Search Results (111)

Pulmonary hypertension (PH) is a progressive disorder characterized by elevated pulmonary arterial pressure and the extensive remodeling of pulmonary vasculature. Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), is a well-established contributor to the pathogenesis of PH. OSA is defined by repetitive episodes of upper airway obstruction during sleep, leading to cycles of hypoxia and reoxygenation that trigger a cascade of deleterious events including oxidative stress, inflammation, endothelial dysfunction, and vascular remodeling. Growing evidence underscores the critical role of transient receptor potential canonical (TRPC) channels in mediating hypoxia-induced vascular alterations that contribute to the development of PH. TRPC channels are non-selective cation channels that regulate calcium influx in response to mechanical stimuli, pro-inflammatory cytokines, oxidative stress, and hypoxia. These channels are expressed in both pulmonary arterial smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs), where they modulate key processes such as proliferation, migration, apoptosis, endothelial permeability, and vasoconstriction. Under hypoxic conditions, the upregulation of TRPC1, TRPC3, TRPC4, and TRPC6 has been implicated in dysregulation of calcium homeostasis and activation of pathological signaling pathways that contribute to increased pulmonary arterial pressure. In this review, we propose that upregulation and functional modulation of TRPC channels under CIH represents a central pathogenic mechanism linking OSA to PH. We hypothesize that TRPC1, TRPC3, TRPC4, and TRPC6 act as critical molecular effectors mediating hypoxia-driven calcium influx and downstream signaling pathways that lead to pulmonary vascular remodeling, endothelial dysfunction, and increased pulmonary arterial pressure. This framework allows us to integrate mechanistic insights from molecular, cellular, and translational studies, and to evaluate the therapeutic potential of targeting TRPC channels in OSA-associated PH. Full article

Asthma is a heterogeneous disease that varies in clinical presentation, severity, and underlying biology but consistently involves airway remodeling (AR) and airway hyperresponsiveness (AHR), which is characterized by excessive airway narrowing in response to various stimuli. Airway smooth muscle (ASM) cells are primary contributors to airway hyperresponsiveness and bronchoconstriction. This review focuses on ASM cells and their role in asthma. We discuss the mechanisms by which ASM mediates AHR, increases airway thickness, and contributes to AR. Signaling through G protein-coupled receptors (GPCRs) regulates many ASM functions, including contraction, growth, and the synthetic activities that drive airway inflammation and remodeling. GPCR-dependent calcium flux serves as a key signaling axis controlling the contractile responses of ASM. Here we provide a comprehensive summary of the major GPCRs as well as other non-GPCRs identified in ASM cells. GPCR-induced calcium mobilization, downstream signaling and how it has been linked to specific ASM functions are also discussed. Furthermore, we highlight the clinical significance of targeting GPCRs in asthma therapy as well as recent development of novel therapeutics in the management of asthma. Thus, this review provides a comprehensive overview of airway smooth muscle in the context of asthma pathophysiology. Full article

Background: Tracheobronchopathia osteochondroplastica (TO) is a rare benign disorder characterized by submucosal cartilaginous and osseous nodules of the tracheobronchial tree, typically sparing the posterior membranous wall. Involvement of the vocal cords is exceedingly rare and may result in critical airway obstruction. The underlying genetic and molecular mechanisms of TO remain largely unexplored. Case presentation: We report a rare case of TO extending from the vocal cords to the bronchi in a 76-year-old man who initially presented with pneumonia and later developed acute respiratory failure due to severe airway narrowing, necessitating emergency tracheostomy. Bronchoscopy and computed tomography revealed diffuse calcified nodules involving the anterior and lateral airway walls, including the subglottic region. Histopathology demonstrated chronic inflammatory cell infiltration with squamous metaplasia. To explore the molecular basis of this condition, whole-genome sequencing (WGS) was performed using peripheral blood samples—the first such application in TO. WGS identified 766 germline mutations (including 27 high-impact variants) and 66 structural variations. Candidate genes were implicated in coagulation and inflammation (KNG1), arachidonic acid metabolism and extracellular matrix remodeling (PLA2G4D), ciliary dysfunction and mineralization (TMEM67), vascular calcification (CDKN2B-AS1), smooth muscle function (MYLK4), abnormal calcification (TRPV2, SPRY2, BAZ1B), fibrotic signaling (AHNAK2), and mucosal barrier integrity (MUC12/MUC19). Notably, despite systemic germline mutations, calcification was restricted to the airway. Conclusions: This case highlights that TO with vocal cord involvement can progress beyond a benign course to cause life-threatening airway obstruction. Integrating clinical, histological, and genomic findings, we propose a novel pathophysiological model in which systemic genetic susceptibility interacts with local immune cell infiltration and fibroblast-driven extracellular matrix remodeling, resulting in airway-restricted dystrophic calcification. This first genomic characterization of TO provides new insights into its pathogenesis and suggests that multi-omics approaches may enable future precision medicine strategies for this rare airway disease. Full article

