Consequences of early postnatal lipopolysaccharide exposure on developing lungs in mice

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infants that is characterized by interrupted lung development. Postnatal sepsis causes BPD, yet the contributory mechanisms are unclear. To address this gap, studies have used lipopolysaccharide (LPS) during the alveolar phase of lung development. However, the lungs of infants who develop BPD are still in the saccular phase of development, and the effects of LPS during this phase are poorly characterized. We hypothesized that chronic LPS exposure during the saccular phase disrupts lung development by mechanisms that promote inflammation and prevent optimal lung development and repair. Wild-type C57BL6J mice were intraperitoneally administered 3, 6, or 10 mg/kg of LPS or a vehicle once daily on postnatal days (PNDs) 3–5. The lungs were collected for proteomic and genomic analyses and flow cytometric detection on PND6. The impact of LPS on lung development, cell proliferation, and apoptosis was determined on PND7. Finally, we determined differences in the LPS effects between the saccular and alveolar lungs. LPS decreased the survival and growth rate and lung development in a dose-dependent manner. These effects were associated with a decreased expression of proteins regulating cell proliferation and differentiation and increased expression of those mediating inflammation. While the lung macrophage population of LPS-treated mice increased, the T-regulatory cell population decreased. Furthermore, LPS-induced inflammatory and apoptotic response and interruption of cell proliferation and alveolarization was greater in alveolar than in saccular lungs. Collectively, the data support our hypothesis and reveal several potential therapeutic targets for sepsis-mediated BPD in infants.

CCR2 Mediates Chronic LPS-Induced Pulmonary Inflammation and Hypoalveolarization in a Murine Model of Bronchopulmonary Dysplasia

“…The specific mechanisms by which TLR4-dependent signals regulate PDGFRa expression, promote abnormal myofibroblast differentiation, and impair lung alveolar growth are incompletely understood and will be the focus of our future studies. When administered systemically or into the airways LPS is a potent stimulator of pro-inflammatory cytokines, including TNF-a, IL-6, IL-1b (42,79). Our findings of higher lung levels of TNF-a, IL-6 and IL-1b following LPS administration into the airways are reminiscent of the higher levels of these cytokines in tracheal aspirates from premature infants with evolving BPD (19,26).…”

“…The inflammatory stimulus during hyperoxic exposure is likely multifaceted. The development of a model of postnatal LPS exposure-induced hypoalveolarization (13,42) confirms a relationship between the bacteria-derived inflammatory stimulus and impaired alveolar development. Our model offers the opportunity to investigate the mechanisms by which inflammation induced by repeated LPS administration into the airway translates into hypoalveolarization.…”

“…CCR2 signaling is required for lung pro-fibrotic responses in mice (37)(38)(39) and partially mediates hyperoxia-induced hypoalveolarization in immature mice (40). Recent studies implicate a role for repetitive LPS exposure in pulmonary hypoalveolarization and inflammation, including increased CCL2 expression (13,(41)(42)(43). However, the role of innate immune cells recruited in response to increased CCL2 expression and their pro-inflammatory signals has not been investigated.…”

Lung development and emerging roles for type 2 immunity

“…Similar effects on murine lung development were observed following lipopolysaccharide (LPS) administration . Early postnatal exposure impaired alveolarisation and angiogenesis , which could be alleviated by administration of vitamin D through reducing interferon (IFN)‐γ . Inhibiting NF‐κB signalling worsened the LPS‐induced phenotype, suggesting an anti‐inflammatory function in the developing lung .…”

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice

“…The primary antibodies were detected by incubation with the appropriate horseradish peroxidase-conjugated secondary antibodies. The immunoreactive bands were detected by chemiluminescence method, and the band densities were quantified by Image lab 5.2.1 software (Bio-Rad Laboratories, Inc., Hercules, CA, USA) [81].…”