bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of 5‐HT receptor and adenosine 2A receptor on intermittent hypoxia‐induced respiratory recovery following mid‐cervical contusion in the rat
Authors: Wu Ming‐Jane , Wen Ming‐Han , Lee Kun‐Ze 
Published: June 2021

The present study was designed to evaluate the therapeutic effectiveness and mechanism of intermittent hypoxia on respiratory function at distinct injured stages following mid‐cervical spinal cord contusion. In the first study, adult male rats were received laminectomy or unilateral contusion at 3rd–4th cervical spinal cord at 9 weeks of age. The ventilatory behavior in response to mild acute intermittent hypoxia [10 episodes of 5 min of hypoxia (10 % O2, 4 % CO2, 86 % N2) with 5 min of normoxia intervals] was measured by the whole body plethysmography at the acute (~3 day), subchronic (~2 week) and chronic (~8 week) injured stage. The minute ventilation of contused animals could be significantly enhanced following intermittent hypoxia due to augmentation of the tidal volume at all time points post‐injury. However, this intermittent hypoxia‐induced ventilatory long‐term facilitation was only observed in uninjured animals at the acute stage. In the second study, the effect of intermittent hypoxia on respiration was examined in contused animals after blockade of serotonin receptors or adenosine 2A receptors. The result demonstrated that intermittent hypoxia‐induced enhancement of minute ventilation was attenuated by serotonin receptor antagonist (methysergide) but rather enhanced by adenosine 2A receptor antagonist (KW6002) at the subchronic and chronic injured stages. These results suggested that intermittent hypoxia can induce respiratory recovery from the acute to chronic injures stages, and the therapeutic effect were dampened by inhibition of serotonin receptors but could be amplified by blockade of adenosine 2A receptors.Support or Funding InformationMinistry of Science and Technology (105‐2628‐B‐110‐002‐MY3), Higher Education Sprout Project (07C030111) and NSYSU‐KMU Joint Research Project (107‐I001)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neurochemical Plasticity of Phrenic Motor Neuron Adenosine 2A Receptors: Effects of Cervical Spinal Injury and Intermittent Hypoxia
Authors: Smith Kristin , Allen Latoya L. , Seven Yasin B. , Ciesla Marissa , Asa Zachary , Simon Alec , Holland Ashley , Santiago Juliet , Stefan Kelsey , Ross Ashley , Gonzalez‐Rothi Elisa J. , Mitchell Gordon S. 
Published: June 2021