Fritillaria pallidiflora Schrenk ex Fisch. & C.A.Mey. (Yi Beimu) is a culturally significant Beimu drug in Northwest China, officially listed in the Chinese Pharmacopoeia and traditionally used to clear heat, moisten the lung, resolve phlegm, and relieve cough and wheeze. This narrative, critical review synthesizes current evidence on ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics/toxicology, and conservation of F. pallidiflora to support sustainable, evidence-based development. Literature was retrieved from major English and Chinese databases and screened for studies that unambiguously involved Yi Beimu or its key constituents. Ethnomedicinal records consistently support antitussive, expectorant, and anti-asthmatic use in Xinjiang and the Ili River Valley. Chemically, F. pallidiflora is rich in cevanine-type steroidal alkaloids (e.g., imperialine, peimine, yibeinones), steroidal saponins (pallidiflosides), polysaccharides, and minor phenolics. Preclinical data show that alkaloids relax airway smooth muscle, suppress inflammatory mediators, and contribute to antitussive and anti-asthmatic effects, while polysaccharides and total alkaloid extracts exhibit antioxidant and cytoprotective activity in cell and animal models of airway injury. Additional studies report cytotoxic saponins and seed-derived antimicrobial peptides. Pharmacokinetic work highlights low to moderate and variable oral bioavailability, shaped by P-glycoprotein efflux and CYP-mediated metabolism, and reveals potential hERG channel inhibition for peimine as a cardiac safety concern. Overharvesting and habitat loss have reduced wild resources, underscoring the need for conservation, cultivation, and marker-guided quality control. Overall, Yi Beimu shows credible ethnopharmacological rationale and promising multi-target pharmacology for respiratory disorders, but translation will require bioactivity-guided isolation coupled with PK–PD-guided in vivo studies, rigorous safety evaluation, and conservation-aware cultivation to move from traditional remedy toward validated therapeutic resource. Full article

Human airways maintain homeostasis through intricate cellular interactomes combining secretome-mediated signalling and mechanotransduction feedback loops. This review presents the first unified map of bidirectional mechanobiology–secretome interactions between airway epithelial cells (AECs), smooth muscle cells (ASMCs), and chondrocytes. We unify a novel three-component regulatory architecture: epithelium functioning as environmental activators, smooth muscle as mechanical actuators, and cartilage as calcium-dependent regulators. Critical mechanotransduction pathways, particularly YAP/TAZ signalling and TRPV4 channels, directly couple matrix stiffness to cytokine release, creating a closed-loop feedback system. During development, ASM-driven FGF-10 signalling and peristaltic contractions orchestrate cartilage formation and epithelial differentiation through mechanically guided morphogenesis. In disease states, these homeostatic circuits become pathologically dysregulated; asthma and COPD exhibit feed-forward stiffness traps where increased matrix rigidity triggers YAP/TAZ-mediated hypercontractility, perpetuating further remodelling. Aberrant mechanotransduction drives smooth muscle hyperplasia, cartilage degradation, and epithelial dysfunction through sustained inflammatory cascades. This system-level understanding of airway cellular networks provides mechanistic frameworks for targeted therapeutic interventions and tissue engineering strategies that incorporate essential mechanobiological signalling requirements. Full article

Asthma is a chronic respiratory disease affecting over 262 million people worldwide, with obesity-associated asthma emerging as a distinct endotype of increasing prevalence characterized by metabolic inflammation and airway remodeling. Unlike allergic asthma, this phenotype is driven by chronic low-grade inflammation, originating from hypertrophic and hypoxic adipose tissue. This dysregulated state leads to the activation of pro-inflammatory pathways and the secretion of cytokines, contributing to airway dysfunction and remodeling. Recent evidence highlights non-coding RNAs (ncRNAs) as key regulators of these processes. MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) influence inflammation and remodeling by modulating immune cell polarization, cytokine secretion, extracellular matrix composition, and airway smooth muscle cell (ASMC) proliferation. Notably, H19, MEG3, GAS5, miR-26a-1-3p, and miR-376a-3p have been implicated in both asthma and obesity, suggesting their role in linking metabolic dysfunction with airway pathology. Moreover, ncRNAs regulate Treg/Th17 balance, fibroblast activation, and autophagy-related pathways, further influencing airway remodeling. Our in silico analysis highlighted the IGF1R signaling pathway as a key enriched mechanism, linking selected ncRNAs with metabolic dysregulation and inflammation in obesity-related asthma. This paper reviews how ncRNAs regulate inflammation and airway remodeling in obesity-associated asthma, emphasizing their potential molecular links between metabolic dysfunction and airway pathology. Full article

