Altered Ion Transport Research Articles

Male Wistar Rats Chronically Fed with a High-Fat Diet Develop Inflammatory and Ionic Transport Angiotensin-(3-4)-Sensitive Myocardial Lesions but Preserve Echocardiographic Parameters.

The central aim of this study was to investigate whether male Wistar rats chronically fed a high-fat diet (HFD) over 106 days present high levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and Na+ and Ca2+ transport alterations in the left ventricle, together with dyslipidemia and decreased glucose tolerance, and to investigate the influence of Ang-(3-4). The rats became moderately overweight with an expansion of visceral adiposity. Na+-transporting ATPases, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA2a), and the abundance of Angiotensin II receptors were studied together with lipid and glycemic profiles from plasma and left-ventricle echocardiographic parameters fractional shortening (FS) and ejection fraction (EF). IL-6 and TNF-α increased (62% and 53%, respectively), but returned to normal levels with Angiotensin-(3-4) administration after 106 days. Significant lipidogram alterations accompanied a decrease in glucose tolerance. Angiotensin II receptors abundance did not change. (Na+ + K+)ATPase and ouabain-resistant Na+-ATPase were downregulated and upregulated, respectively, but returned to normal values upon Angiotensin-(3-4) administration. SERCA2a lost its ability to respond to excess ATP. Echocardiography showed no changes in FS or EF. We conclude that being overweight causes an increase in Ang-(3-4)-sensitive IL-6 and TNF-α levels, and ion transport alterations in the left ventricle that could evolve into future heart dysfunction.

BOS-318 treatment enhances elexacaftor-tezacaftor-ivacaftor (ETI)-mediated improvements in airways hydration and mucociliary transport

BackgroundCFTR triple modulator therapy, elexacaftor-tezacaftor-ivacaftor (ETI) has transformed care for people with cystic fibrosis (pwCF) who have eligible mutations. It is, however, not curative. Response to treatment also varies and lung disease although slowed, remains progressive. We have previously demonstrated that inhibition of the epithelial sodium channel (ENaC) by selective furin inhibition offers an alternative, mutation-agnostic approach to enhance airways hydration and restore mucociliary transport (MCT) in CF. Inhibition of furin therefore, offers a potential therapeutic strategy for those ineligible, intolerant or non-responsive to ETI and may provide a further opportunity for clinical benefit for those currently treated with ETI. The aim of this study was to determine the impact of furin inhibition on ETI responses to assess its utility as an adjunct therapy.MethodsDifferentiated primary human CF bronchial epithelial cells (CF HBECs) were treated with the highly selective furin inhibitor, BOS-318 and ETI. Ion channel function was measured using a 24-channel Transepithelial Current Clamp (TECC-24) system and airways surface hydration was investigated by measuring airway surface liquid (ASL) height and MCT rate.ResultsThe presence of BOS-318 had no effect on the ability of ETI to stimulate CFTR-mediated Cl−secretion but contributed a reduced Na+transportviarobust inhibition of ENaC. This altered ion transport profile effected an improved ASL height and MCT rate which were significantly greater than improvements observed with ETI alone, demonstrating the benefits of the dual approach.ConclusionsSelective furin inhibition has potential to further improve clinical outcomes for all pwCF and offers opportunity as an adjunct to improve responses to currently available CFTR modulator therapies.

Research on Experimental Hypertension in Prague (1966-2009).

The study of ontogenetic aspects of water and electrolyte metabolism performed in the Institute of Physiology (Czechoslovak Academy of Sciences) led to the research on the increased susceptibility of immature rats to salt-dependent forms of hypertension since 1966. Hemodynamic studies in developing rats paved the way to the evaluation of hemodynamic mechanisms during the development of genetic hypertension in SHR. A particular attention was focused on altered renal function and kidney damage in both salt and genetic hypertension with a special respect to renin-angiotensin system. Renal damage associated with hypertension progression was in the center of interest of several research groups in Prague. The alterations in ion transport, cell calcium handling and membrane structure as well as their relationship to abnormal lipid metabolism were studied in a close cooperation with laboratories in Munich, Glasgow, Montreal and Paris. The role of NO and oxidative stress in various forms of hypertension was a subject of a joint research with our Slovak colleagues focused mainly on NO-deficient hypertension elicited by chronic L-NAME administration. Finally, we adopted a method enabling us to evaluate the balance of vasoconstrictor and vasodilator mechanisms in BP maintenance. Using this method we demonstrated sympathetic hyperactivity and relative NO deficiency in rats with either salt-dependent or genetic hypertension. At the end of the first decennium of this century we were ready to modify our traditional approach towards modern trends in the research of experimental hypertension. Keywords: Salt-dependent hypertension o Genetic hypertension o Body fluids o Hemodynamics o Ion transport o Cell membrane structure and function o Renal function o Renin-angiotensin systems.

