Cellular consequences of preterm birth : telomere biology, immune development and oxidative stress

Preterm infants are at risk for oxidative stress just by being born. The extra-uterine environment is relatively oxygen-rich, their antioxidant defenses are immature, diseases and treatments in the neonatal period will trigger inflammatory responses. The cellular effects of preterm birth and the impact on immune development are incompletely understood. The main focus of this thesis is trying to understand the cellular mechanisms of how preterm birth affect the adaptation to extrauterine life. The four papers included involve different aspects of environmental exposures in children delivered preterm; telomere length, inflammation and lung function (paper I), viral respiratory infections and cellular aging using the biological markers telomere length (telomere attrition rate) and predicted DNA methylation biological age (paper II), immune system development and environmental exposures (paper III), and hyperoxia-induced lung damage in an experimental model and the capacity to counter-act surfactant inactivation with a novel antioxidant (paper IV).

We found that telomere length was similar in 10-year-old children born preterm with a history of BPD and term born children with allergic asthma. Impaired lung function with low forced expiratory capacity and male gender were associated with short telomeres irrespectively of preterm birth (paper I). Despite early exposures to risk factors, preterm born children had preserved telomeres and showed no accelerated epigenetic aging during the first 2 years of life (paper II). Measurements of immune system states that cord blood was not representative of postnatal immunity. The immune system of preterm and term children differed at birth but unexpectedly converged early in life and followed a shared stereotypic pattern of adaptation to environmental exposures. Microbial interactions drive early immune system development (paper III). Hyperoxia impaired surfactant function and this could not be prevented by an antioxidant, N-Acetylcysteine amide, however the antioxidant did not affect surfactant function or treatment effect (paper IV). We have developed new sampling methods allowing us to perform comprehensive measurements from minimal blood sample volumes, particularly important in preterm infants with small blood volumes. The resulting “neonate-omics” permits global assessments of immune system composition to be related to biochemical pathways and epigenetic modulations.

In conclusion, preterm birth was not associated with increased cellular aging, suggesting active repair mechanisms compensating for neonatal stressors. Exogenous surfactant is a vehicle for antioxidant treatment to the lung. We describe for the first time the immune adaptation to environmental exposures early in life. With a better understanding of the challenges for a baby born far too early and much too small comes the possibility to develop individualized treatments and modify care to ensure not just survival, but future health.

List of scientific papers

I. Telomere length was similar in school-age children with bronchopulmonary dysplasia and allergic asthma. Ewa Henckel, Ulrika Svenson, Björn Nordlund, Eva Berggren-Broström, Gunilla Hedlin, Sofie Degerman and Kajsa Bohlin. Acta Paediatrica. 2018; 107:1395-401.
https://doi.org/10.1111/apa.14294

II. Hematopoietic cellular aging is not accelerated during the first two years of life in children born preterm. Ewa Henckel, Mattias Landfors, Zahra Haider, Paraskievi Kosma, Magnus Hultdin, Sofie Degerman and Kajsa Bohlin. [Manuscript]

III. Stereotypic Immune System Development in Newborn Children. Axel Olin, Ewa Henckel, Yang Chen, Tadepally Lakshmikanth, Christian Pou, Jaromir Mikes, Anna Gustafsson, Anna Karin Bernhardsson, Cheng Zhang, Kajsa Bohlin and Petter Brodin. Cell. 2018; 174: 1277-92.e14.
https://doi.org/10.1016/j.cell.2018.06.045

IV. Surfactant mixed with the antioxidant N-acetylcysteine amid (NACA) to prevent hyperoxia-induced impaired lung function in an experimental rabbit model. Ewa Henckel, Marie Haegerstrand-Björkman, Svante Norgren, Tore Curstedt and Kajsa Bohlin. [Manuscript]