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

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.

Keywords: TRPA1; TRPC6; TRPV1; TRPV4; asthma; chronic obstructive pulmonary disease (COPD); cystic fibrosis; lung; lung edema; lung fibrosis; non-neuronal; transient receptor potential (TRP) channels.

Figure 1

Cells involved in physiological functions of airways and lungs. See text for more details. Airway SMC, airway smooth muscle cells; Alveolar MP, alveolar macrophages; AT1 cells, alveolar type 1 cells; AT2 cells, alveolar type 2 cells; CO₂, carbon dioxide; EC, erythro-cyte; O₂, oxygen; NP, neutrophil; PASMC, precapillary arterial smooth muscle cells, SP-C, surfactant protein-C.

Figure 2

Pathophysiological changes in the lung. (a) Increasing viscosity of the mucus during the development of cystic fibrosis (CF) disables removal of foreign particles. (b) Contractions of the airways by allergens (*) occur during an asthma attack and prevents gas exchange. (c) Precapillary arterial smooth muscle cell (PASMC) contract to increase pulmonary blood pressure as an initial step in the development of pulmonary hypertension (PH). (d) A hallmark of chronic obstructive pulmonary disease (COPD) is the loss of alveolar septae during the development of emphysema. (e) Increased hydrostatic pressure by PH or damage of the alveolar capillary membrane induce lung edema. (f) Repair processes by myofibroblasts block gas exchange in the alveolar capillary membrane of patients with lung fibrosis.