Purinergic control of apical ion conductance by luminal ATP in rat colonic epithelium

ATP, released e.g. after cell damage or during inflammation, can alter ion transport across the intestinal mucosa via stimulation of purinergic receptors in the basolateral as well as in the apical membrane of epithelial cells. When ATP acts from the serosal side, it induces an increase in short-circuit current (Isc) via Cl− secretion across the colonic epithelium. In contrast, mucosal ATP or its derivative, BzATP, predominantly stimulating ionotropic P2X4 and P2X7 receptors, evoke an increase in Isc, which could not be explained by Cl− secretion. The underlying ion currents after stimulation of apical purinergic receptors in rat distal colon are still unclear and were investigated in the present study.Ussing chamber experiments revealed that the Isc induced by mucosal ATP was dependent on the presence of mucosal Ca2+ and inhibited by the K+ channel blocker, Ba2+, indicating the involvement of Ca2+-dependent K+ channels. Blockade of the transepithelial Isc by lanthanides (La3+, Gd3+) suggests that Ca2+ enters the epithelium via nonselective cation channels. Experiments with basolaterally depolarized epithelia confirmed the activation of apical lanthanide-sensitive Na+- and Ca2+-permeable cation channels by ATP. Putative candidates might be TRP channels, from which several subtypes were detected in colonic tissue in RT-PCR experiments. In addition, the activation of an apical Cl− conductance was observed when suitable Cl− concentration gradients were applied. Consequently, mucosal ATP, acting as ‘danger signal’, stimulates cation and anion channels in the apical membrane to induce a secretory response as part of the local defence mechanism in the intestinal epithelium.

Fermencin B2: A promising heat-stable cationic peptide for targeted inhibition of Staphylococcus aureus

In this study, a novel strain of L. fermentum JF9 with bacteriocin production capacity was firstly isolated from Chinese fermented vinegar Pei, and the significant antibacterial potential and safety of L. fermentum JF9 were confirmed by three-generation whole genome sequencing. The bacteriocin Fermencin B2, secreted by L. fermentum JF9, was purified by series chromatographic separation and LC-MS/MS. Fermencin B2, a cationic peptide containing the HLVRNP amino acid sequence, exhibited a stable β-folded structure and antibacterial activity at different temperatures. Meanwhile, Fermencin B2 had low cytotoxicity and was not hemolytic. The inhibitory activity and mechanisms of Fermencin B2 against S. aureus were investigated using SEM and TEM analysis, molecular docking analysis, assays for membrane proteins and ion levels, nucleic acids, LDH leakage, as well as flow cytometry. Fermencin B2 caused severe damage to the cell membrane of S. aureus, resulting in the disruption of ATPase activity, alteration of ion transport, increased membrane permeability, and disintegration of the cell membrane. This ultimately led to the leakage of nucleic acids and LDH, resulting in bacterial death. Overall, Fermencin B2 could be a novel antibacterial agent and food preservative for targeted inhibition of S. aureus.

The Stria Vascularis: Renewed Attention on a Key Player in Age-Related Hearing Loss.

