Effects of Glial Derived Neurotrophic Factor on Remodeling and Mitochondrial Function in Human Airway Smooth Muscle Cells

Airway smooth muscle (ASM) cells play important roles in airway remodeling of asthma. Our previous studies show that in vivo administration of glial derived neurotrophic factor (GDNF) in mice induces thickening and collagen deposition in bronchial airways, while chelation of GDNF by GFRα1-Fc attenuates airway remodeling in the context of allergen exposure. To determine whether GDNF has direct effects on ASM, in this study, we examined GDNF in ASM cells from normal vs. asthmatic humans. We found that GDNF treatment of human ASM cells had only minor effects on cell proliferation, intracellular expression or extracellular deposition of collagen I, collagen III, and fibronectin. Endoplasmic reticulum (ER) stress response and mitochondrial function have been implicated in asthma. We investigated whether GDNF regulates these aspects in human ASM. We found that GDNF treatment did not affect ER stress protein expression in normal or asthmatic cells. However, GDNF treatment impaired mitochondrial morphology in ASM but without significant effects on mitochondrial respiration. Thus, it is likely that in vivo effects of GDNF on airway remodeling per se involve cell types other than those on ASM, and thus ASM may serve more as a source of GDNF rather than a target.