Yong-Xiao Wang
Albany Medical College, USA
Title: Novel signaling mechanisms for airway remodeling and hyperresponsiveness in chronic obstructive pulmonary disease (COPD)
Biography
Biography: Yong-Xiao Wang
Abstract
Statement of the Problem: COPD is the fourth leading cause of mortality in the world and will be the second leading cause of death by 2020. However, the molecular processes for this devastating disease remain largely unknown, and current treatments are limited. Purposes: This study was to test a novel hypothesis that the reciprocal crosstalks between ion channel-mediated calcium signaling and transcriptional factor-dependent inflammatory signaling are essential for COPD. The current study also sought to determine whether specific genetic and pharmacological targets for these signaling molecules would become effective therapeutics for COPD. Methodology: Ion channel expression and activity were assayed using RT-PCR, Western blotting and patch clamp recordings; airway remodeling and hyperresponsiveness examined using in-situ immunohistological staining and both in-vivo and in-vitro muscle contraction measurements; and targeted molecule activities changed using virus-based genetic modifications. Findings: Among 7 known different gene-encoded classic transient receptor potential (TRPC) channel members, only shows the TRPC3 channel a predominant activity and expression in airway smooth muscle cells (ASMCs). This channel is significantly upregulated in COPD patient ASMCs. Mice with nicotine-induced COPD also show largely increased TRPC3 channel expression and activity in ASMCs. In-vivo lentiviral shRNA-mediated TRPC3 channel knockdown abolishes airway remodeling and hyperresponsiveness in COPD. The channel blocker Pyr3 produces similar effects. The TRPC3 channel promoter has binding sites for NFkB, an important inflammatory transcription factor. NFkB expression and activity are increased in COPD ASMCs. Genetic NFkB function gain and loss, respectively, increases and blocks, TRPC3 channel promoter activity and expression. Vise verse, TRPC3 channel gain and loss, downregulates and upregulates, NFkB activity and expression. Conclusion & Significance: Reciprocal crosstalks between TRPC3 channel-mediated calcium signaling and NFkB-dependent inflammatory signaling are essential for airway remodeling and hyperresponsiveness in COPD. Specific lentiviral TRPC3 channel shRNAs and channel blockers may become novel and effective treatments for COPD.