Bronchopulmonary Dysplasia in a Rat Model Induced by Intra-amniotic Inflammation and Postnatal Hyperoxia: Morphometric Aspects

Abstract

Antenatal inflammation is a known risk factor of bronchopulmonary dysplasia. The authors hypothesized that lipopolysaccharide (LPS) administration amplifies hyperoxia-induced lung injury in neonatal rats. LPS (0.5 or 1.0 g) or normal saline was injected into the amniotic sacs of pregnant rats at 20 d gestation (term 22.5 d). After birth, rats were exposed to 85% oxygen or room air for 1 or 2 wk. Morphometric analysis of lungs was performed on 14 d. One week of hyperoxia without LPS administration resulted in modest lung injury. LPS at 0.5 g alone did not alter lung morphology, but amplified the effect of 1 wk of hyperoxia resulting in marked inhibition of alveolarization (airspaces were enlarged and alveolar surface areas further reduced). LPS at 1.0 g independently induced modest lung injury and also amplified the effect of 1 wk of hyperoxia. However, this sensitizing effect of LPS was not observed in rats subjected to 2 wks of hyperoxia, which in itself caused extensive lung injury (possibly masking the effect of LPS). The authors concluded that intra-amniotic LPS sensitizes neonatal rat lungs, and thus, amplifies the hyperoxia-induced inhibition of alveolarization. (Pediatr Res 65: 323-327, 2009) T he pathophysiology of bronchopulmonary dysplasia (BPD) has evolved from its classical form following the introduction of antenatal glucocorticoid, surfactant replacement therapy, and gentler ventilatory support (1). However, BPD remains a major chronic pulmonary complication in small preterm infants. In previous studies, antenatal inflammation has been shown to increase the risk of BPD (2-5), although ironically antenatal inflammation may improve pulmonary function during the immediate neonatal period (6). Furthermore, in infants who subsequently develop BPD, we have reported increased levels of inflammatory biochemical factors in serum and tracheal aspirate at birth, thus implicating inflammation in the development of BPD (7,8). In addition, prolonged hyperoxic exposure has been found to lead to BPD in clinical and animal studies, but much remains to be determined concerning the role of antenatal inflammation in the development of BPD. Recently, Van Marter et al. (4) reported that mechanically ventilated preterm infants with chorioamnionitis or postnatally acquired sepsis showed a several fold increase in the prevalence of BPD compared with mechanically ventilated preterm infants without these complications. Ikegami and Jobe (9) suggested that endotoxin had a sensitizing effect after observing that fetal sheep exposed to intraamniotic endotoxin showed further increased proinflammatory responses to mechanical ventilation. Jobe (10) subsequently suggested antenatal inflammation has a sensitizing effect and that it increases the incidence and severity of BPD when neonates are exposed to oxygen and mechanical ventilation. A number of animal models of BPD have been devised (9,11,12), but to date this concept that antenatal inflammation increases susceptibility to lung injury by hyperoxia has not been demonst...

Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia

“…The combination of perinatal inflammation and postnatal hyperoxia triggers a severe BPD-like lung disease in rodents (21,22). We selected this double-hit model as the multifactorial etiology of BPD is taken into account.…”

“…Based on previous publications (21,22,38), pregnant C57BL/6J dams received an i.p. injection of 150 μg/kg of LPS or volumematched vehicle (normal saline) at 14 d gestation.…”

Sildenafil Alleviates Bronchopulmonary Dysplasia in Neonatal Rats by Activating the Hypoxia-Inducible Factor Signaling Pathway

“…Preterm infants delivered before 30 weeks of gestation run a high risk of BPD, which involves poor alveolarization and aberrant lung microvasculature (36,37). Intrauterine infection and amniotic inflammation are also considered high risk factors of BPD.…”

Chorioamnionitis, respiratory distress syndrome and bronchopulmonary dysplasia in extremely low birth weight infants

“…4 We recently reported that intra-amniotic lipopolysaccharide-sensitized neonatal rat lungs and, thus, amplified the hyperoxia-induced inhibition of alveolarization. 5 Antenatal lipopolysaccharide alone might not be sufficient to disturb lung development, but rather may exacerbate the deleterious effects of postnatal injury. Notably, Jobe and Kallapur 6 suggested that the decreased surfactant function with the fetal inflammatory response reflects more lung inflammation at birth.…”