Differences mark infants with PH and breathing ills of premature birth

Study in samples from newborns with severe bronchopulmonary dysplasia

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Molecular differences are evident between infants with severe bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) and those with severe BPD but not PH, a pilot study that used an integrated analysis of gene activity and protein production reported.

PH is a common complication of BPD, a breathing disorder in newborns that occurs when the lungs have not yet fully developed, and supplemental oxygen is needed.

Identifying molecular changes — differences in protein production, gene activity, and RNA — in severe BPD, especially when associated with PH, will help in understanding the underlying mechanisms, the researchers noted. They also can help in classifying high-risk infants to allow for better long-term outcomes.

The study detailing the identification of these differences, “Multiomics endotyping of preterm infants with bronchopulmonary dysplasia and pulmonary hypertension—A pilot study,” was published in the journal Pulmonary Circulation.

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Pulmonary hypertension can arise in infants with breathing problems

BPD is a lung disease that affects premature infants with underdeveloped lungs who require supplemental oxygen. Characterized by inflammation and scarring, it also can affect infants with birth defects, heart disease, pneumonia, and other infections.

PH, or high blood pressure in the blood vessels that supply the lungs, is one of BPD’s more severe complications. Affecting about one-third of newborns with BPD (BPD-PH), it carries a high risk of mortality. In infants with severe BPD, the likelihood of developing PH is even higher.

However, little is known about the molecular pathways and mechanisms involved in BPD-PH.

Multiomics endotyping is a new technique that integrates large-scale gene activity and protein production data to identify and characterize the underlying biological processes of disease. It allows for a more comprehensive understanding of a disease, helps find biomarkers to aid in diagnosis, and supports the development of personalized therapies.

A team led by investigators at the Penn State Health Children’s Hospital applied multiomics endotyping to secretions collected from the airways of premature infants — all born at 28 or fewer weeks of gestation — with severe BPD, with and without PH.

“Our main objective is to identify markers to help understand biological processes and characterize infants with pulmonary hypertension associated with bronchopulmonary dysplasia,” the team wrote.

Samples were collected from 46 infants needing mechanical breathing support. Based on echocardiogram results, 25 infants were classified as severe BPD and 21 with BPD-PH.

Researchers first examined differences in microRNA (miRNA), which are small segments of RNA that help to regulate protein production. Analysis revealed significant differences in the production of 12 miRNAs. Of these, nine were generated at significantly higher levels in BPD-PH samples compared with BPD samples, while three were significantly lower.

miRNA differences were associated with cell-to-cell communication and interactions, cell arrangement in tissues and organs, and cellular function and maintenance. The main physiological pathways were linked with the development and function of the nervous and cardiovascular systems. Leading associated diseases included cancer, tissue injury and abnormalities, and gastrointestinal illness.

Gene activity was measured by RNA-Seq, a technique that uses next-generation sequencing to reveal the presence and quantity of messenger RNA, the molecule that carries instructions to make proteins. Here, the activity of six genes was significantly different between BPD-PH and BPD samples.

Differences in gene activity were associated with cellular development, growth, death, and survival. Related physiological pathways were implicated in embryonic development, bloodstream development and function, and blood cell production, while the main associated conditions included cardiovascular disease, developmental disorders, and hereditary illness.

Overall, protein production was assessed from seven BPD-PH and five BPD infant samples. Among 712 proteins that were different between the groups, 64 were significantly different, and eight were at least two times different comparing the two groups.

Differences here were related to disrupted cell function, protein production, and cell death and survival. Physiological pathways were associated with tissue and organ structure and visual system development and function. The top associated diseases were inflammatory responses, cancer, and tissue injury and abnormalities.

By combining all miRNA, gene activity, and protein production data, the team found that several pathways were affected in BPD-PH compared with BPD, including NFkB, VEGF, SERPINA1, insulin, low-density lipoprotein (LDL), ERK1/2, and interleukin-6 (IL-6).

The IL-6 signaling molecule and the NFkB group of proteins are involved in inflammation and immune responses. VEGF is a protein that promotes blood vessel growth, and SERPINA1 is a protein that suppresses blood clotting and inflammation.

Insulin is a hormone that regulates blood sugar levels, LDL is a type of cholesterol often referred to as “bad” cholesterol, while ERK1/2 is a group of proteins that play a role in cell growth.

“We report specific miRNAs, [messenger RNAs], and proteins that could potentially serve as target markers to evaluate predictive and prognostic value in future studies to complement clinical markers,” the researchers concluded.

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