bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammatory Cytokines IL‐13 or IL‐17/TNFα Do Not Alter the Low Paracellular Bicarbonate Permeability of Cystic Fibrosis Airway Epithelia
Authors: Thornell Ian Michael , Rehman Tayyab , Welsh Michael J 
Published: June 2021

The airway‐surface liquid, the thin aqueous layer on the apical side of airway epithelia, maintains a pH that is more acidic than the serosal pH. For human large airways, this acidic pH is the balance of HCO3− secretion by the cystic fibrosis transmembrane conductance regulator (CFTR) and H+ secretion by the H+/K+ pump ATP12A, both transcellular mechanisms. Newborn humans with cystic fibrosis (CF) have an acidic airway‐surface liquid pH compared to non‐CF newborns. With time, the pH difference between CF and non‐CF individuals disappears. However, adult CF epithelia cultured at the air‐liquid interface are more acidic than non‐CF epithelia. We hypothesized that CF‐related inflammation in vivo is responsible for the age‐dependent airway alkalinization. Here, we tested the hypothesis that cytokines increase paracellular movement of HCO3− into the airway‐surface liquid. Dilution potentials observed for cultured CF airway indicate that paracellular transport favored cations (PCl/PNa = 0.7). The paracellular conductance and selectivity were unaffected by changing the pH from 7.4 to 6.0. HCO3− was less permeable than Cl− through the paracellular pathway (PHCO3/PNa = 0.35). Treating cultures with cytokines (IL‐13 or IL‐17 and TNFa), which increase the airway‐surface liquid pH, did not affect paracellular PHCO3/PNa. These data suggest that differences in transcellular pH transport are responsible for cytokine‐mediated ASL pH changes. Similar transcellular mechanisms may cause the longitudinal ASL pH changes observed for CF patients.Support or Funding InformationMJW is an Investigator of the Howard Hughes Medical InstituteCystic Fibrosis Foundation Research Development ProgramNIH HL091842This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
NBCe1 in the Kidney and Lower Urogenital Tract
Authors: Romero Phinea Z , Holmes Heather L , Cadena Mark T , Gibbons Simon J , Farrugia Gianrico , Vezina Chad M , Romero Michael F 
Published: June 2021

NBCe1 is an electrogenic Na+ bicarbonate cotransporter expressed as three isoforms. NBCe1A is mainly found in the kidney (100% activity), NBCe1B is a general isoform (~25% activity), and NBCe1C is found in the nervous system (20% activity). This project was to characterize mice with loss of NBCe1 in the kidney and urogenital tract and to test isoform activity ± IRBIT. Previous work has shown that NBCe1‐B is activated when IRBIT is present and interacts with the N‐terminus (Nt). Even though NBCe1C shares this Nt, the effects of IRBIT on human NBCe1C are unknown. Interstitial Cells of Cajal (ICC)pacemaker cells in the gastrointestinal tract (c‐kit+) have NBCe1C, IRBIT and require bicarbonate for normal gut activity. Developmentally similar ICC cells are found in the urogenital tract; however, NBCe1C locations within the kidney and urogenital tract are unknown. Using c‐kit‐copGFP and NBCe1A‐knockout mice, kidneys, ureters, prostate, bladder, and urethra were dissected and analyzed via direct imaging, sectioning, and immunofluorescence. Oocytes injected with NBCe1C ± IRBIT were voltage clamped to determine the cotransporter's activity. “Strings” of c‐kit+‐cells were found in the copGFP & nbce1A kidneys. In nbce1(+/−)‐(Het) mice (Figure), prostate ducts appeared enlarged, and in nbce1A−/− kidney, c‐kit protein was broadly expressed, showing cluster colocalization with NBCe1C. NBCe1C is not obviously expressed in WT or copGFP mice. Electrophysiology data showed that IRBIT activates NBCe1C by ~10‐fold. As c‐kit is also a marker of stem cells, NBCe1C/c‐kit association and c‐kit increase in nbce1A−/− mice, could suggest that NBCe1A loss elicits kidney repair itself (proliferation) and causes expression of other NBCe1‐isoforms.Support or Funding InformationR25‐DK101405, R01‐DK057061, U54‐DK100227 (Mayo) and U54‐DK104310 (UW‐Madison)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Adrenosterone, Testosterone, and 17β‐Estradiol on the Gene Expression of Insulin‐Like Growth‐Factor Binding Proteins (igfbps) in Atlantic Salmon Smolts
Authors: White Rebecca , Cairnduff Ross , Nilsen Tom , Einarsdottir Ingibjorg , Bjornsson Thrandur , McCormick Stephen , Breves Jason 
Published: June 2021