Prolactin (PRL) is a hormone primarily associated with lactation, but it plays various roles in both men and women. PRL belongs to the family of peptide hormones, including placental lactogen and growth hormone. Interestingly, PRL is a pleiotropic hormone affecting several physiological and pathological conditions, including fertility. Moreover, several pathophysiological roles have been associated with this hormone, including those of the immune system, autoimmune disorders, asthma, and ageing. Additionally, PRL receptors are ubiquitously expressed in tissues, including the mammary gland, gonads, liver, kidney, adrenal gland, brain, heart, lungs, pituitary gland, uterus, skeletal muscle, skin blood cells, and immune system. Therefore, in the present paper, we cover the potential role that PRL may play in asthma by promoting inflammation and modulating immune responses. The detection of its receptor in lung tissue suggests a direct role in airway smooth muscle contractility through activation of signaling pathways such as JAK2-STAT5, MAPK/ERK1/2, and PI3K/Akt, as well as influencing ionic currents that regulate cell contraction, proliferation, and survival. In this sense, this review aims to explore the potential involvement of PRL in asthma pathophysiology by examining its interactions with intracellular signaling pathways and its possible impact on airway smooth muscle contractility and immune modulation. Full article

Background/Objectives: Asthma, a chronic airway inflammatory disease characterized by bronchial narrowing and caused by an inflammatory response, results in airway obstruction and hyperresponsiveness. Stachydrine (STA), an abundant metabolite found in plants and humans, is recognized for its bioactivity in treating fibrosis, cancer, and inflammation. However, its effects on asthma have not been fully elucidated. We aimed to investigate the ameliorating effects of STA on chronic airway inflammation caused by Dermatophagoides pteronyssinus (house dust mite, HDM). Methods: We used a murine model of HDM-induced airway inflammation to assess the change in metabolite profile by chronic airway inflammation. The mice were challenged with HDM (35 challenges in total) for up to 12 weeks. Serum metabolites were analyzed using capillary electrophoresis time-of-flight mass spectrometry. Results: HDM exposure increased airway hypersensitivity, immune cell infiltration, cytokine production, goblet cell hyperplasia, collagen deposition, and alpha smooth muscle actin and fibronectin expression. Serum metabolite analysis revealed that STA levels were lower in the mice with HDM-induced chronic inflammation than in the controls. In vitro analyses demonstrated that HDM sensitization increased cytokine production (interleukin [IL]-6 and IL-8) and extracellular signal-regulated kinase (ERK) activity. However, STA treatment reduced HDM-induced IL-6 and IL-8 production and ERK activity. Co-treatment with a mitogen-activated protein kinase (MAPK) inhibitor and STA resulted in a more pronounced reduction in cytokine production and MAPK activity. Conclusions: These findings suggest that STA, particularly when used in combination with a MAPK inhibitor, effectively suppresses airway inflammation through ERK pathway inhibition, making it a potential therapeutic agent for asthma treatment. Full article

Chronic obstructive pulmonary disease (COPD), whose main risk factor is cigarette smoking, is among the most prevalent diseases worldwide. Previous studies have shown that cigarette smoke extract (CSE) can directly affect pulmonary artery function independently of hypoxia resulting from the airway obstruction. In addition, CSE also affects bronchial smooth muscle, leading to airway hyper-responsiveness. However, its specific impact on the contractile machinery of this compartment remains unclear. In this study, using in vitro experiments with human bronchial smooth muscle cells (hBSMCs), we found that CSE exposure disrupted calcium homeostasis, increased ROS and lipid peroxidation, and reduced cell antioxidant defenses. Furthermore, CSE exposure altered the cell contractile apparatus by decreasing key cytoskeletal proteins and impairing actin dynamics, potentially contributing to the dysregulated contractile response of cells. Notably, these effects were significantly attenuated by antioxidant drugs such as mitoTEMPO and N-acetylcysteine, as well as by the inhibition of the endoplasmic reticulum (ER) calcium channels with 2-aminoethoxydiphenyl borate (2-APB). More importantly, mitoTEMPO partially restored the contractile response of bronchus upon CSE challenge. Collectively, our findings give evidence that CSE-mediated increase in ROS and intracellular calcium contribute to cytoskeletal disruption and functional impairment in airway smooth muscle. Moreover, these results also point to potential therapeutical approaches for mitigating the harmful effects of cigarette smoke in the lung. Full article

