# Maternal-neonatal transmission of protective resolution mechanisms for lung inflammation

> **NIH NIH R56** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $409,580

## Abstract

Abstract
The hygiene hypothesis, first postulated in 1989, suggests that exposure to bacterial-derived products like
endotoxin early in life, contribute towards protection against type 2 pulmonary inflammation, particularly asthma.
The epidemiological and experimental studies spurred by the hygiene hypothesis underscore that the early
postnatal period offers a critical window for the establishment of mucosal protection. Maternal milk represents a
novel transgenerational mechanism by which offspring may acquire early-life immunity. The objective of this
grant is to understand immune protective mechanisms by which maternal milk from mothers to neonates confers
immunity to allergic diseases. In work in progress we have novel and promising data from a new model of
maternal transference of immune protection. In this model, exposure to endotoxin in murine dams postpartum,
resulted in pups obtaining protection against type 2 inflammation to a common indoor allergen, house dust mite
and to a clinical strain of Respiratory Syncytial Virus (RSV). The overall downregulation of type 2 immune
responses to an allergen and a virus indicated that the mechanism of protection was common for different
antigens. Metabololipidomics analysis of murine milk from endotoxin-exposed dams revealed elevated levels of
the specialized pro-resolving mediator (SPM), Resolvin D4(RvD4) derived from the essential fatty acid,
Docosahexaenoic acid. Pups from endotoxin-exposed dams had overall lower type 2 immune response, altered
pulmonary dendritic cell (DC) subsets and lower levels of alarmin cytokine IL-33 in the lungs. Based on published
and preliminary findings, we form our central hypothesis: Maternal airway exposure to select microbial
products influences the generation of specific SPM in milk. These SPM confer protective pulmonary immune
responses in infants by promoting regulatory function in airway DCs and maintaining mucosal homeostasis. We
test this hypothesis through three specific aims. Aim 1: Determine the generation and role of SPMs present in
maternal milk in type 2 pulmonary inflammation. Aim 2: Investigate the impact of SPMs in CD103+ DC subset in
type 2 pulmonary inflammation and resolution. Aim 3: Establish SPM-mediated mechanisms for the modulation
of IL-33 expression in epithelial cells. The findings from these aims will be significant since they will establish
that critical immune pathways targeted by SPMs generated in maternal milk, which confer protection against
allergic diseases. The proposal is innovative since we propose to show that maternal milk provides a novel
transgenerational immunological conduit of protection in a heretofore-unexamined process. The findings from
this study will be vital to our understanding of how indirect early-life microbial exposure modulates the
development of childhood allergic diseases.

## Key facts

- **NIH application ID:** 10101030
- **Project number:** 1R56HL155917-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Nandini Krishnamoorthy
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,580
- **Award type:** 1
- **Project period:** 2021-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101030

## Citation

> US National Institutes of Health, RePORTER application 10101030, Maternal-neonatal transmission of protective resolution mechanisms for lung inflammation (1R56HL155917-01). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10101030. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*