Age-related hearing loss (HL), or presbycusis, is a complex and heterogeneous condition, affecting a significant portion of older adults and involving various interacting mechanisms. Metabolic presbycusis, a type of age-related HL, is characterized by the dysfunction of the stria vascularis, which is crucial for maintaining the endocochlear potential necessary for hearing. Although attention on metabolic presbycusis has waned in recent years, research continues to identify strial pathology as a key factor in age-related HL. This narrative review integrates past and recent research, bridging findings from animal models and human studies, to examine the contributions of the stria vascularis to age-related HL. It provides a brief overview of the structure and function of the stria vascularis and then examines mechanisms contributing to age-related strial dysfunction, including altered ion transport, changes in pigmentation, inflammatory responses, and vascular atrophy. Importantly, this review outlines the contribution of metabolic mechanisms to age-related HL, highlighting areas for future research. It emphasizes the complex interdependence of metabolic and sensorineural mechanisms in the pathology of age-related HL and highlights the importance of animal models in understanding the underlying mechanisms. The comprehensive and mechanistic investigation of all factors contributing to age-related HL, including cochlear metabolic dysfunction, remains crucial to identifying the underlying mechanisms and developing personalized, protective, and restorative treatments.

Deletion of Kcnj16 altered transcriptomic and metabolomic profiles of Dahl salt-sensitive rats

The essential role of inwardly rectifying K+ Channel Kir5.1 (encoded by the Kcnj16 gene) in renal salt handling and blood pressure control has been demonstrated in both human and animal models. However, the underlying mechanisms are still not fully understood. Here, we aimed to integrate transcriptomics and metabolomics to profile the comprehensive changes of genes and metabolites under the deletion of Kcnj16 in the Dahl salt-sensitive (SS) rat background to identify novel mechanisms. For the transcriptomics profiling, we performed RNA-sequencing on kidney cortex tissue of Kcnj16 knockout (KO) and wild-type (WT) SS rats (N=5 per group). For the metabolomics profiling, we performed untargeted metabolomics of kidney cortex tissue, plasma, and urine of KO (N=6) and WT (N=5) rats. Transcriptomics analysis revealed over 6,000 differentially expressed genes in KO rats compared to WT rats, with renin Ren (the gene encoding renin) being the most upregulated gene. Consistent with the phenotype observed in the KO rats, ingenuity pathway analysis (IPA) based on the transcriptomic profile predicted reduced blood pressure and kidney damage and increased ion transport. Canonical pathway analysis suggested activation of metabolic-related pathways [e.g., xenobiotic metabolism, tricarboxylic acid (TCA) cycle, phenylalanine degradation, etc.] and suppression of immune responses-related pathways [e.g., pathogen-induced cytokine storm signaling pathway, macrophage classical activation signaling pathway, nuclear factor of activated T cells (NFAT) pathway, etc.] in KO rats. Untargeted metabolomic analysis suggested distinct metabolic profiles of plasma, urine, and kidneys between WT and KO rats, with 219, 790, and 31 differentially expressed metabolites identified in plasma, urine, and kidney in KO rats compared to WT rats. Canonical pathway analysis identified spermine and spermidine degradation pathways in both plasma and urine and taurine biosynthesis pathways in both urine and kidney. Integration analysis based on transcriptomic and metabolomic profiles suggested an altered TCA cycle, amino acid, and reactive oxygen species metabolism. In conclusion, besides significantly altered ion transport, our transcriptomics and metabolomics data suggest significant suppressed immune responses-related and altered metabolic-related pathways in SS rats lacking Kir5.1, which provides new insights into the underlying mechanisms of the regulation of blood pressure and renal function by Kir5.1. This work is supported by National Institutes of Health Grants R35 HL135749 and R01 DK135644 (to A.S.), Department of Veteran Affairs grant I01 BX004024 (to A.S.), the American Physiological Society Postdoctoral Fellowship (to B.X.) and the American Society of Nephrology Dimitrios G. Oreopoulos Research Fellowship Award (to L.V.D.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Knock-out of dipeptidase CN2 in human proximal tubular cells disrupts dipeptide and amino acid homeostasis and para- and transcellular solute transport.

