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      Modulators of Transient Receptor Potential (TRP) Channels as Therapeutic Options in Lung Disease

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          Abstract

          The lungs are essential for gas exchange and serve as the gateways of our body to the external environment. They are easily accessible for drugs from both sides, the airways and the vasculature. Recent literature provides evidence for a role of Transient Receptor Potential (TRP) channels as chemosensors and essential members of signal transduction cascades in stress-induced cellular responses. This review will focus on TRP channels (TRPA1, TRPC6, TRPV1, and TRPV4), predominantly expressed in non-neuronal lung tissues and their involvement in pathways associated with diseases like asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), lung fibrosis, and edema formation. Recently identified specific modulators of these channels and their potential as new therapeutic options as well as strategies for a causal treatment based on the mechanistic understanding of molecular events will also be evaluated.

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          Chronic obstructive pulmonary disease in non-smokers.

          Sundeep S Salvi, Peter Barnes (2009)
          Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Tobacco smoking is established as a major risk factor, but emerging evidence suggests that other risk factors are important, especially in developing countries. An estimated 25-45% of patients with COPD have never smoked; the burden of non-smoking COPD is therefore much higher than previously believed. About 3 billion people, half the worldwide population, are exposed to smoke from biomass fuel compared with 1.01 billion people who smoke tobacco, which suggests that exposure to biomass smoke might be the biggest risk factor for COPD globally. We review the evidence for the association of COPD with biomass fuel, occupational exposure to dusts and gases, history of pulmonary tuberculosis, chronic asthma, respiratory-tract infections during childhood, outdoor air pollution, and poor socioeconomic status.
          Article 0 comments Cited 397 times – based on 0 reviews     Review now
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            Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.

            Wolfgang Liedtke, Yong Choe, Marc A. Marti-Renom … (2000)
            The detection of osmotic stimuli is essential for all organisms, yet few osmoreceptive proteins are known, none of them in vertebrates. By employing a candidate-gene approach based on genes encoding members of the TRP superfamily of ion channels, we cloned cDNAs encoding the vanilloid receptor-related osmotically activated channel (VR-OAC) from the rat, mouse, human, and chicken. This novel cation-selective channel is gated by exposure to hypotonicity within the physiological range. In the central nervous system, the channel is expressed in neurons of the circumventricular organs, neurosensory cells responsive to systemic osmotic pressure. The channel also occurs in other neurosensory cells, including inner-ear hair cells, sensory neurons, and Merkel cells.
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              Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.

              Peter Barnes (2013)
              Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharmaceuticals (Basel)
                Journal ID (iso-abbrev): Pharmaceuticals (Basel)
                Journal ID (publisher-id): pharmaceuticals
                Title: Pharmaceuticals
                Publisher: MDPI
                ISSN (Electronic): 1424-8247
                Publication date (Electronic): 01 February 2019
                Publication date Collection: March 2019
                Volume: 12
                Issue: 1
                Electronic Location Identifier: 23
                Affiliations
                Walther-Straub-Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), LMU Munich, Nussbaumstr. 26, D-80336 Munich, Germany; Alexander.Dietrich@ 123456lrz.uni-muenchen.de ; Tel.: +49-89-2180-73802
                Author information
                https://orcid.org/0000-0002-1168-8707
                Article
                Publisher ID: pharmaceuticals-12-00023
                DOI: 10.3390/ph12010023
                PMC ID: 6469169
                PubMed ID: 30717260
                SO-VID: 7f3de0cb-2232-4762-920e-b673710b5ef2
                Copyright © © 2019 by the author.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 15 January 2019
                Date accepted : 29 January 2019
                Categories
                Subject: Review

                Keywords: non-neuronal,transient receptor potential (trp) channels,trpa1,trpc6,trpv1,trpv4,lung,asthma,cystic fibrosis,lung fibrosis,lung edema,chronic obstructive pulmonary disease (copd)
                Data availability:
                Keywords: non-neuronal, transient receptor potential (trp) channels, trpa1, trpc6, trpv1, trpv4, lung, asthma, cystic fibrosis, lung fibrosis, lung edema, chronic obstructive pulmonary disease (copd)

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