Cytokines Associated With Bronchopulmonary Dysplasia or Death in Extremely Low Birth Weight Infants

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35249, USA.
PEDIATRICS (Impact Factor: 5.47). 05/2009; 123(4):1132-41. DOI: 10.1542/peds.2008-0526
Source: PubMed


The goal was to develop multivariate logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at postmenstrual age of 36 weeks by using clinical and cytokine data from the first 28 days.
For 1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development, levels of 25 cytokines were measured in blood collected within 4 hours after birth and on days 3, 7, 14, and 21. Stepwise regression analyses using peak levels of the 25 cytokines and 15 clinical variables identified variables associated with bronchopulmonary dysplasia/death. Multivariate logistic regression analysis was performed for bronchopulmonary dysplasia/death by using variables selected through stepwise regression. Similar analyses were performed by using average cytokine values from days 0 to 21, days 0 to 3, and days 14 to 21.
Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. On the basis of results from all models combined, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukin 1beta, 6, 8, and 10 and interferon gamma and lower concentrations of interleukin 17, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor beta. Compared with models with only clinical variables, the addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude.
The overall cytokine pattern suggests that bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T lymphocytes.

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    • "Many researchers have suggested that multiple cytokines must participate in the development of BPD [31]. Inflammatory cytokines such as interleukin-8 (IL-8), macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-alpha (TNF-a) have been shown elevated in tracheal aspirates of neonates which later develop BPD [32]. "
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    ABSTRACT: Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased alveolar number and increased airspace. Previous studies suggested that transforming growth factor-α (TGF-α) may contribute to arrested alveolar development in BPD. Histone deacetylases (HDACs) control cellular signaling and gene expression. HDAC2 is crucial for suppression of inflammatory gene expression. Here we investigated whether HDAC2 was involved in the arrest of alveolarization, as well as the ability of HDAC2 to regulate TGF-α expression in a rat model of BPD induced by intra-amniotic injection of lipopolysaccharide (LPS). Results showed that LPS exposure led to a suppression of both HDAC1 and HDAC2 expression and activity, induced TGF-α expression, and disrupted alveolar morphology. Mechanistic studies showed that overexpression of HDAC2, but not HDAC1, suppressed LPS-induced TGF-α expression. Moreover, the HDAC inhibitor TSA or downregulation of HDAC2 by siRNA both significantly increased TGF-α expression in cultured myofibroblasts. Finally, preservation of HDAC activity by theophylline treatment improved alveolar development and attenuated TGF-α release. Together, these findings indicate that attenuation of TGF-α-mediated effects in the lung by enhancing HDAC2 may have a therapeutic effect on treating BPD.
    PLoS ONE 03/2014; 9(3):e91083. DOI:10.1371/journal.pone.0091083 · 3.23 Impact Factor
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    • "In a BPD model, mitochondrial aconitase activity was significantly decreased after exposure to 100% oxygen for 6–10 days in the lungs of premature baboons (Morton et al., 1998). BPD is also mediated by the exaggerated increase in the pro-inflammatory cytokines such as interleukin- 1β and TNF-α in the bronchoalveolar lavage fluid (Ambalavanan et al., 2009; Sun et al., 2013). In response to hyperoxic exposure, mitochondria showed significantly lowered enzymatic activity of Complex I indicating impaired OXPHOS in newborn mice lungs (Ratner et al., 2009). "
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    ABSTRACT: During mild stressful conditions, cells activate a multitude of mechanisms in an attempt to repair or re-establish homeostasis. One such mechanism is autophagic degradation of mitochondria or mitophagy to dispose damaged mitochondria. However, if stress persists beyond recovery then dysfunctional mitochondria can ignite cell death. This review article summarizes recent studies highlighting the molecular pathways that facilitate mitochondria to alter its morphological dynamics, coordinate stress responses, initiate mitophagy and activate cell death in relevance to pulmonary pathologies. Thorough understanding of how these signaling mechanisms get disrupted may aid in designing new mitochondria-based therapies to combat lung diseases.
    Frontiers in Physiology 12/2013; 4:384. DOI:10.3389/fphys.2013.00384 · 3.53 Impact Factor
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    • "By GO biological process term enrichment analysis, in contrast with non-miRNA-regulated genes, miRNA-regulated genes were particularly enriched for the GO term “immune system process”. Immune system dysfunction has been postulated as a contributing factor in the pathophysiology of BPD, as imbalances of “pro-inflammatory" and "anti-inflammatory" cytokines and impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T lymphocytes has been described [36]. We validated a number of our microarray-based observations using real-time PCR and immunohistochemistry. Interestingly, we observed increased expression of miR29c in conjunction with decreased expression of its predicted mRNA target Ntrk2. "
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    ABSTRACT: Bronchopulmonary dysplasia is a chronic lung disease of premature neonates characterized by arrested pulmonary alveolar development. There is increasing evidence that microRNAs (miRNAs) regulate translation of messenger RNAs (mRNAs) during lung organogenesis. The potential role of miRNAs in the pathogenesis of BPD is unclear. Following exposure of neonatal mice to 80% O2 or room air (RA) for either 14 or 29 days, lungs of hyperoxic mice displayed histological changes consistent with BPD. Comprehensive miRNA and mRNA profiling was performed using lung tissue from both O2 and RA treated mice, identifying a number of dynamically regulated miRNAs and associated mRNA target genes. Gene ontology enrichment and pathway analysis revealed that hyperoxia modulated genes involved in a variety of lung developmental processes, including cell cycle, cell adhesion, mobility and taxis, inflammation, and angiogenesis. MiR-29 was prominently increased in the lungs of hyperoxic mice, and several predicted mRNA targets of miR-29 were validated with real-time PCR, western blotting and immunohistochemistry. Direct miR-29 targets were further validated in vitro using bronchoalveolar stem cells. In newborn mice, prolonged hyperoxia induces an arrest of alveolar development similar to that seen in human neonates with BPD. This abnormal lung development is accompanied by significant increases in the levels of multiple miRNAs and corresponding decreases in the levels of predicted mRNA targets, many of which have known or suspected roles in pathways altered in BPD. These data support the hypothesis that dynamic regulation of miRNAs plays a prominent role in the pathophysiology of BPD.
    BMC Genomics 05/2012; 13(1):204. DOI:10.1186/1471-2164-13-204 · 3.99 Impact Factor
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