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Transient Receptor Potential Cation Channel Subfamily V Member 4 Mediates Pyroptosis in Chronic Obstructive Pulmonary Disease.

ABSTRACT: TRPV4, a calcium permeable cation selective channel, was found to be involved in chronic obstructive pulmonary disease (COPD) through releasing ATP and IL-1β. Pyroptosis, a newly discovered pro-inflammatory cell death, was induced by cigarette smoke (CS) in airway epithelial cells (AECs). More recent studies indicated that blocking Ca²⁺ influx effectively inhibited pyroptosis. Therefore, we asked whether TRPV4 mediated CS-induced pyroptosis of AECs and hence participated in the pathogenesis of COPD. We found that pyroptosis and TRPV4 were upregulated in AECs from patients with COPD and long-term CS-exposed mice. Moreover, pharmacological inhibition or knockdown of TRPV4 function alleviated CS extract (CSE)-induced pyroptosis by inhibiting NACHT, LRP, PYD domains-containing protein 3 (NLRP3) inflammasome/activated caspase-1/gasdermin D pathway, decreasing the number of PI positive cells and lactate dehydrogenase (LDH) release, decreasing the expression of pro- inflammatory interleukin gene (IL)-1β, IL-8, and IL-18 expression, as well as increasing anti-inflammatory gene expression [NAD(P)H quinone dehydrogenase 1 (NQO1), superoxide dismutase 2 (mitochondrial) (MNSOD), and catalase, (CAT)]. Moreover, pharmacological inhibition or knockdown of TRPV4 function significantly relieved CSE-induced mitochondrial damage including decreased mitochondrial membrane potential, mitochondrial fusion protein (OPA1, MFN2) expression, and increased mitochondrial fission protein (DRP1, MFF) expression. Taken together, these findings indicate that TRPV4 mediates AEC pyroptosis via NLRP3/caspase-1/GSDMD pathway in COPD.

SUBMITTER: Rao Y

PROVIDER: S-EPMC8740047 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Detection of oncogenes provides chances to understand tumor development and progression. Transient receptor protein cation channel subfamily A, member 1 (TRPA1) transcript was significantly upregulated in nasopharyngeal carcinoma (NPC) with a stepwise upregulation from low- to high-stage NPCs from a preliminary data analysis in the Gene Expression Omnibus database. The TRPA1 gene is a member of the TRP channel family, encoding integral membrane proteins that functions as cation channels. Loss of calcium homeostasis takes place in cancer cells. METHODS:Immunostaining of TRPA1 was analyzed on 124 biopsies from NPC patients retrospectively. The H-score method was used to evaluate the immunoexpression of TRPA1. The correlations between H-score of TRPA1 protein level and clinicopathological factors, as well as the significances of TRPA1 protein level for disease-specific, distal-metastasis-free and local recurrence-free survivals were assessed. RESULTS:These patients were characterized to be no initial metastasis and medicated with the traditional procedure. The TRPA1 score was found to be associated with clinicopathological parameters and patient survivals. Along with the guideline of 7(th) edition of the American Joint Committee on Cancer, we found that TRPA1 upregulation (50%) was associated with advanced primary tumor (P = 0.009) and overall clinical stage (P = 0.019). In univariate log-rank testing, primary tumor, nodal status, stage and TRPA1 protein level significantly contributed to worse disease-specific survival, distal metastasis-free survival and local recurrence-free survival. In multivariate analysis, high TRPA1 protein level and tumor stage emerged as independent prognostic indicators for inferior disease-specific survival (P = 0.014; P = 0.003), distal metastasis-free survival (P = 0.004; P = 0.034) and recurrence-free survival (P = 0.017; P = 0.015). CONCLUSIONS:The upregulation of TRPA1 protein level is frequently correlated to unfavorable prognosticators and gives rise to cancer progression in NPC patients.

