Electromyographic Responses Across Different Pulse-Widths of Sacral Neuromodulation in Sheep.

OBJECTIVES: In rodents, we reported that short pulse-width (PW) neuromodulation might provide more efficient therapy delivery than traditional 0.21 msec PW. Using fully implanted, commercialized systems in the sheep, the goal of this study was to characterize the relationship of electromyographic (EMG) responses of the external anal sphincter (EAS) to different PWs of sacral neuromodulation (SNM). MATERIALS AND METHODS: In seven sheep, InterStim® quadripolar tined leads were implanted adjacent to the S3 nerve root bilaterally to deliver SNM and two pairs of intramuscular leads were placed on either side of the EAS for EMG sensing. The EMG responses to SNM with different PWs were examined using variable intensities in both anesthetized and conscious conditions. RESULTS: The EMG responses from ipsilateral EAS (IEAS ) and contralateral EAS (CEAS ) were compared. The area under the curve of EMG responses from IEAS were significantly stronger than that from CEAS. The late component EMGs were more sensitive to nerve stimulation with a higher response amplitude in awake sheep. The response threshold-PW relationship from the IEAS as ascertained visually and with EMG in anesthetized and awake sheep were fitted with a monoexponential nonlinear regression; the resulting chronaxies were of 0.05 msec (n = 6), and 0.04 msec (n = 6), and 0.04 msec (n = 8), respectively. CONCLUSIONS: In both anesthetized and awake conditions, a similar motor response may be evoked in the EAS at PWs much shorter (0.04-0.05 msec) than the 0.21 msec typically used with SNM. Potential battery savings manifested by shorter PW would provide more efficient therapy delivery and increased longevity of the stimulator.

Mechanosensitive transient receptor potential vanilloid 4 regulates Dermatophagoides farinae-induced airway remodeling via 2 distinct pathways modulating matrix synthesis and degradation.

Contributions of mechanical signals to airway remodeling during asthma are poorly understood. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, has been implicated in cardiac and pulmonary fibrosis; however, its role in asthma remains elusive. Employing a Dermatophagoides farinae-induced asthma model, we report here that TRPV4-knockout mice were protected from D. farinae-induced airway remodeling. Furthermore, lung fibroblasts that were isolated from TRPV4-knockout mice showed diminished differentiation potential compared with wild-type mice. Fibroblasts from asthmatic lung exhibited increased TRPV4 activity and enhanced differentiation potential compared with normal human lung fibroblasts. Of interest, TGF-ß1 treatment enhanced TRPV4 activation in a PI3K-dependent manner in normal human lung fibroblasts in vitro Mechanistically, TRPV4 modulated matrix remodeling in the lung via 2 distinct but dependent pathways: one enhances matrix deposition by fibrotic gene activation, whereas the other slows down matrix degradation by increased plasminogen activator inhibitor 1. Of importance, both pathways are regulated by Rho/myocardin-related transcription factor-A and contribute to fibroblast differentiation and matrix remodeling in the lung. Thus, our results support a unique role for TRPV4 in D. farinae-induced airway remodeling and warrant further studies in humans for it to be used as a novel therapeutic target in the treatment of asthma.-Gombedza, F., Kondeti, V., Al-Azzam, N., Koppes, S., Duah, E., Patil, P., Hexter, M., Phillips, D., Thodeti, C. K., Paruchuri, S. Mechanosensitive transient receptor potential vanilloid 4 regulates Dermatophagoides farinae-induced airway remodeling via 2 distinct pathways modulating matrix synthesis and degradation.