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

Alexander Dietrich

doi:10.3390/ph12010023

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.

Highlights

IntroductionOur lungs are essential for gas exchange but are exposed to the external environment
Our lungs are essential for gas exchange but are exposed to the external environment.we inhale toxicants, allergens, and infectious agents like bacteria, viruses, and fungi together with vitally important oxygen
We have demonstrated that TRPC6-deficient mice display chronic hypoxia-induced pulmonary hypertension (PH) indistinguishable from those in wild-type (WT) mice [18]

Summary

Introduction

Our lungs are essential for gas exchange but are exposed to the external environment. To its prominent expression in neuronal cells, TRPV1 was identified in arterial smooth muscle cells, where it may control blood flow [70,71], human bronchial fibroblasts [72], and lung epithelial cells [73,74] (see Table 5) In the latter tissue, recent evidence indicate that TRPV1 channels are good candidates for the detection of inhaled toxicants and their antagonists may protect from toxic lung injury and pain related to chronic inflammation (reviewed in [3]). GSK1016790A, the only in vivo tested so-called “superagonist”, causes a lethal drop in blood pressure in mice, cats, and dogs [116], while intravesical instillation caused bladder overactivity in mice [117] Both effects, were only observed in wild-type, but not in TRPV4-deficient mice [116,117], emphasizing the important roles of the channel in endothelium-dependent vasorelaxation and bladder function. +, activating; -, inhibiting; ?, not tested; /, very low activity; ↓, reduction, opt., options, Ref., reference

Non-Neuronal TRPs as Potential Drug Targets in Lung Disease

Asthma

Lung Edema

Lung Fibrosis

Findings

Conclusions