Bronchopulmonary Dysplasia (BPD), a disease characterized by alveolarization arrest, chronic inflammation, and interstitial fibrosis is the major morbidity in preterm infants (1). During the past decade, studies of human infants and experimental animal models have indicated that the central event in the pathogenesis of BPD is the interruption of normal developmental signaling during the period of distal lung development by inflammation /injury that may be initiated in utero by intrauterine infection (1, 2). Ureaplasma parvum and U. urealyticum are the most common organisms isolated from infected amniotic fluid and infant tracheal aspirates (3-5). Ureaplasma respiratory tract colonization in preterm infants is a highly significant risk factor for BPD (6). We provide compelling evidence from studies of human preterm infants (7-9), in vitro studies with cultured monocytes (10) and in experimental murine (11), and immature baboon pneumonia models, that Ureaplasma is proinflammatory and pro-fibrotic in the preterm newborn lung. Our long-term objective is to determine how intrauterine exposure to Ureaplasma at critical stages of lung development contributes to injury, altered developmental signaling, and fibrosis in the immature lung.
The specific aims of this proposal focus on the central hypothesis that intrauterine Ureaplasma infection contributes to BPD by 1) modulating the pulmonary immune response to produce sustained inflammation and altered developmental signaling, and/or 2) augmenting the inflammatory response to subsequent inflammatory signals such as secondary bacterial colonization, barotrauma and hyperoxia. Although experimental antenatal models of Ureaplasma infection have been developed in the immature baboon and sheep, these models are limited by their high cost. The advantages of a mouse model to study Ureaplasma-host interactions are 1) the capacity for genetic manipulation;2) short gestation;3) the relatively low cost;and 4) a juvenile mouse model of Urea-plasma pneumonitis has already been characterized in our laboratory. To facilitate future mechanistic analysis of how Ureaplasma alters developmental signaling in the immature lung, the specific aims of this proposal are: 1) to develop an intrauterine Ureaplasma infection model in C3H/HeN mice and characterize the morphologic and functional phenotype in newborn mice;and 2) to analyze how antenatal Ureaplasma infection affects the pulmonary response to sublethal hyperoxia in newborn mice. Development of this model may lead to the generation of novel therapeutic approaches to counteract the detrimental effects of Ureaplasma on the immature lung.
Babies who are born prematurely with a lung infection with the Ureaplasma bacteria may develop a chronic lung disease called bronchopulmonary dysplasia (BPD). To better understand this infection, this project will develop a mouse model to mimic the human infection.
|Hassan, Hazem E; Othman, Ahmed A; Eddington, Natalie D et al. (2011) Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia. J Clin Pharmacol 51:1264-75|