Inhaled β2 Adrenergic Agonists and Other cAMP-Elevating Agents: Therapeutics for Alveolar Injury and Acute Respiratory Disease Syndrome?

Abstract

Inhaled long-acting b-adrenergic agonists (LABAs) and short-acting b-adrenergic agonists are approved for the treatment of obstructive lung disease via actions mediated by b2 adrenergic receptors (b2-ARs) that increase cellular cAMP synthesis. This review discusses the potential of b2-AR agonists, in particular LABAs, for the treatment of acute respiratory distress syndrome (ARDS). We emphasize ARDS induced by pneumonia and focus on the pathobiology of ARDS and actions of LABAs and cAMP on pulmonary and immune cell types. b2-AR agonists/cAMP have beneficial actions that include protection of epithelial and endothelial cells from injury, restoration of alveolar fluid clearance, and reduction of fibrotic remodeling. b2-AR agonists/cAMP also exert antiinflammatory effects on the immune system by actions on several types of immune cells. Early administration is likely critical for optimizing efficacy of LABAs or other cAMP-elevating agents, such as agonists of other Gs-coupled G protein-coupled receptors or cyclic nucleotide phosphodiesterase inhibitors. Clinical studies that target lung injury early, prior to development of ARDS, are thus needed to further assess the use of inhaled LABAs, perhaps combined with inhaled corticosteroids and/or long-acting muscarinic cholinergic antagonists. Such agents may provide a multipronged, repurposing, and efficacious therapeutic approach while minimizing systemic toxicity.Significance Statement--Acute respiratory distress syndrome (ARDS) after pulmonary alveolar injury (e.g., certain viral infections) is associated with $40% mortality and in need of new therapeutic approaches. This review summarizes the pathobiology of ARDS, focusing on contributions of pulmonary and immune cell types and potentially beneficial actions of b2 adrenergic receptors and cAMP. Early administration of inhaled b2 adrenergic agonists and perhaps other cAMP-elevating agents after alveolar injury may be a prophylactic approach to prevent development of ARDS.

Ex Vivo Pulmonary Oedema after In Vivo Blast-Induced Rat Lung Injury: Time Dependency, Blast Intensity and Beta-2 Adrenergic Receptor Role

“…Ion channels which can be modulated by β 2 -adrenoceptor agonists by their activity or expression include epithelial sodium channel (ENaC) [ 21 , 36 , 37 ], Na + /K + -ATPase [ 30 , 38 , 39 , 40 , 41 ], cystic fibrosis transmembrane conductance regulator (CFTR) [ 42 ], cyclic nucleotide-gated cation (CNG) channels [ 21 ], nonselective cation channel (NSCCa) [ 43 ] and Ca 2+ dependent K + channel (BKCa) [ 44 , 45 ]. Moreover, treatment with β2-agonists increases the secretion of surfactant proteins and exerts anti-inflammatory properties by influencing several types of immune cells and reducing fibrotic remodelling [ 16 , 46 ]. However, β 2 -adrenoceptor agonists have not been shown to be beneficial in two clinical studies of acute respiratory distress syndrome (ARDS) that included multiple causes of lung injuries [ 36 ].…”

“…β 2 -ARs are transmembrane proteins expressed in a variety of cells such as smooth muscle cells, immune cells, epithelial cells, skeletal muscle cells, and glandular cells [ 16 ]. β 2 -AR expression in the lung and in particular in alveoli has been found to be among the highest of all tissues [ 16 ].…”

“…β 2 -ARs are transmembrane proteins expressed in a variety of cells such as smooth muscle cells, immune cells, epithelial cells, skeletal muscle cells, and glandular cells [ 16 ]. β 2 -AR expression in the lung and in particular in alveoli has been found to be among the highest of all tissues [ 16 ]. Stimulation of β 2 -ARs launches several signalling mechanisms/pathways, which are important in physiological and pathophysiological aspects of cell life [ 16 ].…”

“…β 2 -AR expression in the lung and in particular in alveoli has been found to be among the highest of all tissues [ 16 ]. Stimulation of β 2 -ARs launches several signalling mechanisms/pathways, which are important in physiological and pathophysiological aspects of cell life [ 16 ]. Indeed, they have been shown to exert a protective effect by enhancing alveolar and liquid clearance, therefore reducing pulmonary oedema [ 17 ].…”

Advances in the Regulation of Macrophage Polarization by Mesenchymal Stem Cells and Implications for ALI/ARDS Treatment

“…Treatment of ALI/ARDS is supportive. The current clinical treatment of ALI/ARDS is based on lung-protective mechanical ventilation and fluid management therapy ( 9 ), supplemented by glucocorticoids ( 10 , 11 ), surfactants ( 12 , 13 ), N-acetylcysteine ( 14 , 15 ), statins ( 16 , 17 ), β2 agonists ( 18 ), neuromuscular blockade ( 3 , 19 ), extracorporeal membrane pulmonary oxygenation ( 20 ) and prophylaxis for venous thromboembolism ( 21 ). In addition, for infections such as sepsis-induced ARDS, antimicrobial drugs can be used pertinently ( 22 ).…”