High-mobility group box-1 protein in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia and steroid therapy

Aghai, Zubair H.; Saslow, Judy; Meniru, C; Porter, Charles A.; Eydelman, Riva; Bhat, Vishwanath; Stahl, Gary E.; Sannoh, Sulaiman; Pyon, Kee H.; Hewitt, Charles W.; Bhandari, Vineet

doi:10.1038/jp.2010.16

Cited by 24 publications

(25 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Increased airway HMGB1 is associated with bronchopulmonary dysplasia in preterm infants (1), severe asthma in children (2), and chronic obstructive pulmonary disease in adults (3,4). HMGB1 is a biomarker for lung disease progression in patients with cystic fibrosis (CF) (4,5).…”

Section: Clinical Relevancementioning

confidence: 99%

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

Zheng

Kummarapurugu

Afosah

et al. 2017

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

High mobility group box 1 (HMGB1) is an alarmin released from macrophages after infection or inflammation and is a biomarker of lung disease progression in patients with cystic fibrosis. We reported that 2-O, 3-O desulfated heparin (ODSH) inhibits the release of HMGB1 from murine macrophages triggered by neutrophil elastase both in vivo and in vitro. HMGB1 shuttles between the nucleus and the cytoplasm. When acetylated at lysine residues in the nuclear localization signal domains, HMGB1 is sequestered in the cytoplasm and is fated for secretion. In this study, we investigated the mechanism by which ODSH blocks HMGB1 secretion. We tested whether ODSH inhibits the activity of p300, a histone acetyltransferase that has been linked to HMGB1 acetylation and release. ODSH inhibited both neutrophil elastase and LPStriggered HMGB1 release from the murine macrophage cell line RAW264.7 in a concentration-dependent manner. Fluoresceinlabeled ODSH was taken up by RAW264.7 cells into the cytoplasm as well as the nucleus, suggesting an intracellular site of action of ODSH for blocking HMGB1 release. ODSH inhibited RAW264.7 cell nuclear extract, human macrophage nuclear extract, and recombinant p300 HAT activity in vitro, resulting in the failure to acetylate HMGB1. In silico molecular modeling predicted that of the numerous possible ODSH sequences, a small number preferentially recognizes a specific binding site on p300. Fluorescence binding studies showed that ODSH bound p300 tightly (dissociation constant z1 nM) in a highly cooperative manner. These results suggest that ODSH inhibited HMGB1 release, at least in part, by direct molecular inhibition of p300 HAT activity.Keywords: p300; heparin; high mobility group box 1 Clinical RelevanceWe report that a modified heparin, 2-O, 3-O desulfated heparin (ODSH), inhibits high mobility group box 1 release from macrophages via inhibition of a histone acetyltransferase, p300, required for acetylation. This is a novel mechanism by which ODSH blocks inflammation, and this finding supports the development of ODSH as an antiinflammatory therapy for cystic fibrosis.High mobility group box 1 (HMGB1) is found at high concentrations in the airways of patients with chronic inflammatory lung diseases. Increased airway HMGB1 is associated with bronchopulmonary dysplasia in preterm infants (1), severe asthma in children (2), and chronic obstructive pulmonary disease in adults (3, 4). HMGB1 is a biomarker for lung disease progression in patients with cystic fibrosis (CF) (4, 5). Furthermore, a polymorphism in the gene Ager, which encodes the HMGB1 receptor, receptor for advanced glycation end products (RAGE), results in increased RAGE expression

show abstract

Section: Clinical Relevancementioning

confidence: 99%

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

Zheng

Kummarapurugu

Afosah

et al. 2017

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…Aside from the glycation end-products which gave the receptor its name, ligands for RAGE include damage-associate products, including HMGB1 (47), which have been associated with BPD (48) and, as noted above, is released from damaged lungs and A549 cells (36). …”

Section: The Rage Receptormentioning

confidence: 99%

Potential Contribution of Type I Alveolar Epithelial Cells to Chronic Neonatal Lung Disease

Rozycki

2014

Front. Pediatr.