The growth hormone (Gh)/insulin‐like growth‐factor (Igf) system is a key regulator of growth in teleost fishes, including salmonids. Igfs interact with a suite of binding proteins, termed Igf binding proteins (Igfbps), which modify their biological activities. Atlantic salmon (Salmo salar) express an expanded array of igfbp gene transcripts in liver, the primary site of Igfbp production. While gonadal steroids are known to impact the growth of fishes, there is little information on how androgens and estrogens affect the expression of various igfbps. In the current study, we characterized how 14‐day implants of adrenosterone (OA), testosterone (T) or 17β‐estradiol (E2) affected the Gh/Igf/Igfbp network in Atlantic salmon smolts. OA did not affect any of the parameters studied. There were no effects of T or E2 on body mass, plasma levels of Igf1, or hepatic igf1, igf2 or gh receptor mRNA levels. E2 stimulated hepatic estrogen receptor α mRNA levels by 17‐fold, while E2 and T stimulated hepatic vitellogenin mRNA levels by 140‐ and 19‐fold, respectively. Hepatic igfbp1b1 and igfbp4 mRNA levels were diminished by E2 but not T, whereas igfbp2a was diminished by T, but not E2. Alternatively, both T and E2 stimulated igfbp5a. igfbp2b2, igfbp5b2 and igfbp6b were not impacted by any of the tested steroids. Our findings suggest that steroid‐specific effects on the gene expression of various igfbps provide a means for gonadal steroids to modulate the Gh/Igf system.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influence of Codeine on Swallow in the Anesthetized Cat: Evidence for Peripheral and Central Actions of Opioids to Induce Dysregulation of Deglutition
Authors: Bolser Donald C , Shen Tabitha Y , Musselwhite M Nicholas , Rose Melanie J , Davenport Paul W , Morris Kendall M , Pitts Teresa 
Published: June 2021

Systemic administration of opioids has been associated with aspiration and swallow dysfunction in humans. The extent to which these outcomes are due to solely central, or both central and peripheral actions, of these drugs is unknown. Codeine is a commonly prescribed opioid that has both central and peripheral actions to affect the cough reflex in animal models. We speculated that systemic administration of codeine would induce dysfunctional swallowing and that this effect would have a peripheral component. Experiments were conducted in spontaneously breathing, anesthetized cats (n=19). The animals were tracheotomized and EMG electrodes were placed in upper airway and chest wall respiratory muscles for recording swallow related motor activity. The animals were allocated into three groups: vagal intact (VI), cervical vagotomy (CVx), and supra‐nodose ganglion vagotomy (SNVx). A dose‐response to intravenous codeine (0.1–10 mg/kg) was performed in each animal. Swallowing was elicited by injection of 3 ml of water into the oropharynx. Results demonstrated a significant dose‐related increase in spontaneous swallowing (per 7 minute period between doses) in each group (VI: vehicle 0.2±0.2 to 10 mg/kg codeine 6.6±4.0, SNVx: vehicle 0.2±0.2 to 10 mg/kg codeine 4.0±2.3, CVx: vehicle 2.3±1.3 to 13±6.0 10 mg/kg codeine). Additionally, the number of induced swallows after vehicle was significantly higher in the VI group than in SNVx (p<0.04), and in the CVx compared to the SNVx group at 10mg/kg (p<0.05). Codeine also demonstrated dose‐dependent effects on upper airway motor drive during the induced swallow trials. The thyropharyngeus muscle EMG activation was significantly increased in the VI and CVx groups by 2–4 fold in a dose‐related manner (p<0.01). Also, in the CVx group, the geniohyoid muscle EMG activation was significantly increased (p<0.05). Under control conditions the presence of spontaneous swallows is rare, and their presence in response to codeine supports a strong central action and likely a dysregulation of the inhibitory influences on the swallow pattern generator. Unlike cervical vagotomy, section of the vagus nerve rostral to the nodose ganglion eliminates superior laryngeal nerve afferents. At the highest dose of codeine, the reduced spontaneous swallow number in the SNVx group relative to CVx is consistent with a peripheral excitatory action of codeine either on pharyngeal/laryngeal receptors or in the nodose ganglion itself.Support or Funding InformationSupported by OT2OD023854‐01, HL109025, HL131716.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Vagal and spinal pulmonary afferents contribute to respiratory variability and gender‐specific response to mechanical challenge
Authors: Huff Alyssa D , Reed Mitchell D , Mian Seema , Iceman Kimberly , Pitts Teresa 
Published: June 2021