Project description:The cornea is innervated by three main functional classes of sensory neurons: polymodal nociceptors, pure mechano-nociceptors and cold-sensing neurons. Here we explored transient receptor potential cation channel subfamily V member 1 (TRPV1) expression in guinea pig corneal sensory neurons, a widely used molecular marker of polymodal nociceptors. We used retrograde tracing to identify corneal afferent neurons in the trigeminal ganglion (TG) and double label in situ hybridization and/or immunohistochemistry to determine their molecular profile. In addition, we used immunohistochemistry to reveal the neurochemistry and structure of TRPV1 expressing nerve endings in the corneal epithelium. Approximately 45% of corneal afferent neurons expressed TRPV1, 28% expressed Piezo2 (a marker of putative pure mechano-nociceptors) and 8% expressed the transient receptor potential cation channel subfamily M member 8 (TRPM8; a marker of cold-sensing neurons). There was no co-expression of TRPV1 and Piezo2 in corneal afferent neurons, but 6% of TRPV1 neurons co-expressed TRPM8. The TRPV1 expressing corneal afferent neurons could be divided into three subpopulations on the basis of calcitonin gene-related peptide (CGRP) and/or or glial cell line-derived neurotrophic factor family receptor alpha3 (GFRα3) co-expression. In the corneal epithelium, the TRPV1 axons that co-expressed CGRP and GFRα3 ended as simple unbranched endings in the wing cell layer. In contrast, those that only co-expressed GFRα3 had ramifying endings that branched and terminated in the squamous cell layer, whereas those that only co-expressed CGRP had simple endings in the basal epithelium. This study shows that the majority of TRPV1 expressing corneal afferent neurons (>90%) are likely to be polymodal nociceptors. Furthermore, TRPV1 expressing corneal afferent neurons can be subdivided into specific subpopulations based on their molecular phenotype, nerve terminal morphology and distribution in the corneal epithelium.

Project description:BackgroundAirway remodeling and inflammation are considered the main characteristics of chronic obstructive pulmonary disease (COPD). Cigarette smoke promotes the occurrence of inflammation, oxidative stress, and pyroptosis. Halotherapy has been shown to dilute secretions in the airways and promote drainage, but the mechanism remains unclear. In this study, we evaluated the anti-inflammatory and antioxidant effects of halotherapy in COPD rats and investigated the underlying mechanism.MethodsA COPD rat model was constructed by cigarette smoke and lipopolysaccharide tracheal instillation. A total of 120 male Sprague-Dawley (SD) rats were randomly divided into control, model, halotherapy, terbutaline, halotherapy + terbutaline, and Ac-YVAD-CMK (Caspase-1 inhibitor) groups. After modeling and treatment, the pulmonary function of the rats was measured. Pathological changes in the lungs were measured by hematoxylin-eosin (H&E) staining. Serum interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), and nitric oxide (NO) levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. Malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity in the lungs were determined by biochemical tests. The levels of cluster of differentiation 4 (CD4+) and CD8+ T cells in the blood were determined by flow cytometry. The expression levels of Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), gasdermin-D (GSDMD), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), Caspase-1, and IL-1β in lung tissues were detected by immunohistochemistry, Western blotting, or quantitative polymerase chain reaction (qPCR).ResultsHalotherapy recovered the clinical symptoms of COPD rats, and reduced lung inflammatory cell infiltration and air wall attenuation. It also relieved oxidative stress in the lung tissue of COPD rats, reduced CD4+ and CD8+ T cell accumulation in lung tissue, and decreased inflammatory factor production in the serum of COPD rats. Furthermore, it inhibited the TLR4/NF-κB/GSDMD and NLRP3/ASC/Caspase-1 signaling pathways. Ac-YVAD-CMK could not completely inhibit the therapeutic effect of halotherapy on COPD rats.ConclusionsHalotherapy improves lung function by inhibiting the NLRP3/ASC/Caspase-1 signaling pathway to reduce inflammation and pyroptosis in COPD rats, and may be a new option for the prevention and treatment of COPD.

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Transient Receptor Potential Cation Channel Subfamily V Member 4 Mediates Pyroptosis in Chronic Obstructive Pulmonary Disease.

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