# Aryl hydrocarbon receptor signaling in Airway Inflammation

> **NIH NIH R01** · NORTH DAKOTA STATE UNIVERSITY · 2024 · $613,934

## Abstract

Abstract
 Asthma is influenced by multiple factors including genetics, infections, diet, and environmental
exposures, with the immune response and subsequent regulatory mechanisms influencing pathophysiology,
disease progression and severity. The aryl hydrocarbon receptor (AhR) is an intracellular sensor for organic
compounds and toxins that regulates cellular homeostasis and physiological responses. Recent studies suggest
an important role for AhR in regulating airway epithelial and immune cell responses to lung inflammation. While
interest in AhR signaling has centered around immune cells and epithelium, how AhR activation influences
airway smooth muscle (ASM) per se, particularly in inflammation/asthma, are not known. In this regard, some
unresolved questions are A) Is ASM AhR signaling important, and if so, what is its expression and function during
inflammation and asthma? B) What roles do ASM AhR play in regulating mechanism that promotes airway
hyperresponsiveness and remodeling? Our novel preliminary studies show: 1) Human ASM expresses AhR,
which is enhanced during asthma; 2) AhR activation represses gene expression, particularly those involved in
proliferation and remodeling pathways; 3) AhR activation inhibits mitogen and/or diesel exhaust particle (DEP)-
induced ASM cell proliferation and migration; 4) AhR activation also reduces TGFβ-mediated ECM production
and deposition; 5) In a mixed allergen (MA)-induced asthma mouse model, smooth muscle specific AhR
knockout mice (AhRfl/fl/smMHCCre/0) show exacerbated hyperresponsiveness and worsening of lung function
compared to WT mice; 6) TCDD (AhR agonist) inhibits airway hyperresponsiveness and remodeling in MA-
challenged mice; 7) ASM AhR activation in vivo confirmed by increased ASM CYP1B1 expression. Thus, our
overall hypothesis is that activation of ASM AhR signaling inhibits inflammation-induced hyperresponsiveness
and remodeling in asthma. This will be tested via the following Specific Aims. 1) In human ASM, determine the
mechanisms of AhR expression and regulation in inflammation and asthma. 2) In human ASM, determine the
role of AhR signaling in proliferation and remodeling in the context of inflammation and asthma. 3) To determine
the in vivo importance of ASM-specific AhR signaling in airway remodeling in a chronic allergen mouse model of
asthma. Aim 1 explores AhR and ARNT (AhR nuclear translocator) expression and their underlying mechanisms
in the presence/absence of pro-inflammatory cytokines relevant to airway inflammation/asthma, MA, and DEP.
Aim 2 explores the AhR effects on ASM cell proliferation, migration, ECM, and their underlying mechanisms
relevant to airway remodeling. Aim 3 will integrate in vitro results in a clinically-relevant MA adult mouse model
of allergic asthma with/without chronic inhaled AhR agonist. Using AhRfl/fl/smMHCCre/0 mice, studies will assess
airway function, structure (remodeling), and changes in ASM proteins for mechanisms explored in Aims 1 and ...

## Key facts

- **NIH application ID:** 10979081
- **Project number:** 1R01HL171245-01A1
- **Recipient organization:** NORTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Rodney Britt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $613,934
- **Award type:** 1
- **Project period:** 2024-07-19 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979081

## Citation

> US National Institutes of Health, RePORTER application 10979081, Aryl hydrocarbon receptor signaling in Airway Inflammation (1R01HL171245-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979081. Licensed CC0.

---

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