In a diverse cohort of asthma patients, we found that participants with OSA had increased asthma morbidity, independent of L-arginine metabolite profiles. Though not associated with asthma morbidity, asthmatics with OSA had higher serum levels of NOS inhibitor ADMA, reduced L-arginine availability for NOS (lower L-arginine to ornithine ratio), and increased arginase activity (elevated L-ornithine and proline) compared to those without OSA. While not associated with asthma morbidity, it is possible that the differences in L-arginine metabolites between OSA and non-OSA asthmatics plays a role in shared pathophysiology, which was not investigated by this study.
Our findings that OSA is associated with decreased quality of life and asthma control, even after adjusting for BMI, is consistent with prior work.(29) We found no association with OSA and asthma morbidity as measured by oral corticosteroid use or ED visits. Other observational studies have shown increased asthma exacerbations among those with OSA,(30–33) though this relationship is not consistently seen across the body of literature(34).
This study adds to the understanding of OSA and asthma as it is the first study to compare L-arginine metabolism among asthma patients with and without OSA. Our observation of increased ADMA in asthma patients with OSA is consistent with prior studies of obesity associated asthma(9, 10) and among OSA patients,(13–15) though has not been previously evaluated in patients with both comorbidities, though this association did not remain statistically significant after adjustment for BMI. The association of increased serum L-ornithine and proline among asthma subjects with OSA remained significant after accounting for BMI. While an increase in serum proline was recently described in patients with mild-to-moderate OSA,(16) this association has not previously been reported among asthma patients with OSA.
In addition to increased serum ADMA, we found that those with OSA and asthma had lower L-arginine to ornithine ratios and increased L-ornithine and proline. The decreased L-arginine to ornithine ratio suggests preferred metabolism of L-arginine by arginase vs NOS. L-ornithine, the product of arginase activity, is further metabolized to proline, a precursor of collagen deposition. This may ultimately lead to airway remodeling and subsequent decrease in lung function and poor asthma control. While increased ADMA and arginase had been described in asthma before, this study provides the first data suggesting an even greater increase in arginase activity in asthma patients with OSA. Of note, we measured serum levels of circulating L-arginine metabolites, which may be more informative in obesity and comorbid OSA but may not be an adequate representation of airway L-arginine metabolism.
In interpreting the results from this study, it is important to consider the following limitations. We conducted a cross sectional study and could not determine which condition, asthma or OSA, developed first in each patient. The main predictor of interest, OSA, was self-reported, which could have resulted in some misclassification of OSA (e.g., women are more likely than men to underreport OSA(35)). Data on CPAP usage was not available and variability in the treatment of OSA may have affected L-arginine metabolites and asthma outcomes among this group. Study data were not collected to assess the relationship between OSA, L-arginine metabolites and asthma morbidity outcomes, therefore the study may have been underpowered for the analyses presented here. Finally, some participants did not provide blood samples, therefore there were some missing data for L-arginine metabolites that could have introduced bias and further decreased statistical power. While this cohort had significant racial and ethnic diversity, participants were predominantly female, limiting some of the external generalizability.
Despite these limitations, this is the first study to show differences in L-arginine metabolism among asthma patients with and without OSA. The finding of increased L-arginine metabolism by arginase demonstrated by the reduction in L-arginine to ornithine ratio and increase ornithine and proline levels may provide potential therapeutic options for management of asthma in patients with comorbid OSA. The finding of increased ADMA is concordant with studies on obesity. What is not clear based on our results, is whether the increases seen in serum L-ornithine and proline is secondary to increased arginase expression and activity or whether this is secondary to increased channeling of L-arginine through arginase secondary to NOS inhibition by increased ADMA.
The mechanisms driving the relationship between OSA and asthma are not well defined, though there is likely a reciprocal relationship whereby each disease worsens control of the other. Independently, patients with OSA or asthma have both been found to have increased levels of ADMA, lower L-arginine bioavailability, and increased arginase activity.(9, 10, 13–15) In OSA patients, the imbalance between ADMA and L-arginine, leading to NOS uncoupling, is thought to contributed to pulmonary vasculature dysfunction via vascular oxidative stress(36) whereas in asthma this imbalance is thought to lead to increased airway oxidative stress. Whether this imbalance arises first in one disease then worsens or leads to the development of the other is unknown. The increase in proline among those with OSA seen in our study suggests that OSA may cause an increase in proline, which may lead to long-term vascular and/or airway remodeling.
Therapeutic interventions that may result in increasing L-arginine availability for NOS include arginase inhibition and L-arginine or L-citrulline supplementation. A recent study on L-citrulline supplementation has shown improvement in lung function and asthma control among those with obesity associated asthma.(5) A better understanding of the mechanisms of asthma morbidity among patients with concomitant OSA will help drive therapeutic discovery.