View full text Add to dashboard Cite

The alveolar surface is covered by large flat Type I cells (alveolar epithelial cells 1, AEC1). The normal physiological function of AEC1s involves gas exchange, based on their location in approximation to the capillary endothelium and their thinness, and in ion and water flux, as shown by the presence of solute active transport proteins, water channels, and impermeable tight junctions between cells. With the recent ability to produce relatively pure cultures of AEC1 cells, new functions have been described. These may be relevant to lung injury, repair, and the abnormal development that characterizes bronchopulmonary dysplasia (BPD). To hypothesize a potential role for AEC1 in the development of lung injury and abnormal repair/development in premature lungs, evidence is presented for their presence in the developing lung, how their source may not be the Type II cell (AEC2) as has been assumed for 40 years, and how the cell can be damaged by same type of stressors as those which lead to BPD. Recent work shows that the cells are part of the innate immune response, capable of producing pro-inflammatory mediators, which could contribute to the increase in inflammation seen in early BPD. One of the receptors found exclusively on AEC1 cells in the lung, called RAGE, may also have a role in increased inflammation and alveolar simplification. While the current evidence for AEC1 involvement in BPD is circumstantial and limited at present, the accumulating data supports several hypotheses and questions regarding potential differences in the behavior of AEC1 cells from newborn and premature lung compared with the adult lung.

show abstract

“…The host response is similar to the activation triggered by noninfectious tissue injuries like trauma, burns and ischemic reperfusion events [30] , making it difficult to distinguish them from another. The newly identified alarmin molecule High Mobility Group Box 1 (HMGB1), which has been recognized as an important mediator of sepsis [30] , is also thought to play an important role in lung injury and the pathogenesis of BPD [55] . HMGB1, an activator of NF-κB, is released by necrotic, but not apoptotic cells, and sustains the inflammatory process after the resolution of the early stage of inflammation [55] .…”

Section: Sepsis and Noninfectious Inflammationmentioning

confidence: 99%

“…The newly identified alarmin molecule High Mobility Group Box 1 (HMGB1), which has been recognized as an important mediator of sepsis [30] , is also thought to play an important role in lung injury and the pathogenesis of BPD [55] . HMGB1, an activator of NF-κB, is released by necrotic, but not apoptotic cells, and sustains the inflammatory process after the resolution of the early stage of inflammation [55] . As mentioned, one of the anti-inflammatory potentials of n-3 LCPUFAs is the ability to inhibit the activation of NF-κB [33] , and thereby possibly modulate an inappropriate inflammatory response.…”

Section: Sepsis and Noninfectious Inflammationmentioning

confidence: 99%

Long-Chain Polyunsaturated Fatty Acids and Clinical Outcomes of Preterm Infants

Lapillonne

Moltu

2016

Ann Nutr Metab

View full text Add to dashboard Cite

Long-chain polyunsaturated fatty acids (LCPUFAs) play specific roles during the perinatal period and are very important nutrients to consider. The possible effects of LCPUFAs, particularly docosahexaenoic acid (DHA), on various clinical outcomes of preterm infants are discussed in this paper. Since DHA accumulates in the central nervous system during development, a lot of attention has focused on the effects of DHA on neurodevelopment. Experimental studies as well as recent clinical trials show that providing larger amounts of DHA than currently and routinely provided is associated with better neurological outcomes at 18 months to 2 years. This early advantage, however, does not seem to translate into detectable change in visual and neurodevelopmental outcomes or behavior when assessed in childhood. There is growing evidence that, in addition to effects on development, omega-3 LCPUFAs may reduce the incidence or severity of neonatal morbidities by affecting different steps of the immune and anti-inflammatory response. Studies in preterm infants suggest that the omega-3 LCPUFAs may play a significant role by reducing the risk of bronchopulmonary dysplasia, necrotizing enterocolitis and possibly retinopathy of prematurity and sepsis. Overall, evidence is increasing to support the benefits of high-dose DHA for various health outcomes of preterm infants. These findings are of major clinical relevance mainly because infants born preterm are at particularly high risk for a nutritional deficit in omega-3 fatty acids, predisposing to adverse neonatal outcomes. Further studies are warranted to address these issues as well as to more precisely determine the LCPUFA requirement in order to favor the best possible outcomes of preterm infants.

show abstract

High-mobility group box-1 protein in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia and steroid therapy

Cited by 24 publications

References 34 publications

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

Potential Contribution of Type I Alveolar Epithelial Cells to Chronic Neonatal Lung Disease

Long-Chain Polyunsaturated Fatty Acids and Clinical Outcomes of Preterm Infants

Contact Info

Product

Resources

About