Respiratory variability is important in order to respond to internal and external perturbations. While vagal afferents have been shown to be important for feedback during breathing, the influence of spinal afferents has not been as well described. We hypothesized that disruption of vagal and spinal afferents reduces respiratory variability during eupnea and alters respiratory response during thoracic mechanical restriction (banding). We measured costal diaphragm and thyroarytenoid electromyography (EMG) activity in sodium pentobarbital anesthetized spontaneously breathing male and female Sprague Dawley rats. We conducted three sets of experiments to elucidate contributions of vagal, and spinal afferents: A) inhalation of 10% nebulized lidocaine to attenuate pulmonary vagal afferents B) bilateral injections of 10% lidocaine into the pleural space to attenuate thoracic afferent feedback; C) bilateral tracheal vagotomy caudal to the larynx. Solutions of 10% lidocaine were mixed with saline and 2% Evans Blue dye to confirm the distribution of lidocaine following nebulization and injection. Additionally, banding was performed before and after each experimental protocol. Banding significantly increased costal diaphragm amplitude which was further increased with each intervention, however there was a gender specific increase in thyroarytenoid activity with only ~50% of males demonstrating this phenomenon. Both lidocaine protocols demonstrated features of vagotomy including reduction of each eupneic phase duration coefficient of variance as well as alterations in EMG amplitude. These results demonstrate gender‐specific effects of the respiratory system to challenges, and provide preliminary evidence of the importance of non‐vagal pulmonary feedback. Moreover, this present study could have broad clinical implications in disorders such as spinal cord injury.Support or Funding InformationThis work was supported by NIH grants HL 111215, HL 103415 and OT20D001983, the Craig F. Neilson Foundation Pilot Research Grant 546714, Kentucky Spinal Cord and Head Injury Research Trust, and the Commonwealth of Kentucky Challenge for Excellence.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cough Hypersensitivity Induced by Eosinophil Granule‐Derived Major Basic Protein in Awake Mice
Authors: Athukorala Ashami , Lin An‐Hsuan , Lin Ruei‐Lung , Khosravi Mehdi , Gleich Gerald , Lee Lu‐Yuan 
Published: June 2021

Non‐asthmatic eosinophilic bronchitis is one of the major causes of chronic cough. Major basic protein (MBP), an eosinophil granule‐derived cationic protein, is known to induce airway mucosal inflammation and hypersensitivity of airway sensory nerves. However, little is known about the effects of MBP on cough sensitivity. This study was carried out to determine the effect of MBP on modulating cough responses to inhalation of sulfur dioxide (SO2) and ammonia (NH3), air pollutants and chemical irritants, in a murine model. Awake mice were each placed in a recording chamber that was ventilated with a constant flow (300 ml/min) of air or irritant gas mixture. Coughs were detected by analyzing the pressure changes inside the chamber and in the intrapleural space (via telemetry), in conjunction with the audio and video signals recorded simultaneously. Cough responses to SO2 and NH3 inhalation (300 and 600 ppm, 0.1% and 0.2% balanced in air) were determined for 3 days before and ~10 days after 0.02 mg of MBP instillation into the trachea of the mouse. Our preliminary data obtained in 8 mice (the group of SO2 inhalation) and 6 mice the group of NH3 inhalation) showed: 1) inhalation of SO2 elicited cough responses in a dose‐dependent manner; 2) after the administration of MBP, cough responses to both concentrations of SO2 were significantly elevated; 3) the cough hyperresponsiveness to SO2 reached the peak ~2 days after the MBP treatment, and returned to baseline after ~7 days; 4) inhalation of NH3 also elicited cough responses in a dose‐dependent manner, which was augmented after the MBP treatment in a pattern similar to that of SO2. In conclusion, these findings suggest a possible role of MBP in the chronic cough associated with eosinophilic bronchitis.Support or Funding InformationNIH grants UL1TR001998 and AI123832This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Perception of Intensity and Unpleasantness for 1‐Breath, 10‐Breath and 10‐Minute Inspiratory Resistive Loaded Breathing in Healthy Adults
Authors: Davenport Matthew P. , Davenport Paul Wesley , Feinstein Justin , Khalsa Sahib , von Leupoldt Andreas 
Published: June 2021

