Dysregulated Metabolism in the Pathophysiology of Non-Allergic Obese Asthma

Matthew McCravy, Jennifer L Ingram, Loretta G Que Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USACorrespondence: Matthew McCravyDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Box 102349, Durham, NC, 27710, USATel +1 731-571-4816Email matthew.mccravy@duke.eduAbstract: Asthma is an obstructive airway disease that is characterized by reversible airway obstruction and is classically associated with atopic, TH 2 driven inflammation. Landmark studies in the second half of the twentieth century identified eosinophils as a key mediator of inflammation and steroids, both inhaled and systemic, as a cornerstone of therapy. However, more recently other phenotypes of asthma have emerged that do not respond as well to traditional therapies. In particular, obese patients who develop asthma as adults are less likely to have eosinophilic airway inflammation and do not respond to traditional therapies. Obese patients often have metabolic comorbidities such as impaired glucose tolerance and dyslipidemias, also known as metabolic syndrome (MetS). The unified pathophysiology of metabolic syndrome is not known, however, several signaling pathways, such as the neuropeptide glucagon-like peptide-1 (GLP-1) and nitric oxide (NO) signaling have been shown to be dysregulated in MetS. These pathways are targeted by commercially available medications. This review discusses the potential roles that dysregulation of the GLP-1 and NO signaling pathways, along with arginine metabolism, play in the development of asthma in obese patients. GLP-1 receptors are found in high density in the lung and are also detectable in bronchoalveolar lavage fluid. NO has long been associated with asthma. We hypothesize that these derangements in metabolic signaling pathways underpin the asthmatic phenotype seen in obese patients with non-eosinophilic airway inflammation and poor response to established ...