# SANDIA: Supplementing L-citrulline to overweight late Asthma oNset phenotypes to increase airway L-arginine/ADMA ratio and Improve Asthma control

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $745,579

## Abstract

ABSTRACT
Obesity affects approximately 40% of adult asthmatics in the U.S. Obese patients who develop asthma after
childhood (Late onset), can be highly symptomatic and poorly controlled despite having lower exhaled nitric oxide
(FeNO) levels. This type of late onset asthma is a frequent phenotype encountered in adults, particularly among
obese females. Because these asthmatics have predominantly non-T2 type airway inflammation, they often fail to
respond to conventional therapy and are burdened by uncontrolled symptoms imploring the identification of novel
precision therapeutic approaches for this predominant asthma phenotype.
 Several key clinical observations have led to our identification of a potential mechanistic pathway in late
onset obese asthmatics that can account for their reduced FeNO and worsening respiratory symptoms. Among
these subjects, increasing BMI associates with reduced bioavailability of NO, an important endogenous
bronchodilator. The reduction of NO occurs through uncoupling of NO synthase (NOS), by accumulation of
asymmetric di-methyl arginine (ADMA). This preferentially promotes reactive oxygen species (ROS) formation at
the expense of NO production, which can also result in loss of S-nitrosoglutathione (GSNO), a potent endogenous
bronchodilator, further promoting bronchoconstriction. In these asthmatics, lower plasma L-arginine/ADMA ratios,
are associated with lower FeNO, reduced lung function and asthma related quality of life, as well as increased
respiratory symptom frequency. Moreover, in primary human airway epithelial cells low L-arginine uncouples
inducible NOS (iNOS), reducing NO bioavailability, and increasing ROS. L-arginine deficiency can also contribute
to increased free radical formation and airway inflammation by impairing mitochondrial function. In our pilot studies,
the administration of L-citrulline to patients with late onset asthma augments sputum L-arginine and the L-
arginine/ADMA ratio, increasing FEV1 and FeNO, while improving asthma control. Further, in asthmatic airway
epithelial cells, L-citrulline reverses ADMA-mediated NOS uncoupling and decreases nitrotyrosine formation. We
hypothesize that L-citrulline supplementation is a safe, novel drug strategy to treat obese late onset asthma by
restoring L-arginine/ADMA ratio, decreasing oxidative and nitrosative stress, and ultimately reducing bronchial
hyperresponsiveness and improving asthma control.
 To test this hypothesis, we will treat late onset obese asthmatics with L-citrulline in a proof of concept
(POC) study (Aim 1). Before and after blinded treatment, bronchoscopic lavage and epithelial brushing analyses
will be performed in a subset of study participants to identify underlying mechanisms at the cellular (Aim 2) and
subcellular levels (Aim 3).
 As current medications have limited efficacy in obese late onset asthma, new therapeutics are needed. This
study allows us the unique opportunity to test a novel therapy for obese asthma and focus...

## Key facts

- **NIH application ID:** 9968367
- **Project number:** 5R01HL146542-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Fernando Holguin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $745,579
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968367

## Citation

> US National Institutes of Health, RePORTER application 9968367, SANDIA: Supplementing L-citrulline to overweight late Asthma oNset phenotypes to increase airway L-arginine/ADMA ratio and Improve Asthma control (5R01HL146542-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9968367. Licensed CC0.

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