Although of potential biomedical relevance, dipeptide metabolism has hardly been studied. We found the dipeptidase carnosinase-2 (CN2) to be abundant in human proximal tubules, which regulate water and solute homeostasis. We therefore hypothesized, that CN2 has a key metabolic role, impacting proximal tubular transport function. A knockout of the CN2 gene (CNDP2-KO) was generated in human proximal tubule cells and characterized by metabolomics, RNA-seq analysis, paracellular permeability analysis and ion transport. CNDP2-KO in human proximal tubule cells resulted in the accumulation of cellular dipeptides, reduction of amino acids and imbalance of related metabolic pathways, and of energy supply. RNA-seq analyses indicated altered protein metabolism and ion transport. Detailed functional studies demonstrated lower CNDP2-KO cell viability and proliferation, and altered ion and macromolecule transport via trans- and paracellular pathways. Regulatory and transport protein abundance was disturbed, either as a consequence of the metabolic imbalance or the resulting functional disequilibrium. CN2 function has a major impact on intracellular amino acid and dipeptide metabolism and is essential for key metabolic and regulatory functions of proximal tubular cells. These findings deserve invivo analysis of the relevance of CN2 for nephron function and regulation of body homeostasis.

Ginkgo biloba L. exocarp petroleum ether extract inhibits methicillin-resistant Staphylococcus aureus by modulating ion transport, virulence, and biofilm formation in vitro and in vivo

Ethnopharmacological relevanceAs reported in the Ancient Chinese Medicinal Books, Ginkgo biloba L. fruit has been used as a traditional Chinese medicine for the treatment asthma and cough or as a disinfectant. Our previous study demonstrated that G. biloba exocarp extract (GBEE), an extract of a traditional Chinese herb, inhibits the formation of methicillin-resistant Staphylococcus aureus (MRSA) biofilms. However, GBEE is a crude extract that contains many components, and the underlying mechanisms of purified GBEE fractions extracted with solvents of different polarities are unknown. Aim of the studyThis study aimed to investigate the different components in GBEE fractions extracted with solvents of different polarities and their antibacterial effects and mechanisms against MRSA and Staphylococcus haemolyticus biofilms both in vitro and in vivo. MethodsThe components in different fractions were detected by high-performance liquid chromatography–high resolution mass spectrometry (HPLC–HRMS). Microbroth dilution assays and time growth curves were used to determine the antibacterial effects of the fractions on 15 clinical bacterial isolates. Crystal violet staining, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were utilized to identify the fractions that affected bacterial biofilm formation. The potential MRSA targets of the GBEE fraction obtained with petroleum ether (PE), denoted GBEE-PE, were screened by transcriptome sequencing, and the gene expression profile was verified by quantitative polymerase chain reaction (qPCR). ResultsHPLC–HRMS analysis revealed that the four GBEE fractions (extracted with petroleum ether, ethyl acetate, n-butanol, and water) contained different ginkgo components, and the antibacterial effects decreased as the polarity of the extraction solvent increased. The antibacterial activity of GBEE-PE was greater than that of the GBEE fraction extracted with ethyl acetate (EA). GBEE-PE improved H. illucens survival and reduced MRSA colonization in model mouse organs. Crystal violet staining and SEM and TEM analyses revealed that GBEE-PE inhibited MRSA and S. haemolyticus biofilm formation. Transcriptional analysis revealed that GBEE-PE inhibits MRSA biofilms by altering ion transport, cell wall metabolism and virulence-related gene expression. In addition, the LO2 cell viability and H. illucens toxicity assay data showed that GBEE-PE at 20 mg/kg was nontoxic. ConclusionThe GBEE fractions contained different components, and their antibacterial effects decreased with increases in the polarity of the extraction solvent. GBEE-PE limited MRSA growth and biofilm formation by affecting ion transport, cell wall synthesis, and virulence-related pathways. This research provides a more detailed overview of the mechanism by which GBEE-PE inhibits MRSA both in vitro and in vivo and suggests that GBEE-PE is a new prospective antimicrobial with the potential to be used in MRSA therapeutics in the future.

The cell biology of ferroptosis.

Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular mechanisms mediating the execution and regulation of ferroptosis. We first consider how the accumulation of membrane lipid peroxides leads to the execution of ferroptosis by altering ion transport across the plasma membrane. We then discuss how metabolites and enzymes that are distributed in different compartments and organelles throughout the cell can regulate sensitivity to ferroptosis by impinging upon iron, lipid and redox metabolism. Indeed, metabolic pathways that reside in the mitochondria, endoplasmic reticulum, lipid droplets, peroxisomes and other organelles all contribute to the regulation of ferroptosis sensitivity. We note how the regulation of ferroptosis sensitivity by these different organelles and pathways seems to vary between different cells and death-inducing conditions. We also highlight transcriptional master regulators that integrate the functions of different pathways and organelles to modulate ferroptosis sensitivity globally. Throughout this Review, we highlight open questions and areas in which progress is needed to better understand the cell biology of ferroptosis.

