TY - JOUR
T1 - Consequences of early postnatal lipopolysaccharide exposure on developing lungs in mice
AU - Shrestha, Amrit Kumar
AU - Bettini, Matthew L.
AU - Menon, Renuka T.
AU - Gopal, Vashisht Y.N.
AU - Huang, Shixia
AU - Edwards, Dean P.
AU - Pammi, Mohan
AU - Barrios, Roberto
AU - Shivanna, Binoy
N1 - Funding Information:
This work was supported by National Institutes of Health Grants HD-073323 (to B. Shivanna), P30-CA-125123 (to D. P. Edwards and S. Huang), and P30-DK-056338 (to Digestive Disease Center Core at the Baylor College of Medicine); Cancer Prevention and Research Institute of Texas Proteomics and Metabolomics Core Facility Support Award RP170005 (to D. P. Edwards and S. Huang); American Heart Association Award BGIA-20190008 (to B. Shivanna); and American Lung Association Award RG-349917 (to B. Shivanna).
Publisher Copyright:
© 2019 the American Physiological Society.
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - Bronchopulmonary dysplasia
KW - Inflammation
KW - Lipopolysaccharide
KW - Proteomics
KW - T-regulatory cells
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U2 - 10.1152/ajplung.00560.2017
DO - 10.1152/ajplung.00560.2017
M3 - Article
C2 - 30307313
AN - SCOPUS:85059244845
SN - 1040-0605
VL - 316
SP - L229-L244
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 1
ER -