Asthma is deemed an inflammatory disease, yet the defining diagnostic feature mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial death when cells become too crowded. In this work, we show pathological crowding of bronchoconstrictive attack causes so much it damages airways, resulting in inflammation and mucus secretion both mice humans. Although relaxing airways with rescue treatment albuterol did not affect...

Inhalation of environmental particulate matter (PM) is correlated with adverse health effects in humans, but gene products that couple detection cellular responses, and the specific properties PM target different pathways, have not been fully elucidated. TRPA1 V1 are two cation channels expressed by sensory neurons non-neuronal cells respiratory tract implicated as possible mediators toxicity. The goals this research were to determine if preferentially activated elucidate criteria...

Cigarette smoke, diesel exhaust, and other combustion-derived particles activate the calcium channel transient receptor potential ankyrin-1 (TRPA1), causing irritation inflammation in respiratory tract. It was hypothesized that wood smoke particulate select chemical constituents thereof would also TRPA1 lung cells, potentially explaining adverse effects of forms biomass on system. activation assessed using imaging assays TRPA1-overexpressing HEK-293 mouse primary trigeminal neurons, human...

Ozone (O 3 ) is a ubiquitous pollutant known to produce acute, transient inflammation through oxidative injury and inflammation. These effects are exacerbated in susceptible populations, such as the elderly those exhibiting genetic mutations central nodes of pulmonary function. To comprehend impact these predisposing factors, present study examines structural, mechanical, immunological responses single acute O exposure (0.8 ppm, 3h) young (8-14 week old), middle-aged (44-52 old (>80 old)...

Environmental particulate matter (PM) pollutants adversely affect human health, but the molecular basis is poorly understood. The ion channel transient receptor potential vanilloid-1 (TRPV1) has been implicated as a sensor for environmental PM and mediator of adverse events in respiratory tract. objectives this study were to determine whether TRPV1 can distinguish chemically physically unique that represents important sources air pollution; elucidate activation by PM; ascertain contributions...

Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated the pathogenesis of asthma. Our hypothesis was that particulate materials via a mechanism distinct from chemical agonists that, cohort children with asthma living location prone to high levels air pollution, expression uniquely sensitive forms may correlate reduced control. Variant were constructed by mutating residues known...

Here, we examine how prenatal inflammation shapes tissue function and immunity in the lung by reprogramming tissue-resident immune cells from early development. Maternal, but not fetal, type I interferon-mediated provokes expansion hyperactivation of group 2 innate lymphoid (ILC2s) seeding developing lung. Hyperactivated ILC2s produce increased IL-5 IL-13 are associated with acute Th2 bias, decreased Tregs, persistent eosinophilia into adulthood. ILC2 is recapitulated adoptive transfer fetal...

Endogenous agonists of transient receptor potential vanilloid-1 (TRPV1) (endovanilloids) are implicated as mediators lung injury during inflammation. This study tested the hypothesis that endovanilloids produced following lipopolysaccharide (LPS) treatment activate TRPV1 and cause endoplasmic reticulum stress/GADD153 expression in cells, representing a mechanistic component injury. The agonist nonivamide induced GADD153 caused cytotoxicity immortalized primary human bronchial,...

Transient receptor potential (TRP) channels are activated by environmental particulate materials. We hypothesized that polymorphic variants of transient vanilloid-1 (TRPV1) would be uniquely responsive to insoluble coal fly ash compared with the prototypical soluble agonist capsaicin. Furthermore, these changes manifest as differences in lung cell responses agonists and perhaps correlate asthma symptom control. The TRPV1-I315M -T469I were more capsaicin ash. I585V variant was less particles...

Abstract Mucus hypersecretion is a pathological feature of acute inflammatory and chronic obstructive pulmonary diseases. Exposure to air pollutants can be cause mucus overproduction, but mechanisms by which different forms elicit this response are not fully understood. In study, particulate matter (PM) generated from burning pine wood other types biomass was used determine these PM stimulate mucin gene expression secretion primary human bronchial epithelial cells (HBECs). Biomass <...

Background: Transient receptor potential ankyrin-1 [transient cation channel subfamily A member 1 (TRPA1)] and vanilloid-1 V (TRPV1)] detect inhaled irritants, including air pollutants have roles in the development exacerbation of asthma. Objectives: This study tested hypothesis that increased expression TRPA1, stemming from loss-of-function TRPV1 (I585V; rs8065080) polymorphic variant by airway epithelial cells may explain prior observations worse asthma symptom control among children with...

Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown long-term use of oral contraceptives decreased the onset asthma age. In current study, we hypothesized steady-state levels estrogen would reduce inflammation and hyperresponsiveness to methacholine challenge.Ovariectomized BALB/c mice (Ovx) were implanted with subcutaneous hormone pellets (estrogen, OVX-E2) deliver consistent [68 ± 2 pg/mL], or...

Wood/biomass smoke particulate materials (WBSPM) are pneumotoxic, but the mechanisms by which these affect lung cells not fully understood. We previously identified transient receptor potential (TRP) ankyrin-1 as a sensor for electrophiles in WBSPM and hypothesized that other TRP channels expressed might also be activated WBSPM, contributing to pneumotoxicity. Screening channel activation using calcium flux assays revealed TRPV3 obtained from burning multiple types of wood under fixed...