Cervical spinal adenosine 2A receptor activation is necessary for certain forms of spinal respiratory motor plasticity, such as phrenic long‐term facilitation elicited by severe acute intermittent hypoxia (AIH; Nichols et al., 2012) or moderate AIH with acute cervical spinal injury (cSCI; Navarette‐Opazo et al., 2016). Whereas cervical spinal A2A receptor activation is sufficient to elicit phrenic motor facilitation (pMF; Golder et al., 2008), it undermines other, serotonin‐dependent forms of pMF via cross‐talk inhibition (Hoffman et al., 2010; Navarette‐Opazo et al., 2017). Thus, A2A receptors exert complex effects on phrenic motor plasticity. However, it is not known if conditions such as cSCI and/or repetitive exposure to intermittent hypoxia elicit neurochemical plasticity in A2A receptor expression (and associated phrenic motor plasticity). Thus, we characterized A2A receptor expression in phrenic motor neurons after chronic cSCI and prolonged exposure to different protocols of intermittent hypoxia. A2A receptor expression was determined in male Sprague Dawley rats with and without C2 spinal hemisection (C2Hx; 12 wks post‐injury) that were exposed to 28 days of: 1) normoxia; 2) daily AIH (10, 5‐min 10.5% O2 episodes with 5‐min intervals per day; 1.5 hrs/day); 3) moderate CIH (CIH 5/5: 5‐min 10.5% O2 episodes, 5‐min intervals; 8 hrs/day); and 4) high dose CIH (CIH 2/2: 2‐min 10.5% O2 episodes, 2 min intervals; 8 hrs/day). Rats were then perfused, and cervical spinal cords sectioned (40μm). C3 to C5 sections were processed for A2A receptor and Cholera toxin B subunit (CtB, injected 14 days before C2Hx). Using a custom MATLAB algorithm, optical density in CtB‐positive phrenic motor neurons was quantified. Statistical analysis was performed using MANOVA (SAS JMP). C2Hx decreased A2A receptor expression in phrenic motor neurons (p<0.05). Intermittent hypoxia exerted protocol‐specific effects on A2A receptor expression (CIH 2/2 > CIH 5/5 > daily AIH; p=0.014). Although intermittent hypoxia appeared to increase A2A receptor expression more after C2Hx, this effect was only marginally significant (injury/treatment interaction; p=0.061). The dual effects of injury and intermittent hypoxia on A2A receptor expression suggest that adenosine receptor plasticity may be important in the development of new therapeutic strategies to improve breathing after spinal cord injury.Support or Funding InformationSupported by: NIH T32 HD043730 (LLA) OT2OD023854 (SPARC), NIH K12 HD055929 (EGR), McKnight Brain Institute.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ErbB Family Members in Human Pulmonary Microvascular Endothelial Cells Respond Differently when Exposed to Hypoxia
Authors: Regan Christopher , Jin Yi Childrens , Pool Caitlyn Childrens , Liu Yusen , Chen Bernadette , Nelin Leif Childrens 
Published: June 2021

Pulmonary hypertension (PH) is seen in diseases associated with hypoxia (WHO classification Group 3), and one of those diseases is bronchopulmonary dysplasia (BPD). BPD is the most common co‐morbidity following preterm birth, and the incidence is as high as 100% in babies born at 22 weeks' gestation. There are currently no available preventative or curative therapies for PH associated with BPD. Vascular remodeling is a hallmark of PH diseases including that seen with BPD. The proliferation of pulmonary endothelial cells, as well as release of pro‐proliferative substances from endothelial cells that can induce vascular smooth muscle cells to proliferate, are central to the pathogenesis of vascular remodeling in PH. We have previously shown that human pulmonary microvascular endothelial cells (hPMVEC) respond to hypoxia by proliferating. We have also shown that hypoxia‐induced proliferation depends on epidermal growth factor (EGF) release resulting in epidermal growth factor receptor (EGFR) activation. EGFR is a member of the ErbB family of receptor proteins, of which there are 4 described and EGFR is also known as ErbB1. We have recently shown that hPMVEC express ErbB2 and ErbB4, but that ErbB3 mRNA and protein are absent in hPMVEC. We hypothesized that hypoxia would also regulate ErbB2 and ErbB4 expression levels in hPMVEC. We used standard western blotting techniques to identify ErbB2 and ErbB4 protein levels in fetal hPMVEC incubated in normoxia (21% O2, 5% CO2) or hypoxia (1% O2, 5% CO2, balance N2) at 37° C for 24 hours. We found that ErbB4 protein levels were similar between normoxic and hypoxic hPMVEC's, while ErbB2 protein levels were lower in hypoxic hPMVEC than in normoxic hPMVEC. The absence of change in ErbB4 protein expression levels in hypoxia does not exclude the possibility for alteration in ErbB4 signaling in hypoxia. To begin to explore the role of ErbB4 signaling in hypoxia we determined if the ErbB4 ligand neuregulin‐4 would increase protein levels of ErbB4 in hPMVEC and we found that in normoxic hPMVEC addition of neuregulin‐4 increased protein levels of ErbB4. To determine if ErbB4 siRNA would knockdown ErbB4 specifically, i.e. without affecting ErbB1 or ErbB2 protein levels, we used an siRNA approach. Results show notable decreased protein expression level of ErbB4 exposed to siRNA as compared to cells exposed to scramble controls, but no notable changes in the expression levels of ErbB2 protein. We speculate that ErbB4 is involved in the hypoxic response of hPMVEC to hypoxia and may represent a potential novel therapeutic target for pulmonary hypertensive disorders associated with hypoxia.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intermittent Hypoxia Induces Pulmonary Vascular Remodeling and Increases the Expression of STIM‐activated TRPC‐ORAI Channels in the Lung
Authors: Castillo‐Galan Sebastian , Arenas German A , Arias Paulina , Reyes Victor Roberto , Krause Bernardo , Iturriaga Rodrigo 
Published: June 2021

