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TRPV4: physiological role and therapeutic potential in respiratory diseases

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Abstract

Members of the family of transient receptor potential (TRP) channels have been implicated in the pathophysiology of a host of lung diseases. The role of these multimodal cation channels in lung homeostasis is thought to stem from their ability to respond to changes in mechanical stimuli (i.e., shear and stretch), as well as to various protein and lipid mediators. The vanilloid subfamily member, TRPV4, which is highly expressed in the majority of lung cell types, is well positioned for critical involvement in several pulmonary conditions, including edema formation, control of pulmonary vascular tone, and the lung response to local or systemic inflammatory insults. In recent years, several pharmacological inhibitors of TRPV4 have been developed, and the current generation of compounds possess high affinity and specificity for TRPV4. As such, we have now entered a time where the therapeutic potential of TRPV4 inhibitors can be systematically examined in a variety of lung diseases. Due to this fact, this review seeks to describe the current state of the art with respect to the role of TRPV4 in pulmonary homeostasis and disease, and to highlight the current and future roles of TRPV4 inhibitors in disease treatment. We will first focus on genera aspects of TRPV4 structure and function, and then will discuss known roles for TRPV4 in pulmonary diseases, including pulmonary edema formation, pulmonary hypertension, and acute lung injury. Finally, both promising aspects and potential pitfalls of the clinical use of TRPV4 inhibitors will be examined.

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Acknowledgments

NMG is supported by The PSI Foundation and The Canadian Anesthesiologists’ Society. WMK is supported by operating grants from the Deutsche Forschungsgemeinschaft (DFG), the Canadian Institutes of Health Research (CIHR), and the Heart & Stroke Foundation Canada.

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Authors and Affiliations

  1. Department of Anesthesia, University of Toronto, Toronto, ON, Canada

    Neil M. Goldenberg

  2. The Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, 30 Bond Street, Bond Wing 2-021, Toronto, ON, M5B 1W8, Canada

    Neil M. Goldenberg, Krishnan Ravindran & Wolfgang M. Kuebler

  3. German Heart Institute, Berlin, Germany

    Wolfgang M. Kuebler

  4. Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Wolfgang M. Kuebler

  5. Departments of Surgery and Physiology, University of Toronto, Toronto, ON, Canada

    Wolfgang M. Kuebler

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  1. Neil M. Goldenberg
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  2. Krishnan Ravindran
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  3. Wolfgang M. Kuebler
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Correspondence to Wolfgang M. Kuebler.

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Goldenberg, N.M., Ravindran, K. & Kuebler, W.M. TRPV4: physiological role and therapeutic potential in respiratory diseases. Naunyn-Schmiedeberg's Arch Pharmacol 388, 421–436 (2015). https://doi.org/10.1007/s00210-014-1058-1

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