Pulmonary implications of perinatal acetaminophen exposure

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PROJECT SUMMARY OF THE FUNDED PARENT AWARD Acetaminophen (APAP)is one of the most commonly used analgesics in the world, and overwhelmingly perceived to be safe. This perception has contributed to ubiquitous exposures during gestation and among newborns in the neonatal intensive care unit. These exposures occur during critical windows of human development where pre-clinical and clinical data demonstrating safety are lacking. Alarmingly, clinical data support the hypothesis that the developing lung may be adversely affected by perinatal APAP exposures. The toxicity of APAP is dependent on its conversion by the xenobiotic-metabolizing enzyme CYP2E1 the mitochondrial toxin N-acetyl-para-benzo-quinone imine (NAPQI). Our preliminary data demonstrate that pulmonary CYP2E1 expression peaks during the saccular stage of development and is limited to the myofibroblast. Additionally, we show that postnatal APAP exposures induce Cyp2e1 expression in the late saccular/early alveolar stage lung. Consistent with CYP2E1 expression, we show that the developing lung is susceptible to APAP-induced injury. These preliminary data have led us to develop the following hypothesis: The saccular/early alveolar stage lung is susceptible to APAP-induced injury due to developmentally- regulated pulmonary CYP2E1 expression. We propose three specific aims to test this hypothesis. In Aim 1, we will test the hypothesis that in utero APAP exposures during the saccular stage of lung development injure pulmonary myofibroblasts and disrupt alveolarization. In Aim 2, we will test the hypothesis that postnatal APAP exposures during the late saccular/early alveolar stage induce lung CYP2E1 expression causing oxidative stress and increase sensitivity to injury. In Aim 3, we will test the hypothesis that inhibiting TLR9/NFκB innate immune signaling will attenuate APAP-induced newborn lung injury. Our collaborative team bridging developmental pulmonary biology, physiology, immunology and mitochondrial/oxidative stress biology is well positioned to fill critical gaps in our understanding of the developmentally-regulated, cell-type specific CYP2E1 expression and APAP-induced lung injury. These studies will help determine the safety profile of APAP to inform both maternal use and newborn exposures while identifying therapeutic targets to limit adverse effects. into