It has long been recognised that airway smooth muscle cells (ASMCs) possess an abundance of M2 muscarinic receptors (M2Rs). However, the contribution of postjunctional M2Rs to contractions of airway smooth muscle (ASM) induced by the release of acetylcholine (ACh) from parasympathetic nerves was thought to be minimal. Instead, it was believed that these responses were exclusively mediated by activation of M3Rs. However, evidence is emerging that postjunctional M2Rs may have a greater role than previously realised. In this review, we discuss ACh signalling in airways, highlighting the well-established autoinhibitory role of prejunctional M2Rs and the putative roles of postjunctional M2Rs to cholinergic contractions of ASM. The cellular mechanisms that underpin M2R-dependent contractions of ASM are reviewed, with a particular emphasis on the role of ion channels in these responses. The regulation of M2R signalling pathways by β-adrenoceptor activation is also considered, along with the potential involvement of postjunctional M2Rs in airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Full article

On-chip microfluidics are advanced in vitro models that simulate lung tissue’s native 3D environment more closely than static 2D models to investigate the complex lung architecture and multifactorial processes that lead to pulmonary disease. Current microfluidic systems can be restrictive in the quantities of biological sample that can be retrieved from a single micro-channel, such as RNA, protein, and supernatant. Here, we describe a newly developed large-scale airway-on-chip model that employs a surface area for a cell culture wider than that in currently available systems. This enables the collection of samples comparable in volume to traditional cell culture systems, making the device applicable to any workflow utilizing these static systems (RNA isolation, ELISA, etc.). With our construction method, this larger culture area allows for easier handling, the potential for a wide range of exposures, as well as the collection of low-quantity samples (e.g., volatiles or mitochondrial RNA). The model consists of two large polydimethylsiloxane (PDMS) cell culture chambers under an independent flow of medium or air, separated by a semi-permeable polyethylene (PET) cell culture membrane (23 μm thick, 0.4 μm pore size). Each chamber carries a 5 × 18 mm, 90 mm² (92 mm² with tapered chamber inlets) surface area that can contain up to 1–2 × 10⁴ adherent structural lung cells and can be utilized for close contact co-culture studies of different lung cell types, including airway epithelial cells, fibroblasts, smooth muscle cells, and endothelial cells. The parallel bi-chambered design of the chip allows for epithelial cells to be cultured at the air–liquid interface (ALI) and differentiation into a dense, multi-layered, pseudostratified epithelium under biological flow rates. This millifluidic airway-on-chip advances the field by providing a readily reproducible, easily adjustable, and cost-effective large-scale fluidic 3D airway cell culture platform. Full article

In severe asthma, symptoms are unstable despite intensive treatment based on high doses of inhaled corticosteroids and on-demand use of oral corticosteroids. Although, recently, various biological agents related to Th2 cytokines have been added to intensive controller medications for severe asthma, a significant progress has not been observed in the management for symptoms (dyspnea, wheezing and cough). Medical treatment focused on Type 2 inflammation is probably insufficient to maintain good long-term management for severe asthma. Airway eosinophilia and decreased reversibility in forced expiratory volume in 1 second (FEV₁) are listed as major predictors for exacerbation-prone asthma. However, it is generally considered that asthma is complex and heterogeneous. It is necessary to establish precision medicine using treatable traits based on a multidimensional approach related to asthma. Since phospholipids generate lysophospholipids and arachidonic acid by phospholipases, lysophospholipids can be associated with the pathogenesis of this disease via action on smooth muscle, endothelium, and epithelium in the airways. Lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingosine 1-phosphate (S1P) are increased in bronchoalveolar fluid after allergen challenge. LPA, LPC, and S1P recruit eosinophils to the lungs and cause β₂-adrenergic desensitization. LAP and S1P cause contraction and hyperresponsiveness in airway smooth muscle. Moreover, lysophosphatidylserine and S1P are associated with the allergic reaction related to IgE/FcεRI in mast cells. Lysophospholipid action is probably comprised of corticosteroid resistance and is independent of Type 2 inflammation, and may be corelated with oxidative stress. Lysophospholipids may be a novel molecular target in advancing the management and treatment of asthma. This review discusses the clinical relevance of lysophospholipids in asthma. Full article