The physicochemical properties of combustion particles that promote lung toxicity are not fully understood, hindered by the fact vary based on fuel and conditions. Real-world combustion-particle also continually change as new fuels implemented, engines age, engine technologies evolve. This work used laboratory-generated produced under controlled conditions in an effort to understand relationship between different particle activation established toxicological outcomes human cells (H441...

Climate change and human activities have caused the drying of marine environments around world. An example is Great Salt Lake in Utah, USA which at a near record low water level. Adverse health effects been associated with exposure to windblown dust originating from dried lakebed sediments, but mechanistic studies evaluating these dusts are limited. Monitoring data images highlight impact local crustal sediment on Valley/Wasatch front airshed. derived PM< 3.1 (quasi-PM2.5 or qPM2.5)...

Bryostatin 1 is a protein kinase C (PKC α, β, δ) activator with anti-inflammatory effects. We hypothesized that bryostatins and 3 could modulate transient receptor potential (TRP) channels via PKC alter TRP-mediated proinflammatory signaling in lung epithelial cells challenged stimulus, coal fly ash (CFA). Bryostatins inhibited icilin-induced calcium flux HEK-293 overexpressing full-length human melastatin-8 (TRPM8) but did not inhibit activation by menthol or the activities of ankyrin 1,...

Diesel exhaust particulate (DEP) causes pulmonary irritation and inflammation, which can exacerbate asthma other diseases. These effects may arise from the activation of transient receptor potential ankyrin-1 (TRPA1). This study shows that a representative DEP activate TRPA1-expressing C-fibers in mouse lung. Furthermore, collected idling vehicles at an emissions inspection station, tailpipe on-road "black smoker" diesel truck, waste filter regeneration machine, NIST SRM 2975 human TRPA1...

BACKGROUND: Remimazolam is an ester-based short-acting benzodiazepine currently in clinical trials for IV administration. This study explored the feasibility of delivering remimazolam alone and as adjunct to remifentanil via inhalation rodent models. METHODS: Mice were exposed inhalation; sedation was assessed using time movement outside a set perimeter. Rats also aerosol combination with inhaled remifentanil, analgesia quantified by tail flick meter. Pulmonary injury mice mechanics...

Asthmatic women tend to develop severe airway disease in their reproductive years, and 30%–40% of asthmatic have peri-menstrual worsening asthma symptoms. This indicates that fluctuations ovarian hormones are involved advancement exacerbation Group 2 innate lymphoid cells, or ILC2, readily detected allergic conditions, such as rhinosinusitis, individuals nasal polyps do allergen exposures, asthma. ILC2 localized immune cells activated by IL-33, an cytokine perpetuates inflammation driving...

Perimenstrual worsening of asthma occurs in up to 40% women with asthma, leading increased acute exacerbations requiring clinical care. The role sex hormones during these times remains unclear. In the current study, we used a translational approach determine whether progesterone exacerbates allergic inflammation traditional chicken egg ovalbumin (OVA) model BALB/c mice. Simultaneously, peripheral blood mononuclear cells (PBMC) from healthy human donors assess effects on circulating group 2...

Genetic variation among inhaled corticosteroid (ICS)-metabolizing enzymes may affect asthma control, but evidence is limited. This study tested the hypothesis that single-nucleotide polymorphisms (SNPs) in Cytochrome P450 3A5 (CYP3A5) would outcomes. Patients aged 2-18 years with persistent were recruited to use electronic AsthmaTracker (e-AT), a self-monitoring tool records weekly medication use, and A subset of patients provided saliva samples for SNP analysis participated pharmacokinetic...

Transient receptor potential vanilloid-3 (TRPV3) is a member of the TRPV subfamily TRP ion channels. The physiological functions TRPV3 are not fully understood, in part due to lack selective agonists and antagonists that could both facilitate elucidation roles for mammalian physiology, as well potentially serve therapeutic agents modulate conditions which altered function has been implicated. In this study, Microsource Spectrum Collection was screened using alterations calcium flux...

To better understand how adverse health effects are caused by exposure to particulate materials, and develop preventative measures, it is important identify the properties of particles molecular targets that link with specific biologic outcomes. Coal fly ash (CFA) a by-product coal combustion can affect human health. We report transient receptor potential melastatin-8 (TRPM8) an N-terminally truncated TRPM8 variant (TRPM8-Δ801) activated CFA calcium-rich nanoparticles and/or soluble salts...

This study investigated the roles of transient receptor potential (TRP) ankyrin-1 (TRPA1) and TRP vanilloid-3 (TRPV3) in regulating endoplasmic reticulum stress (ERS) cytotoxicity human bronchial epithelial cells (HBECs) treated with pneumotoxic wood smoke particulate matter (WSPM) chemical agonists each channel. Functions TRPA1 TRPV3 pulmonary remain largely undefined. shows that activity localizes to plasma membrane (ER) cells, whereas resides primarily ER. Additionally, treatment using...