# Early life exposures and chronic lung disease

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $390,000

## Abstract

Emerging data suggest that the development of chronic obstructive lung diseases is greatly influenced
(and perhaps pre-determined) by adverse exposures in early life. However, the exact causes and mechanisms
responsible for such long-lasting events remain unclear. We explored how early life exposure to tobacco
components might promote maladaptions that lead to the development of chronic obstructive lung disease in the
adult. We focused on nicotine as this tobacco plant alkaloid readily traverses the placenta and impacts cell
functions via activation of nicotinic acetylcholine receptors (nAChRs). In earlier work, we showed that exposure
of embryonic murine lung explants to nicotine resulted in aberrant lung branching morphogenesis. Further work
revealed that peri-natal nicotine exposure in vivo resulted in abnormal airway structure and function in the young
lung characterized by alterations in airway branching and increased ext racellular matrix (ECM) deposition around
the airways; these changes were associated with airway hyperreactivity. Notably, these effects were found to
be mediated via  nAChRs, thereby unveiling potential targets for intervention. More relevant to this proposal,
we recently observed that chronic exposure to nicotine starting during embryogenesis promoted lung structural
and functional abnormalities detectable later in life (adulthood). Further experiments suggested a link between
these changes and aberrant expression of ECM genes via epigenetic mechanisms of action. Finally, we
observed that Influenza A infection of the young lung also promoted long-lasting effects, and these amplified the
effects of nicotine. These observations led to the hypothesis that exposure to nicotine starting in early life
promotes long-standing structural and functional abnormalities in lung through the activation of nAChRs, and via
alterations in the expression of ECM genes involved in pre-natal and post-natal lung development through
epigenetic mechanisms of action. These effects can be amplified by a second hit (i.e., viral infection early after
birth). This hypothesis will be tested in aims designed to: 1) Determine the role of nAChRs in these events
using genetic and pharmacological interventions (Aim 1), Examine the nicotine-dependent, gene-specific,
promoter-associated epigenetic modifications regulating ECM gene expression in primary lung fibroblasts (Aim
2), and Investigate the impact of a second hit (e.g., early post-natal viral infection) on nicotine-induced changes
in the adult mammalian lung (Aim 3).

## Key facts

- **NIH application ID:** 10129997
- **Project number:** 5R01HL147088-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** JESSE ROMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129997

## Citation

> US National Institutes of Health, RePORTER application 10129997, Early life exposures and chronic lung disease (5R01HL147088-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129997. Licensed CC0.

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