Respiratory load is key in various respiratory diseases, accompanied by ventilatory compensation, cognitive awareness and affective perception. Loaded breathing can occur for a few breaths, minutes or days. Inspiratory loads elicit breathing sensations associated with behavioral modulation of breathing elicit breathing patterns to maintain alveolar ventilation, minimize work of breathing and minimize aversive load sensations. Increased inspiratory load is associated with cognitively sensing load magnitude and aversive perception of loaded breathing. The aim of this study was to determine the relationship between intensity and unpleasantness perception of 1‐breath, 10‐breath and 10‐minute breathing against extrinsic inspiratory loads. We hypothesized longer inspiration time against an extrinsic load will illicit greater intensity and unpleasant perceptions of the load. Additionally greater magnitude loads will increase perceived intensity and unpleasantness with longer breathing times. Healthy participants were tested while breathing through a non‐rebreathing circuit with inspiratory flow‐resistive loads. For one trial, the subjects inspired for 10 consecutive breaths for each of 5 load magnitudes (R=0, 5, 10, 25, 50, 100 cmH2O/L/s). Subjects estimated their perceived load intensity (MEInt) and unpleasantness (MEUn) for breaths 1 and 10. In a separate trial, the individuals respired with no‐load for 1 minute, then the R=50 cmH2O/l/s load for 10 minutes, followed by 1 minute of no‐load breathing. Subjects estimated their perceived load MEInt and MEUn every minute. In the 10‐breath loading trials, the MEInt increased with increasing load magnitude. There was an increase in MEInt from breath 1 to 10 for R=50 and R=100 cmH2O/L/s. MEUn increased with load magnitude however MEUn breath 1 v. 10 was not significant. The MEInt and MEUn increased from 60 to 600 sec in the 10‐minute trial. These results suggest load magnitude and loaded breathing duration are critical factors in the perception of intensity and unpleasantness.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reactive Oxygen Species activate the NLRP3 Inflammasome in a model of lung transplant
Authors: Chatterjee Shampa , Tao Jian Qin 
Published: June 2021

BackgroundLung transplant involves a period of storage (ischemia) followed by the transplant (reattachment or reperfusion) event. The resultant ischemia‐reperfusion (I/R) injury, clinically known as primary graft dysfunction (PGD), is the most common cause for post‐transplant failure. Indeed, studies have shown that the poor outcome of lung transplant is primarily due to PGD that drives morbidity and mortality in ~30% of lung transplant recipients. We showed earlier, that one of the pivotal events with lung I/R associated with transplant is the production of reactive oxygen species (ROS). We also showed that this ROS generation is not the result of hypoxia‐deoxygenation as the lung oxygen supply is not compromised with stop or restart of blood flow. ROS produced with lung I/R reflects “flow” sensitive endothelial signaling that triggers NADPH oxidase‐2 (NOX2) activation. We postulated that injury with transplant was caused due to ROS initiated inflammation signaling. Among the inflammatory moieties of interest to us was the NOD like receptor protein 3 (NLRP3 inflammasome), which has been reported to be a major cause of cell death with I/R in systemic organs via pathways that were anoxia/hypoxia dependent. Could NLRP3 be activated by normoxic lung I/R as well? To answer this, we investigated NLRP3 activation and the mechanism of its regulation with lung I/R. Our hypothesis was that NOX2 activated with I/R regulates the NLRP3 inflammasome which in turn is a major driver of graft injury (PGD).MethodsMice (wild type and NOX2 null) were subjected lung I/R by hilar clamp and NLRP3 inflammasome activation measured by monitoring the colocalization of NLRP3 with its adaptor molecule ASC. Lung Injury was monitored by indices such as lipid peroxidation, isoprostanes and lung wet to dry ratio. The correlation between NLRP3 and PGD in post‐transplant human subjects was assessed by monitoring plasma NLRP3 and PGD outcome (obtained from Lung Transplant Outcomes Group Database).ResultsWe observed a ROS dependent increase in NLRP3 activation post lung I/R. We also found that NLRP3 blockade significantly reduced lung injury. Additionally, post‐transplant (human) recipients with detectable NLRP3 protein in plasma developed PGD.ConclusionThe NLRP3 inflammasome is regulated via NOX2 induced ROS production and plays a crucial role in injury with I/R. It can thus be considered as a risk factor with PGD.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Long Term Hypoxia Reduces Levels of Oxylipins in Pulmonary Arteries and Venous Plasma of Fetal Sheep
Authors: Lopez Vanessa , La Frano Michael , Bosviel Remy , Hillman Tyler C , Newman John , Thorpe Richard , Fiehn Oliver , Zhang Lubo , Wilson Sean M 
Published: June 2021

