory states from either intra-uterine or extra-uterine sources are commonly associated with preterm birth (Britt et al 2013; Genc and Onderdonk 2011; Murthy and Kennea 2007) . Perinatal exposure to inflammation and post-natal hyperoxia and/or hypoxia exposure can be proinflammatory and deleterious not only to alveolar development, but also to airway structure and function.…”

“…Neonatal lung diseases, including bronchopulmonary dysplasia (BPD), neonatal wheezing, and asthma are particularly prevalent in this population, in large part due to inciting factors to which premature infants are disproportionately exposed. Pathophysiology of these lung diseases is complex and may involve genetic predisposition, perinatal inflammation, environmental toxin exposure, maternal diet, and frequent requirement of respiratory support, including supplemental oxygen in the perinatal period (Britt et al 2013; Jobe and Kallapur 2010; Martin et al 2013). …”