Novel Therapeutic Strategies for Adult Obese Asthmatics

The adult obese patient with worsening asthma despite appropriate controller drug therapy is extraordinarily complicated to manage and treat. For example, consider a 40 year old woman with a medical history notable for adult-onset, non-allergic asthma, obesity, diabetes mellitus, and sleep apnea whose course has been punctuated by several emergency department admissions in the past year. She already requires continuous oral prednisone and four drug therapy for her asthma. How should such a patient be evaluated and treated for the foreseeable future? While asthma is a complex syndrome that affects an estimated 26 million people in the United States, there are gaps in the recognition and management of asthmatic subgroups asthmatics. Extrapolating results from short-term, randomized clinical trials to a broad, heterogeneous population of asthmatics treated in community settings is fraught with difficulty and can result in repeated trial-and-error therapeutic interventions. We still lack the ability to recognize different asthma phenotypes, to adapt and integrate care when comorbidities exist, and adopt new treatments. While published guidelines, including the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report-3 (EPR-3) and the World Health Organization (WHO) Global Initiative for Asthma (GINA) present step-wise evaluation and therapeutic recommendations for chronic persistent asthma management, they do not outline coherent plans for the care of adult-onset, obese asthmatics. In this manuscript, we propose alternative approaches that may prove to be future treatments for adult obese asthmatics that do not respond to the standard controller asthma therapies of inhaled corticosteroids, bronchodilators, and anti-leukotriene drugs. We draw parallels between seemingly disparate therapeutics through their common signaling pathways (Figure 1). Specifically, we describe how metformin and statins potentially improve airway inflammation through activation of adenosine monophosphate activated protein kinase (AMPK), a key regulator of cellular metabolism and energy production, and through their effects on nitric oxide (NO). In addition, we discuss nutritional supplements, such as L-arginine, omega-3 fatty acids, and other minerals and vitamins that are currently studied and may potentially be used in combination with conventional therapies. Figure 1 Potential therapeutics for obese, adult asthmatics described in this review modulate pathways common to several metabolic and nutritional disorders. This allows for the treatment of several comorbidities by targeting their common dysfunction as opposed ... Metformin, insulin resistance, and asthma The metabolic syndrome with insulin resistance may characterize subsets of asthmatics more than we recognize. The relationship between obesity, insulin resistance and asthma has been clearly established, however the mechanisms by which they influence the pathogenesis of asthma is unclear1. Metformin is a biguanidine class oral anti-diabetic drug used to treat type 2 diabetes and insulin resistance. Although metformin reduces glucose production in the liver through inhibition of gluconeogenesis, the precise mechanisms are unknown and it may have differing modalities in different cell types. Metformin may indirectly activate AMPK by increasing AMP:ATP ratios through mild but specific inhibition of the mitochondrial respiratory chain complex I in hepatocytes, skeletal muscle, endothelial cells, pancreatic B-cells and neurons2. Peroxynitrite, generated by inhibition of complex I, activates AMPK through a c-Src and PI3K-dependent pathway in bovine aortic endothelial cells3. Metformin also directly activates AMPK the inhibitions of AMP deaminase in isolated skeletal muscle4. In the lung, metformin up-regulates AMPK expression and activity and diminishes pro-inflammatory cytokine secretion in human bronchial epithelial cells, downregulating IkK activity and inhibiting NF-κB5. Obese asthmatics are less responsive to typical asthma controller therapy possibly because of contributing factors such as an increased pro-inflammatory environment that blunt the efficacy of treatment6, yet there have been studies that have shown no difference in induced sputum eosinophils, a biomarker of airway inflammation, between obese and lean asthmatics7,8. However, in a study of obese and lean asthmatics by Desai et al, there were similarities in sputum eosinophil counts between the two groups, but an increase in interleukin-5 (IL5), a mediator of eosinophil activation, in the sputum and increased eosinophil accumulation in the submucosal layer of the obese asthmatic group9. The results from a study utilizing a high fat-diet-induced obese mouse model (male C57BL6/J) of allergic airway inflammation are in agreement with patient observations. While eosinophil numbers in the bronchoalveolar lavage (BAL) from allergen-challenged, obese mice were decreased compared to their lean counterparts, the levels of infiltrated eosinophils in the lung tissue were higher in the obese mice. Treatment of these allergen-challenged obese mice with metformin reduced tissue eosinophil infiltration and increased the number of cells in the BAL fluid suggest differing modes of regulation for eosinophil migration and function between obese and lean asthmatics, possibly through decreased NF-kB activation10. Another mouse study utilizing lean BALB/C female mice demonstrated that metformin decreases eosinophilic inflammation, peribronchial fibrosis and mucin secretion coupled with increased ratios of activated phospho-AMPK to total AMPK and decreased oxidative stress as measured by the ratio of reduced to oxidized glutathione11. Metformin can also increase nitric oxide synthase 3 (NOS3, endothelial NOS, eNOS) production of NO and improve endothelial function through AMPK-dependent positive regulation of NOS3 activity and inhibition of NOS3 negative regulators. Treatment of endothelial cell lines and mice with metformin increases AMPK dependent NOS3 phosphorylation at the regulatory site Ser 1177/1179 and NO production12–14. NOS3 activity is negatively regulated through phosphorylation of Thr495 by protein kinase C-β (PKCβ), which is up-regulated in human asthmatics and patients with insulin resistance15. Pharmacologic inhibition of PKCβ in endothelial cells freshly isolated from diabetics decreases basal levels of Thr495 phosphorylated NOS3 and improved insulin-mediated signaling of NOS3. Overall NOS expression and activity is also reduced in murine models of allergic inflammation and human asthmatics16–18. Overexpression of NOS3 in a mouse model of allergic asthma attenuates airway inflammation and airway hyperresponsiveness; possibly acting through increased levels of S-nitrosothiols in the lung or decreased interferon- γ (IFN-γ), IL5 or IL1019. Further studies are necessary to uncover whether NOS3 could be regulated by metformin in models of asthma or asthmatics. These findings suggest that introducing metformin in conjunction with standard asthma controller therapy could prove beneficial for outcomes in obese asthmatics by modulation of NOS3 activity or other AMPK-dependent metabolic signaling pathways.