High‐altitude long term hypoxia (LTH) during gestation compromises the development and function of the pulmonary vasculature in the fetus and later in the newborn. This may manifest as fetal growth restriction as well as pulmonary hypertension following birth. While the physiological regulation regarding the effects of hypoxia are well‐known, the dysregulation that occurs at the cellular and molecular level is not yet completely understood. Exploring the effects of LTH using a metabolomic approach is advantageous in deciphering the etiology associated with the development of disease. LTH is well regarded for inducing oxidative stress and causing inflammation. A number of possible regulators associated with LTH stress include oxylipins and endocannabinoids, products of polyunsaturated fatty acid (PUFA) oxidation. We hypothesized that high‐altitude LTH would reduce the levels of oxylipins and endocannabinoids of pulmonary arteries and plasma in fetal sheep. To test the hypothesis, we obtained samples of plasma and pulmonary arteries from fetal normoxic and hypoxic sheep raised at 3,800 m. altitude starting on gestation day 30. Metabolite levels were quantified using ultra performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS). Chemical similarity enrichment analyses and visualization by complex pathway analyses was performed on the datasets. Our results support our hypothesis that select oxylipin concentrations were diminished in both venous plasma and pulmonary arteries. Omega‐3 PUFAs alpha linolenic acid (ALA) and eicosapentaenoic acid (EPA) were reduced in both plasma and pulmonary arteries. 15‐HEPE and 12‐HEPE, derivatives of EPA and important anti‐inflammatory mediators, were also significantly reduced by LTH in plasma and pulmonary arterial samples from fetal animals. We believe that our studies provide insight toward identifying key biomarkers of LTH stress that will afford effective and prompt diagnosis of the neonate's physiological response. This is important when it comes to treating diseases associated with gestational hypoxia, which affects numerous mothers and newborns worldwide.Support or Funding InformationThis material is based upon work supported by NIH grants P01HD083132 (LZ) and 1U24DK097154 through a pilot project grant to SMW. VL is a recipient of the American Physiological Society's Short‐Term Research Education Program to Increase Diversity in Health‐Related Research (STRIDE) Fellowship funded by the APS and a grant from the National Heart, Lung and Blood Institute R25HL115473.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
S‐nitroso‐L‐cysteine increases intracellular calcium in prenatal rat carotid body glomus cells
Authors: Getsy Paulina M , Coffee Gregory A , Ghosh Monica , Damron Derek , Lewis Stephen J 
Published: June 2021

Carotid body (CB) glomus (Type I) cells detect decreases in arterial oxygen (O2) tension (hypoxia) by depolarizing, opening voltage‐gated calcium channels (VGCCs) and releasing neurotransmitters. These neurotransmitters activate chemoafferent terminals within the carotid sinus nerve (CSN), which signal respiratory regions of the brainstem to increase ventilation and restore blood O2 levels. Low‐molecular mass S‐nitrosothiols (SNOs), such as S‐nitroso‐Lcysteine (LSNC), are recently being used as chemical agents for studying the biochemistry underlying the ventilatory response to hypoxia. Unpublished work from our lab shows that LSNC alters macroscopic outward potassium currents in carotid body glomus cells under both normoxic and hypoxic conditions. However, the effect of LSNC on intracellular calcium concentration ([Ca2+]i) is unknown. Our objective was to determine whether LSNC elicits changes in [Ca2+]i in CB glomus cells. We hypothesized that LSNC increases [Ca2+]i via influx through VGCCs. To test this we isolated CB glomus cells from postnatal (P) P11–P15 Sprague Dawley male rat pups, and used Ca2+ imaging to investigate for the first time the effect of LSNC on CB glomus cell [Ca2+]i. Our preliminary data reveals that 50μM LSNC causes a rise in [Ca2+]i under normoxic conditions (n=2). This data suggests that LSNC increases CB glomus cell [Ca2+]i, and this rise may trigger Ca2+‐dependent release of neurotransmitters and activation of chemoafferent fibers within the CSN.Support or Funding InformationNIH SPARC 1OT2OD023860‐02 SJLewisThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.