Background: Chronic obstructive pulmonary disease (COPD) is characterized by progressive and incurable airflow obstruction and chronic inflammation. Both TGF-β1 and CXCL8 have been well described as fundamental to COPD progression. DNA methylation and histone acetylation, which are well-understood epigenetic mechanisms regulating gene expression, are associated with COPD progression. However, a deeper understanding of the complex mechanisms associated with DNA methylation, histone post-translational changes and RNA methylation in the context of regulatory pathways remains to be elucidated. We here report on how DNA methylation and histone acetylation inhibition differentially affect CXCL8 signaling in primary human non-COPD and COPD airway cells. Methods: Airway smooth muscle (ASM) cells, a pivotal cell type in COPD, were isolated from the small airways of heavy smokers with and without COPD. Histone acetylation and DNA methylation were inhibited before the TGF-β1 stimulation of cells. Subsequently, CXCL8 production and the abundance and activation of pertinent transcription regulatory proteins (NF-κB, p38 MAPK and JNK) were analyzed. Results: TGF-β1-stimulated CXCL8 release from ASM cells from ‘healthy’ smoker subjects was significantly modulated by DNA methylation (56.32 pg/mL and 56.60 pg/mL) and acetylation inhibitors (27.50 pg/mL and 48.85 pg/mL) at 24 and 48 h, respectively. However, modulation via the inhibition of DNA methylation (34.06 pg/mL and 43.18 pg/mL) and acetylation (23.14 pg/mL and 27.18 pg/mL) was observed to a lesser extent in COPD ASM cells. These changes were associated with differences in the TGF-β1 activation of NF-κB and MAPK pathways at 10 and 20 min. Conclusions: Our findings offer insight into differential epigenetics in controlling COPD ASM cells and provide a foundation warranting future studies on epigenetic differences associated with COPD diagnosis. This would provide a scope for developing therapeutic interventions targeting signaling and epigenetic pathways to improve patient outcomes. Full article

Despite the significant progress in diagnostic and therapeutic strategies, vascular diseases, such as cardiovascular diseases (CVDs) and respiratory diseases, still cannot be successfully eliminated. Vascular cells play a key role in maintaining vascular homeostasis. Notably, a variety of cells produce and secrete platelet-derived growth factors (PDGFs), which promote mitosis and induce the division, proliferation, and migration of vascular cells including vascular smooth muscle cells (SMCs), aortic SMCs, endothelial cells, and airway SMCs. Therefore, PDGF/PDGR receptor signaling pathways play vital roles in regulating the homeostasis of blood vessels and the onset and development of CVDs, such as atherosclerosis, and respiratory diseases including asthma and pulmonary arterial hypertension. Recently, accumulating evidence has demonstrated that microRNA, long-chain non-coding RNA, and circular RNA are involved in the regulation of PDGF/PDGFR signaling pathways through competitive interactions with target mRNAs, contributing to the occurrence and development of the above-mentioned diseases. These novel findings are useful for laboratory research and clinical studies. The aim of this article is to conclude the recent progresses in this field, particular the mechanisms of action of these non-coding RNAs in regulating vascular remodeling, providing potential strategies for the diagnosis, prevention, and treatment of vascular-dysfunction-related diseases, particularly CVDs and respiratory diseases. Full article

Severe asthma is characterized by increased cell volume (hypertrophy) and enhanced contractile function (hyperresponsiveness) of the airway smooth muscle cells (ASMCs). The causative relationship and underlying regulatory mechanisms between them, however, have remained unclear. Here, we manipulated the single-cell volume of in vitro cultured human ASMCs to increase from 2.7 to 5.2 and 8.2 × 10³ μm³ as a simulated ASMC hypertrophy by culturing the cells on micropatterned rectangular substrates with a width of 25 μm and length from 50 to 100 and 200 μm, respectively. We found that as the cell volume increased, ASMCs exhibited a pro-contractile function with increased mRNA expression of contractile proteins, increased cell stiffness and traction force, and enhanced response to contractile stimulation. We also uncovered a concomitant increase in membrane tension and Piezo1 mRNA expression with increasing cell volume. Perhaps more importantly, we found that the enhanced contractile function due to cell volume increase was largely attenuated when membrane tension and Piezo1 mRNA expression were downregulated, and an auto-regulatory loop between Piezo1 and YAP mRNA expression was also involved in perpetuating the contractile function. These findings, thus, provide convincing evidence of a direct link between hypertrophy and enhanced contractile function of ASMCs that was mediated via Piezo1 mRNA expression, which may be specifically targeted as a novel therapeutic strategy to treat pulmonary diseases associated with ASMC hypertrophy such as severe asthma. Full article