The exposome-lung interplay in early life

Overview

Epidemiological evidence indicates that pre- and perinatal exposures can have profound effects not only on perinatal outcomes, but importantly also on lung trajectories over the course of the entire life-span. As such, the interplay between the exposome and the developing lungs in early life is a significant determinant of the development of chronic lung diseases. Mechanistic insight into the impact of early life exposures on the developing lungs and immune system, and priming of the susceptibility to respiratory conditions such as bronchopulmonary dysplasia (BPD), asthma and COPD, is currently emerging.

Our understanding of lung development from a cellular and molecular perspective has deepened greatly, evidenced by publications on the cell atlas of the developing lung, and the role of cellular crosstalk in/molecular regulation of cell fate and differentiation. These findings are corroborated using sophisticated in vitro models of lung development, which also provide mechanistic insight. Similarly, significant progress has been made in understanding the neonatal immune system’s development and its interaction with lung development. Post-birth exposures are crucial for training the naive immune system to differentiate between activation and tolerogenic responses. Research has focused on factors like diet and gut microbiome in driving immune maturation.

Already before birth, in utero exposures can profoundly affect lung and immune system development, regardless of whether the infant is born at term or preterm. Adverse exposures through the maternal-fetal interface disturb fetal development and can lead to prematurity. These immature lungs often receive adverse consecutive hits which can culminate into BPD. The lack of a diagnostic test and consistent definition, the complex etiology and heterogenous presentation complicates mechanistic research into BPD and makes it challenging to improve long-term outcomes, which are clear from epidemiological studies. While exogenous surfactant therapy has lessened BPD severity, it has not reduced its incidence, and improved survival of extremely preterm infants may be linked to rising BPD rates. Preterm birth, whether or not BPD develops, can significantly affect lifelong respiratory health, increasing the risk of asthma-like symptoms in childhood and early COPD. It is therefore of utmost importance to understand which factors harm lung development, when their impact is greatest, and the underlying pathogenic mechanisms.

Also the incidence of childhood allergies and asthma is unfortunately still rising, which may be further fueled by climate change and environmental and life-style related factors. There is a pivotal role for a type 2 skewed inflammatory response to early life exposures in the pathogenesis of childhood asthma and atopy. Dysbiosis of the microbiome is a critical factor as well.

Importantly, not all pediatric asthma is Th2-driven, and distinguishing phenotypes and endotypes helps to improve treatment of individual children. Understanding how time-dependent risk factors affect lung and immune development in genetically susceptible infants is helping to unravel the pathogenesis of distinct childhood asthma endotypes.

New insights into lung development are opening doors to regenerative treatments for adult lung diseases, while early life offers a chance to prevent them. Understanding how early exposures affect neonatal lungs and increase susceptibility to later respiratory issues is key. Promising new therapies are being explored in preclinical research and phase 1 trials to accelerate lung development and to properly educate the immune system.

During this in-person research seminar the key issues mentioned above will be discussed by clinicians, and basic and translational scientists in order to determine ways to optimise each newborn’s lung trajectory into adulthood and contribute to the prevention of chronic lung diseases at large.

Objectives

The seminar aims brings together clinicians, epidemiologists, biologists, pharmacologists and pathologists to:

• Provide a state-of-the-art understanding of the mechanisms underlying healthy lung development, and the co-development and maturation of the immune system (starting in utero, and into adolescence).
• Address adverse effects of various pre- and perinatal, as well as childhood exposures, including life-style factors, on the developing lungs and immune system, and to provide insight into the current knowledge on underlying mechanisms through which these contribute to the initiation and progression of respiratory diseases across the life-span.
• Discuss how a better start to life could be achieved and life-long respiratory deficits can be avoided, by focusing on protective exposures and novel therapeutic approaches in early life.

Outcomes

• A state-of-the-art, back-to-basics review article authored by the organisers and faculty, to be published in the European Respiratory Journal.
• A session proposal for the ERS Congress 2027.