TRPPing up bronchiectasis

Airway smooth muscle (ASM) controls the physical state of the airways (4). The mechanisms of ASM dysfunction in disease have received significant attention since ASM hypercontractility and remodeling occur in asthma (6). Conversely, ASM tone loss and airway dilation define bronchiectasis, thought to be due to repeated, robust inflammatory responses that drive airway dilation (7).

Intriguingly, up to a third of patients with autosomal dominant polycystic kidney disease (ADPKD) have radiographic evidence of bronchiectasis (3, 9). Roughly 15% of ADPKD patients have mutations in the polycystin-2 (PKD2) gene. PKD2 codes for TRPP2, also known as transient receptor potential polycystin 2, which is a member of a cation ion channel superfamily called TRP channels. TRPs have a broad range of notable structural features; many of these ion channels show multimodal activation by chemicals like vanilla and menthol, and by environmental stimuli like temperature and force (8). TRP channels are functionally relevant in a variety of smooth muscle cells in the lung, including ASM (15) and pulmonary artery smooth muscle (14). Specifically, TRPP2 channel localizes primarily to endoplasmic reticulum (ER) and to the cilia membranes (2), which is especially relevant because disassembly of cilia genes leads to bronchiectasis (5). TRPP2 is thought to be mechanosensitive when it interacts with other channels (13), and, interestingly, can sense voltage, temperature, and osmoles. TRPP2 is known to contribute to smooth muscle tone (10, 11, 13). However, whether TRPP2 is involved in ASM function and ADPKD-related bronchiectasis remained unclear.

The study by Sang et al. (12) in this issue of American Journal of Physiology-Lung Cellular and Molecular Physiology hypothesized that TRPP2 dysfunction in ASM could be contributing to bronchiectasis (Fig. 1). The authors generated mice with a smooth muscle-specific TRPP2 knockout; they found several structural and functional respiratory abnormalities consistent with bronchiectasis: increases in bronchial cross section, respiratory rate, and decreases in carbachol-induced contraction and isoprenaline-induced relaxation. The authors then pursued the mechanism and found TRPP2 coprecipitation with the inositol 1,4,5-trisphosphate (IP₃) receptor, as well as a decreased calcium entry into primary ASM cells in TRPP2 knockouts. Thus, TRPP2-deficient mouse smooth muscle has structural abnormalities consistent with bronchiectasis, and functional abnormalities that include reduced cytoplasmic Ca²⁺ and decreased ASM contractility. In all, the current study suggests ASM TRPP2 contribution to PKD2-related ADPKD bronchiectasis and therefore has valuable mechanistic and translational implications.

Fig. 1.

Smooth muscle-specific transient receptor potential polycystin 2 (TRPP2) knockout leads to a decrease in smooth muscle Ca²⁺ and airway dilation.

The exciting results in this landmark study also spur intriguing questions. There are three considerations relating to the models used and how well we can generalize the results. First, since the models used here were smooth muscle cell-specific constitutive knockouts, it remains unclear whether TRPP2-deficient smooth muscle cells in other structures, like blood vessels, may contribute to the observed phenotype. For example, the vascular smooth muscle expresses TRPP2 (10), and ADPKD patients have vascular abnormalities, like aneurysms (1). Second, since the models used were constitutive rather than inducible knockouts, we do not know whether developmental consequences from TRPP2 knockout contribute to this phenotype. Third, TRPP2 knockout is different from ADPKD-associated TRPP2 mutations that affect function but often do not result in complete ablation of TRPP2. It will be necessary to compare the phenotypes and functional consequences of the current study with those of similar experiments in models with ADPKD TRPP2 mutations.

As we learn here about TRPP2 implication in ASM function and dysfunction, we may begin to draw up models of TRPP2 roles in ASM. TRPP2 is a part of a multiprotein complex that may endow cilia with mechanosensation properties (13), and we recently learned that ASM-relevant stimuli, like transmembrane voltage and osmotic forces, play a role in TRPP2 gating. Further, TRPP2 is also proposed to have a role in the intracellular membranes, where it interacts with IP₃ receptors, similar to current results (12). However, we do not know whether plasma membrane or intracellular TRPP2 may be relevant for ASM function, what stimuli gate TRPP2 in ASM, what mechanisms are downstream of TRPP2 in ASM, and whether TRPP2 activation in ASM leads to an immune response in lung tissue that mediates bronchiectasis. Future studies will need to resolve the localization of functionally relevant TRPP2 channels in ASM, relevant stimuli, and downstream mechanisms.

In conclusion, in addition to new physiologic implications, this study forwards a novel concept of TRPP2-related ASM dysfunction in the pathophysiology of obstructive pulmonary diseases. It marks the path for greater focus on the role of smooth muscle in these diseases, and the lessons learned from ASM dysfunction may have implications for smooth muscle function in other organs, like vasculature, gut, bladder, and uterus.

GRANTS

This work was supported in part by National Institute of General Medical Sciences Grant GM065841 (A. Mercado-Perez), National Institute of Diabetes and Digestive and Kidney Diseases Grants DK119683 and DK052766 (A. Beyder), and National Center for Complementary and Alternative Medicine Grant AT10875 (A. Beyder).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.M.-P. and A.B. prepared figure; A.M.-P. and A.B. drafted manuscript; A.B. edited and revised manuscript; A.B. approved final version of manuscript.