Taxonomic Identification of the Arctic Strain Nocardioides Arcticus Sp. Nov. and Global Transcriptomic Analysis in Response to Hydrogen Peroxide Stress.

Microorganisms living in polar regions rely on specialized mechanisms to adapt to extreme environments. The study of their stress adaptation mechanisms is a hot topic in international microbiology research. In this study, a bacterial strain (Arc9.136) isolated from Arctic marine sediments was selected to implement polyphasic taxonomic identification based on factors such as genetic characteristics, physiological and biochemical properties, and chemical composition. The results showed that strain Arc9.136 is classified to the genus Nocardioides, for which the name Nocardioides arcticus sp. nov. is proposed. The ozone hole over the Arctic leads to increased ultraviolet (UV-B) radiation, and low temperatures lead to increased dissolved content in seawater. These extreme environmental conditions result in oxidative stress, inducing a strong response in microorganisms. Based on the functional classification of significantly differentially expressed genes under 1 mM H2O2 stress, we suspect that Arc9.136 may respond to oxidative stress through the following strategies: (1) efficient utilization of various carbon sources to improve carbohydrate transport and metabolism; (2) altering ion transport and metabolism by decreasing the uptake of divalent iron (to avoid the Fenton reaction) and increasing the utilization of trivalent iron (to maintain intracellular iron homeostasis); (3) increasing the level of cell replication, DNA repair, and defense functions, repairing DNA damage caused by H2O2; (4) and changing the composition of lipids in the cell membrane and reducing the sensitivity of lipid peroxidation. This study provides insights into the stress resistance mechanisms of microorganisms in extreme environments and highlights the potential for developing low-temperature active microbial resources.

Effect of Chronic Hydrogen Peroxide Exposure on Ion Transport in Gills of Common Carp (Cyprinus carpio)

High environmental hydrogen peroxide (H2O2) has been demonstrated to be toxic for fish. However, the response mechanism of fish to chronic H2O2 exposure is not yet well understood. Therefore, this study aimed to investigate the alteration in ion transport in gills and analyzed the potential response mechanism after chronic H2O2 exposure. The common carps were exposed to 0, 0.25, 0.50, and 1.00 mM of H2O2 for 14 days. The histopathological evaluation results indicated that H2O2 exposure caused incomplete gill filament structure. In the plasma, H2O2 exposure suppressed the potassium (K+) concentration but increased sodium (Na+) concentration. In the gills, the calcium (Ca2+) level was raised, but the K+ and chlorine (Cl−) levels were decreased after H2O2 exposure. After 14 days of exposure, H2O2 prompted the activities of Ca2+/Mg2+-ATPase and H+/K+-ATPase but suppressed Na+/K+-ATPase activity in the gills. Gene transcription analysis showed that the ion-regulation-related genes including nkaa and rhbg were downregulated after H2O2 exposure. In addition, H2O2 exposure upregulated the mRNA levels of cam and camk II, indicating that the Ca2+ singling pathway was activated. In conclusion, our data showed that chronic H2O2 exposure altered gill structure and disturbed ion transport, which further negatively affected the equilibrium of ions and osmotic pressure.

Mechano-electrochemical coupling in flexible all-solid-state lithium metal batteries

Bending and stretching are critical mechanical behaviors affecting the electrochemical performance of flexible batteries in wearable electronic devices. Herein, a mechano-electrochemical model is developed for solid-state Li metal batteries under bending deformation. It is found that bending alters ion transport and electric potential in solid polymer electrolytes, and its influence relies on the bending direction. By means of the curvature and coupling coefficient, a phase map is constructed for the critical current density that leads to ion depletion at the Li metal-electrolyte interface. In addition, a positive curvature helps to decrease the overpotential for electrochemical reactions on the Li metal electrode. Though the direct influence of bending on electrochemical kinetics is limited, the bending deformation could substantially increase the stress and cause potential mechanical failure of electrodes and electrode-electrolyte interfaces, thereby degrading electrochemical performance.

