The endocannabinoid anandamide is an airway relaxant in health and disease

Abstract

Chronic obstructive airway diseases are a global medical burden that is expected to increase in the near future. However, the underlying mechanistic processes are poorly understood so far. Herein, we show that the endocannabinoid anandamide (AEA) induces prominent airway relaxation in vitro and in vivo. In contrast to 2-arachidonlyglycerol-induced airway relaxation, this is mediated by fatty acid amide hydrolase (FAAH)-dependent metabolites. In particular, we identify mouse and also human epithelial and airway smooth muscle cells as source of AEA-induced prostaglandin E2 production and cAMP as direct mediator of AEA-dependent airway relaxation. Mass spectrometry experiments demonstrate reduced levels of endocannabinoid-like compounds in lungs of ovalbumin-sensitized mice indicating a pathophysiological relevance of endocannabinoid signalling in obstructive airway disease. Importantly, AEA inhalation protects against airway hyper-reactivity after ovalbumin sensitization. Thus, this work highlights the AEA/FAAH axis as a critical regulator of airway tone that could provide therapeutic targets for airway relaxation.

New insights into the mechanisms of anandamide-induced airway dilation placing its degradation enzyme, FAAH center stage. Commentary on: Simon A, von Einem T, Seidinger A, Matthey M, Bindila L, Wenzel D (2022) The endocannabinoid anandamide is an airway relaxant in health and disease. Nat Commun 13:6941

“…It is to be expected that a better understanding of the pulmonary endocannabinoid system likely will open tailored treatment options [10]. The limited number of preclinical studies that addressed the effect of endocannabinoids on airway smooth muscle tone yielded divergent results as to whether or not AEA relaxed airways [1,3,[7][8][9]11], but in most reports, its effects were ascribed to activation of cannabinoid receptors on axon terminals of airway nerves [1,3,8,9,11].…”

“…The two most abundant phytocannabinoids, Δ 9 tetrahydrocannabinol (THC) and cannabidiol (CBD) and the later discovered endocannabinoids, N-arachidonyl ethanolamine (anandamide, AEA) and 2-arachidonylglyerol (2-AG) activate the same G-protein coupled receptors, CB1 and CB2 [ 5 ]. The endocannabinoids, the cannabinoid receptors, and the biosynthetic and degradative enzymes are collectively referred to as endocannabinoid system, components of which are expressed in all organs [ 5 ] including the lung [ 7 ] affecting organ homeostasis. Cannabis may have beneficial effects in the lung as smoking marijuana exerts potent bronchodilation.…”

“…Understudied is the fact that degradation of anandamide by fatty acid amide hydrolase (FAAH) generates the bioactive lipid, arachidonic acid [ 5 ], the precursor of eicosanoids known to affect airway smooth muscle tone [ 2 ]. In this new contribution, Daniela Wenzel and her group [ 7 ] provide compelling evidence that relaxation of murine airways by anandamide (AEA) is not mediated by cannabinoid receptors but rather by FAAH-dependent degradation products. The evidence is based on an impressive range of sophisticated physiological as well as biochemical and immuno-histochemical approaches in mice.…”

“…Then, using CB1/CB2 null mice, they established that relaxation did not depend on cannabinoid receptors but rather on FAAH, as relaxation was absent in FAAH null mice. Active FAAH is expressed in mouse airways [ 7 ]. In line with these experiments, an inhibitor of FAAH prevented AEA-induced relaxation, and a non-hydrolysable AEA analog was ineffective.…”

“…Arachidonic acid, which itself potently relaxed the trachea preparations, is metabolized to eicosanoids by cyclooxygenase (COX), 5-lipoxygenase (5-LOX), and CYP450 [ 2 ]. Using small molecule inhibitors, the authors found that the COX inhibitor, indomethacin, but not inhibitors of the other enzymes attenuated AEA-induced relaxation [ 7 ]. COX generated products are the potent smooth muscle relaxants, prostacyclin (PGI) and prostaglandin E (PGE) [ 2 ].…”