Glial‐derived neurotrophic factor in human airway smooth muscle

Abstract

Airway smooth muscle (ASM) cells modulate the local airway milieu via production of inflammatory mediators and growth factors including classical neurotrophins, such as brain-derived neurotrophic factor (BDNF). The glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs) are nonclassical neurotrophins and their role in the airway is barely understood. The major GFLs, GDNF and Neurturin (NRTN) bind to GDNF family receptor (GFR) α1 and α2 respectively that pair with Ret receptor to accomplish signaling. In this study, we found GDNF is expressed in human lung and increased in adult asthma, while human ASM expresses GDNF and its receptors. Accordingly, we used human ASM cells to test the hypothesis that ASM expression and autocrine signaling by GFLs regulate [Ca 2+ ] i . Serum-deprived ASM cells from nonasthmatics were exposed to 10 ng/ml GDNF or NRTN for 15 min (acute) or 24 h (chronic). In fura-2 loaded cells, acute GDNF or NRTN alone induced [Ca 2+ ] i responses, and further enhanced responses to 1 µM ACh or 10 µM histamine. Ret inhibitor (SPP86; 10 µM) or specific GDNF chelator GFRα1-Fc (1 µg/ml) showed roles of these receptors in GDNF effects. In contrast, NRTN did not enhance [Ca 2+ ] i response to histamine. Furthermore, conditioned media of nonasthmatic and asthmatic ASM cells showed GDNF secretion. SPP86, Ret inhibitor and GFRα1-Fc chelator markedly decreased [Ca 2+ ] i response compared with vehicle, highlighting autocrine effects of secreted GDNF. Chronic GDNF treatment increased histamine-induced myosin light chain phosphorylation. These novel data demonstrate GFLs particularly GDNF/GFRα1 influence ASM [Ca 2+ ] i and raise the possibility that GFLs are potential targets of airway hyperresponsiveness.

Evaluation of the concentration of growth associated protein-43 and glial cell-derived neurotrophic factor in degenerated intervertebral discs of the lumbosacral region of the spine

“…36 Thus, it seems that in a microenvironment in which advanced degeneration occurs, the expression of GDNF increases under the influence of proinflammatory factors. 37,38 Our findings indicate that there is a significant increase in GDNF concentration and an invasion of GDNF-positive nerve fibers in degenerated IVDs. However, it is interesting to note that when the degree of radiological degeneration was graded 5, there was a significant decrease in the concentration of GDNF and the number and concentration of GDNF-positive nerve fibers.…”

“… 36 Thus, it seems that in a microenvironment in which advanced degeneration occurs, the expression of GDNF increases under the influence of pro-inflammatory factors. 37 , 38 …”

Neurons enhance blood-brain barrier function via upregulating claudin-5 and VE-cadherin expression due to GDNF secretion

“…GDNF forms a heterohexameric complex with two GFR α 1 molecules and two RET receptors to activate the GDNF-GFR α 1-RET signaling (Fielder et al, 2018). The RET receptor tyrosine kinase inhibitor SPP-86 (Bhallamudi et al, 2021) and Src-type kinase inhibitor PP2 (Morita et al, 2006) were used to further investigate whether GDNF upregulated the expression of claudin-5 and VE-cadherin in hCMEC/D3 cells by activating the GDNF-GFR α 1-RET signaling pathway. Both SPP-86 and PP2 markedly attenuated claudin-5 and VE-cadherin expression induced by GDNF (Figure 2K) and US-CM (Figure 2L).…”

Anti-inflammatory effects of oral prednisolone at stable state in people treated with mepolizumab: a proteomic and bulk transcriptomics analysis

“…GDNF signals through the NCAM receptor 31 . In vitro , GDNF expression is increased in human airway smooth muscle cells in asthma and influences intracellular calcium responses 32 . In rat asthma models, GDNF expression was significantly higher than in controls and central sensitisation to GDNF injected in the lateral ventricle led to a significant increase in bronchial IL-4 and Th2 cells, and significant decrease in pulmonary function 33 .…”