Bronchopulmonary Dysplasia (BPD), a severe form of chronic inflammatory lung disease in preterm infants, is associated with the persistence of activated neutrophils in the lungs. The unique pathology of BPD suggests that neutrophils from these babies exhibit developmental defects in signaling pathways that down regulate their activity and up regulate their clearance via apoptosis. Recent evidence suggests that resolution of the inflammatory response is regulated by sequential changes in the production of eicosanoids generated from arachidonic acid via cyclooxygenase-2 and lipoxygenase. This """"""""eicosanoid class-switch"""""""" results in the transition from inflammatory to anti-inflammatory prostaglandins and lipoxins at sites of tissue injury. We hypothesize that persistence of neutrophils in the lungs of neonates and the development of BPD are due to maturational defects in anti-inflammatory eicosanoid activity. Moreover, exposure of preterm infants in the NICU to toxicants that exacerbate these defects may contribute to the pathologic process. Hospitalized neonates are exposed to numerous PVC-rich devices containing the plasticizer di-(2-ethylhexyl) phthalate (DEHP). Levels of DEHP and its bioactive metabolite, MEHP, are significantly higher in preterm neonates than in any other population. Recent studies have shown that phthalates may be antagonists of the transcription factor PPAR-(, which mediates the actions of anti-inflammatory eicosanoids. We speculate that phthalates contribute to BPD by interfering with PPAR-(-mediated eicosanoid signaling. To test our hypothesis, studies are planned to: 1) determine if anti-inflammatory eicosanoid production and activity are altered in term and preterm neonatal neutrophils relative to adults and 2) analyze mechanisms underlying impaired responsiveness of neonatal neutrophils to anti-inflammatory eicosanoids and assess whether phthalates alter these responses. The American Academy of Pediatrics, U.S. FDA, and the Center for the Evaluation of Risks to Human Reproduction have all recently noted that there is an urgent public health need for more data on the toxicity of phthalates in human neonates, including the role of PPAR signaling in these effects. Results from our studies will suggest novel approaches to preventing or treating BPD and other inflammatory diseases in newborns.

Public Health Relevance

Bronchopulmonary Dysplasia (BPD), a form of chronic pulmonary injury in premature infants, is associated with abnormal persistence of activated neutrophils in the lungs. We will investigate the hypothesis that impaired down regulation and removal of these cells in newborns are due to maturational defects in the regulation of inflammation by eicosanoids, a class of bioactive lipid mediators. Moreover, widespread exposure of hospitalized newborns to phthalate plasticizers may further impair anti- inflammatory eicosanoid signaling. The American Academy of Pediatrics and U.S. Food and Drug Administration have expressed the urgent need for further study examining the toxicity of phthalates in human neonates, including their role in BPD. The proposed studies will address this need, suggesting ways to decrease the incidence of BPD and other adverse outcomes that result from inflammation in newborns.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Raju, Tonse N
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University of Medicine & Dentistry of NJ
Schools of Medicine
United States
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