Mechanistic insights into the primary and secondary alterations of renal ion and water transport in the distal nephron.

The kidneys, by equilibrating the outputs to the inputs, are essential for maintaining the constant volume, pH, and electrolyte composition of the internal milieu. Inability to do so, either because of internal kidney dysfunction (primary alteration) or because of some external factors (secondary alteration), leads to pathologies of varying severity, leading to modification of these parameters and affecting the functions of other organs. Alterations of the functions of the collecting duct (CD), the most distal part of the nephron, have been extensively studied and have led to a better diagnosis, better management of the related diseases, and the development of therapeutic tools. Thus, dysfunctions of principal cell-specific transporters such as ENaC or AQP2 or its receptors (mineralocorticoid or vasopressin receptors) caused by mutations or by compounds present in the environment (lithium, antibiotics, etc.) have been demonstrated in a variety of syndromes (Liddle, pseudohypoaldosteronism type-1, diabetes insipidus, etc.) affecting salt, potassium, and water balance. In parallel, studies on specific transporters (H+ -ATPase, anion exchanger 1) in intercalated cells have revealed the mechanisms of related tubulopathies like distal renal distal tubular acidosis or Sjögren syndrome. In this review, we will recapitulate the mechanisms of most of the primary and secondary alteration of the ion transport system of the CD to provide a better understanding of these diseases and highlight how a targeted perturbation may affect many different pathways due to the strong crosstalk and entanglements between the different actors (transporters, cell types).

Metabolic Pathways and Ion Channels Involved in Skeletal Muscle Atrophy: A Starting Point for Potential Therapeutic Strategies.

Skeletal muscle tissue has the important function of supporting and defending the organism. It is the largest apparatus in the human body, and its function is important for contraction and movements. In addition, it is involved in the regulation of protein synthesis and degradation. In fact, inhibition of protein synthesis and/or activation of catabolism determines a pathological condition called muscle atrophy. Muscle atrophy is a reduction in muscle mass resulting in a partial or complete loss of function. It has been established that many physiopathological conditions can cause a reduction in muscle mass. Nevertheless, it is not well known the molecular mechanisms and signaling processes causing this dramatic event. There are multiple concomitant processes involved in muscle atrophy. In fact, the gene transcription of some factors, oxidative stress mechanisms, and the alteration of ion transport through specific ion channels may contribute to muscle function impairment. In this review, we focused on the molecular mechanisms responsible for muscle damage and potential drugs to be used to alleviate this disabling condition.

Bioelectricity Buzz.

Bioelectricity Buzz.

Interactions of a high‐fat Western diet and crystalline silica inhalation on airway epithelial ion transport and airway reactivity

Silicosis, an irreversible occupational lung disease caused by crystalline silica inhalation, is a serious health risk for silica‐exposed workers. NIOSH reports that Appalachian coal miners have higher rates of obesity and metabolic dysfunction (MetDys) compared to the general U.S. adult population. MetDys is a risk factor for lung function impairment, pulmonary hypertension, and asthma. Consumption of a high‐fat Western diet (HFWD) is associated with obesity and MetDys. In this study, we investigated the effects of, and determine interactions between, HFWD‐consumption and silica‐exposure on airway epithelial ion transport and smooth muscle reactivity in the F344 rat. Six‐week‐old male F344 rats were fed either a HFWD [40.6% fat (19.5% lard), 40.6% total carbohydrate (20% sucrose), 14.8 % protein] or standard rat chow (STD) [6.2 % fat, 44.2 % carbohydrate (grain sources), 18.6 % protein] for the duration of the study. Following 16 weeks of diet‐consumption, inhalation exposure to respirable crystalline silica (Min‐U‐Sil 5®, 15 mg/m3, 6 h/d, 5 d/wk, for 39 d) or filtered air began, with endpoint experiments conducted at 0, 4, and 8 wk post‐exposure. Airway epithelial ion transport maintains airway surface liquid osmolarity and depth required for effective cilia motility and clearance of xenogens. Changes in ion transport were determined ex vivo by measurement of transepithelial potential difference (Vt), short‐circuit current (ISC) and transepithelial resistance (Rt) in rat tracheal segments mounted in Ussing chambers, and administered the ion transport inhibitors amiloride (Na+ channel blocker; apical), 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB; Clˉ channel blocker; apical), and ouabain (Na+, K+‐pump blocker; basolateral). Airway hyperresponsiveness is associated with obesity and pulmonary diseases such as asthma and COPD; thus, the isolated perfused trachea apparatus was employed to ascertain whether silica or HFWD altered airway smooth muscle reactivity to serosal or mucosal applied methacholine (MCh). HFWD‐consumption had no effect on basal Vt. Silica exposure increased Na+ transport at 0 wk, decreased basal ISC at 4 wk, and reduced Cl‐ channel and Na+, K+‐pump activity at both 4 wk and 8 wk compared to STD+AIR controls. HFWD‐consumption caused a reduction in Cl‐ transport and Na+, K+‐pump activity at 4 wk, while increasing Rt in response to ouabain at 0 wk and NPPB at 8 wk compared to STD+AIR. HFWD+SIL increased basal ISC at 0 and 4 wk, caused reduction in Cl‐ transport and Na+, K+‐pump activity at 4 wk, while reducing Rtin response to ouabain at 4 wk compared to STD+SIL. No significant changes in tracheal reactivity to MCh were observed. In conclusion, HFWD and silica altered epithelial ion transport, but the combined effects of HFWD+SIL were not synergistic.

