Formoterol, the Most Effective Bronchodilator, Has No Anti-Inflammatory nor Metabolic Modulatory Effects in Severe Asthma Induced by Aspergillus fumigatus

Abstract

In an increasing number of asthma studies, modulation of pulmonary metabolic reprogramming using therapeutic agents targeting metabolic enzymes promoted bronchodilatory, anti-inflammatory, and antiremodeling effects. Although formoterol is the bronchodilator of choice for asthma management, its anti-inflammatory and metabolic modulatory effects in severe asthma have not been investigated. The present study aimed to explore formoterol’s anti-inflammatory and metabolic modulatory potential in Aspergillus fumigatus (Af)-induced severe asthma model to establish additional benefits in the difficult-to-treat severe asthma subtype. Formoterol was administered via nebulization in an Af-induced severe asthma mouse model. Airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, and metabolic pathways on glycolysis and oxidative phosphorylation in the lungs were assessed. An in-depth analysis of formoterol’s effect on airway smooth muscle metabolism was also performed. Inhaled formoterol significantly inhibited methacholine-induced AHR in Af-induced severe asthma in a dose-dependent manner (p < 0.001). However, it did not reduce airway immune cell counts, inflammation score of hematoxylin and eosin-stained lung sections, airway mucus hypersecretion, lung levels of proinflammatory cytokines and chemokines, and α-smooth muscle actin-positive airway smooth muscle wall thickness. In addition, formoterol did not show any effects on lung single-cell glycolytic and oxidative phosphorylation activities or on the levels of metabolic enzymes in lung tissues and α-smooth muscle actin-positive airway smooth muscle in Af-induced severe asthma. Inhaled formoterol is an entirely potent and effective bronchodilator against Af-induced severe asthma, with no effect on airway inflammation, airway remodeling, and pulmonary metabolism.