Glucagon induces airway smooth muscle relaxation by nitric oxide and prostaglandin E2

Abstract

Glucagon is a hyperglycemic pancreatic hormone that has been shown to provide a beneficial effect against asthmatic bronchospasm. We investigated the role of this hormone on airway smooth muscle contraction and lung inflammation using both in vitro and in vivo approaches. The action of glucagon on mouse cholinergic tracheal contraction was studied in a conventional organ bath system, and its effect on airway obstruction was also investigated using the whole-body pletysmographic technique in mice. We also tested the effect of glucagon on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and inflammation. The expression of glucagon receptor (GcgR), CREB, phospho-CREB, nitric oxide synthase (NOS)-3, pNOS-3 and cyclooxygenase (COX)-1 was evaluated by western blot, while prostaglandin E 2 (PGE 2 ) and tumour necrosis factor-a were quantified by enzyme-linked immunoassay and ELISA respectively. Glucagon partially inhibited carbacholinduced tracheal contraction in a mechanism clearly sensitive to des-His1-[Glu9]-glucagon amide, a GcgR antagonist. Remarkably, GcgR was more expressed in the lung and trachea with intact epithelium than in the epithelium-denuded trachea. In addition, the glucagon-mediated impairment of carbachol-induced contraction was prevented by either removing epithelial cells or blocking NOS (L-NAME), COX (indomethacin) or COX-1 (SC-560). In contrast, inhibitors of either heme oxygenase or COX-2 were inactive. Intranasal instillation of glucagon inhibited methacholine-induced airway obstruction by a mechanism sensitive to pretreatment with L-NAME, indomethacin and SC-560. Glucagon induced CREB and NOS-3 phosphorylation and increased PGE 2 levels in the lung tissue without altering COX-1 expression. Glucagon also inhibited LPS-induced AHR and bronchoalveolar inflammation. These findings suggest that glucagon possesses airway-relaxing properties that are mediated by epithelium-NOS-3-NO-and COX-1-PGE 2 -dependent mechanisms.

Diabetes Downregulates Allergen-Induced Airway Inflammation in Mice

“…One possible explanation is the hyperglucagonemia that is present in diabetic animals [ 29 ]. In line with this idea, we demonstrated that glucagon inhibited LPS-induced neutrophil influx and TNF- α production in BAL of mice [ 30 ].…”

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice

“…Pulmonary dysfunction was measured as we previously described ( 27 , 33 , 34 ). For invasive in vivo assessment, mice were anesthetized and tracheostomized, then were placed in a whole-body plethysmograph to maintain spontaneous breathing connected to a computer-controlled ventilator (Forced Pulmonary Maneuver System ® , Buxco Research Systems © , Wilmington, North Carolina USA).…”

“…and after 10 s, a new set of maneuvers were conducted to assess Rl changes. Non-invasive in vivo assessment of respiratory frequency and Penh was performed using barometric whole-body plethysmography (Buxco Research System, Wilmington, NC, USA) as we previously described ( 34 ). Measurements were recorded for 5 min for each animal in conscious, spontaneously breathing mice.…”

A machine learning and network framework to discover new indications for small molecules

“…These connections are supported by the fact that hormonal agents like glucocorticoids and beta adrenergic agonists have been used for decades to relax the airway musculature in patients with reactive airways disease and chronic obstructive pulmonary disease 22 . Interestingly, our analysis identified glucagon, a peptide hormone that increases blood glucose levels, as a candidate for “Respiratory System” repurposing and this use already has clinical support 23,24 . Additionally, drugs classified as “Respiratory System” and “Dermatological” were also observed to be highly associated because of interactions such as the one between ciclesonide and hydrocortisone (8.43 CATNIP score).…”