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Maternal IL-1β Production Prevents Lung Injury in a Mouse Model of Bronchopulmonary Dysplasia

¹ Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden

Correspondence and requests for reprints should be addressed to Kristina Bry, M.D., Ph.D., Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, SWE-416 85 Gothenburg, Sweden. E-mail: kristina.bry{at}pediat.gu.se

Little is known about the influence of maternal inflammation on neonatal outcome. Production of IL-1β in the lungs of newborn infants is associated with bronchopulmonary dysplasia. Using bitransgenic (bi-TG) mice in which human (h) IL-1β is expressed with a doxycycline-inducible system controlled by the Clara cell secretory protein promoter, we have shown that hIL-1β expression causes a bronchopulmonary dysplasia–like illness in infant mice. To study the hypothesis that maternal hIL-1β production modifies the response of the newborn to hIL-1β, doxycycline was administered to bi-TG and control dams from Embryonic Day 0, inducing production of hIL-1β by the bi-TG dams before hIL-1β production started in their bi-TG fetuses, or from Embryonic Day 15, inducing simultaneous production of hIL-1β by both the bi-TG dams and their bi-TG fetuses. In addition to the lungs, hIL-1β was expressed at low levels in the uteri of bi-TG dams. Maternal inflammation preceding fetal inflammation increased the survival and growth of hIL-1β–expressing pups, enhanced alveolarization, and protected the airways against remodeling and goblet cell hyperplasia. Maternal hIL-1β production preceding fetal hIL-1β production caused silencing of several inflammatory genes, including CXC and CC chemokines, murine IL-1β, serum amyloid A3, and Toll-like receptors 2 and 4, and suppressed the expression of chitinase-like lectins Ym1 and Ym2 in the lungs of infant mice. Maternal inflammation protects the newborn against subsequent hIL-1β–induced lung inflammation and injury. In contrast, induction of hIL-1β production simultaneously in bi-TG dams and their fetuses offered no protection against inflammatory lung disease in the neonate.

Key Words: lung morphogenesis • cytokine • chemokine • premature birth

CLINICAL RELEVANCE Bronchopulmonary dysplasia (BPD) is the major inflammatory lung disease in premature infants. Although maternal inflammation is a common antecedent of premature birth, little is known about the influence of maternal inflammation on the development of BPD. The present results show that maternal inflammation preceding inflammation in the fetal lung protects the newborn against inflammatory lung disease. These unexpected findings help us to understand the complexity of the responses of newborn infants to perinatal inflammation and infection.