375: Exposure to healthy or cystic fibrosis sputum alters ion transport across human bronchial epithelial cells

375: Exposure to healthy or cystic fibrosis sputum alters ion transport across human bronchial epithelial cells

Mouse organoid culture is a suitable model to study esophageal ion transport mechanisms.

Altered esophageal ion transport mechanisms play a key role in inflammatory and cancerous diseases of the esophagus, but epithelial ion processes have been less studied in the esophagus because of the lack of a suitable experimental model. In this study, we generated three-dimensional (3D) esophageal organoids (EOs) from two different mouse strains and characterized the ion transport processes of the EOs. EOs form a cell-filled structure with a diameter of 250-300 µm and were generated from epithelial stem cells as shown by FACS analysis. Using conventional PCR and immunostaining, the presence of Slc26a6 Cl-/HCO3- anion exchanger (AE), Na+/H+ exchanger (NHE), Na+/HCO3- cotransporter (NBC), cystic fibrosis transmembrane conductance regulator (CFTR), and anoctamin 1 Cl- channels was detected in EOs. Microfluorimetric techniques revealed high NHE, AE, and NBC activities, whereas that of CFTR was relatively low. In addition, inhibition of CFTR led to functional interactions between the major acid-base transporters and CFTR. We conclude that EOs provide a relevant and suitable model system for studying the ion transport mechanisms of esophageal epithelial cells, and they can be also used as preclinical tools to assess the effectiveness of novel therapeutic compounds in esophageal diseases associated with altered ion transport processes.

Transport Phenomena in Low Temperature Lithium-Ion Battery Electrolytes

Lithium-ion batteries face low temperature performance issues, limiting the adoption of technologies ranging from electric vehicles to stationary grid storage. This problem is thought to be exacerbated by slow transport within the electrolyte, which in turn may be influenced by ion association, solvent viscosity, and cation transference number. How these factors collectively impact low temperature transport phenomena, however, remains poorly understood. Here we show using all-atom classical molecular dynamics (MD) simulations that the dominant factor influencing low temperature transport in LP57 (1 M LiPF6 in 3:7 ethylene carbonate (EC)/ethyl methyl carbonate (EMC)) is solvent viscosity, rather than ion aggregation or cation transference number. We find that ion association decreases with decreasing temperature, while the cation transference number is positive and roughly independent of temperature. In an effort to improve low temperature performance, we introduce γ-butyrolactone (GBL) as a low viscosity co-solvent to explore two alternative formulations: 1 M LiPF6 in 15:15:70 EC/GBL/EMC and 3:7 GBL/EMC. While GBL reduces solution viscosity, its low dielectric constant results in increased ion pairing, yielding neither improved bulk ionic conductivity nor appreciably altered ion transport mechanisms. We expect that these results will enhance understanding of low temperature transport and inform the development of superior electrolytes.