Bronchopulmonary Dysplasia and inflammatory biomarkers in the premature neonate

Bronchopulmonary dysplasia (BPD) is the most common, serious sequela of premature birth. Lung inflammation is a major contributor to the pathogenesis of BPD. Often initiated by a pulmonary fetal inflammatory response to bacteria and other organisms in the amniotic cavity, the lung inflammation is exacerbated by mechanical ventilation and exposure to supplemental oxygen. In response to these initiators of lung injury, a complex network of interactions occurs between the proteins involved. These proteins may represent important biomarkers of BPD development.
A first class of proteins is represented by chemokines, i.e. molecules able to attract inflammatory cells. The role of chemokines in the development of BPD is supported by the presence of increased quantities of a number of chemokines in epithelial lining fluid from infants who develop BPD.
Adhesion molecules facilitate the trans-endothelial migration of inflammatory cells from blood vessels. These proteins appear to be critical in the development of parenchymal damage, and increased airway concentrations of some adhesion molecules have been observed at 10 days of age in BPD infants.
The tissue damage associated with inflammatory injury is mediated by pro-inflammatory cytokines. These proteins are synthesized by neutrophils and other inflammatory cells in the airway and interstitium, in addition to a variety of cells of the lung parenchyma. TNFα, IL1, IL6 and IL8 are among the most extensively studied cytokines and are important biomarkers for the prediction of adverse pulmonary outcomes in preterm infants. Similarly, matrix metalloproteinases are critical in the damage resulting from inflammatory lung injury because they cause destruction of the alveolar/capillary interface and extracellular matrix proteins. High concentrations of these molecules and/or low concentrations of tissue inhibitors of metalloproteinases in tracheal aspiration fluid are associated with the development of BPD.
Finally, several other proteins may be involved in the development of BPD, while hormones, growth factors, and other substances that control lung cell homeostasis may influence recovery from inflammatory injury.
Although studies of biomarkers in human neonates have provided some insight into the role of inflammation in the development of BPD, most previous studies have limitations. Few have searched rigorously for evidence of early initiators of inflammation, and most studies have examined mediators at a single time point, not considering the phasic nature of the inflammatory process. Those that have followed inflammatory mediators over time have investigated only a low number of mediators. Moreover, cytokines and other proteins are context-specific. For example, under one set of circumstances, some cytokines contribute to programmed cell death, yet under other circumstances they reduce the probability of cell death.
The role of inflammation in the development of BPD may be adequately investigated only by repeatedly measuring many relevant proteins. Future investigation of the role of lung inflammation in the development of BPD should include large time-oriented epidemiologic studies that will help in creating risk profiles of each infant's vulnerability. These risk profiles will also permit to group infants who are truly comparable, and thus will have the potential to improve the quality of future observational and clinical studies. Such studies may facilitate laboratory investigation of molecular mechanisms of injury and the development of targeted therapies.

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