Obstructive sleep apnea (OSA), a breathing disorder characterized by episodes of chronic intermittent hypoxia (CIH) and re‐oxygenation during sleep, is an independent risk for systemic hypertension. Furtheremore, 20–60% of OSA patients develop moderate pulmonary hypertension. Rats exposed to CIH developed pulmonary vascular remodeling, but the mechanisms underlaying the vascular remodeling are not well known. Stim‐activated TRP‐CORAI channel (STOC), cationic calcium‐permeable channels, are overexpressed in the lung and plays a key role in the development of pulmonary vascular remodeling in animals exposed to sustained hypoxia. However, whether these channels are involved in the pulmonary vascular remodeling induced by CIH have not been addressed. We studied the time‐course of the vascular pulmonary remodeling and the changes in STOC expression, in a rodent model of OSA. Male Sprague‐Dawley rats (~200g) were exposed for 14 to 28 days to CIH (5% O2, 12 times/h, for 8h). At 14, 21 and 28 days of CIH animals were euthanized and lungs dissected to determine the vascular remodeling index by histology analysis, and the pulmonary mRNA and protein levels of the STOC forming subunits TRPC1, TRPC4, TRPC6, ORAI 1, ORAI 2 and STIM1 by qPCR and western blot, respectively. Results were compared with age‐matched controls. CIH increased the pulmonary expression of TRPC 6, ORAI 1, ORAI 2 and STIM1 at 21 and 28 days compared with controls. In addition, CIH was associated to an increased in pulmonary arteries medial thickness at 21 and 28 days (66.6% ± 2.4, 66.3% ± 4.2 vs 45.4 ± 1.6, 21 and 28 days of CIH vs control respectively, p < 0.05). Present results shown that CIH increased the pulmonary STOC expression, and these changes paralleled the vascular remodeling.Support or Funding InformationFondecyt grants 1150040 and 1180341This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intravascular Delivery of TAT‐conjugated Focal Adhesion Kinase Protects against Acute Lung Injury
Authors: Quadri Sadiqa , Das Shonit , Emine Memet , Mohammad Islam N , Bhattacharya Sunita , Bhattacharya Jahar 
Published: June 2021

Acute lung injury (ALI), a major cause of high mortality in all age groups, occurs because of endothelial barrier failure. But it lacks a cure. We showed that endothelial focal adhesion kinase (FAK) is barrier protective (PMID: 23033075), suggesting FAK may be a cure for ALI. To test this hypothesis, we purified wild type FAK (FAKWT) and FAK with YàF mutation at tyrosine 925 (FAKMUT), which is expressed in FAK's focal adhesion targeting domain. Then we non‐covalently conjugated the proteins with the cell‐permeable peptide TAT (HIV‐1 transactivator of transcription). We intranasally instilled LPS in anesthetized mice. After 24h, we intravenously infused TAT‐FAKp or TAT‐FAKpY925F. After 4 h, we gave intravenous Evans Blue‐albumin (EBA). After a further 4 h, we assayed ALI in terms of EBA concentration and leukocyte counts in the bronchoalveolar lavage (BAL). Also, by live confocal microscopy of isolated, blood‐perfused lungs, we assayed endothelial F‐actin in terms of the lung endothelial fluorescence of Rhodamin Phalloidin. LPS increased EBA and leukocytes two‐times above baseline (p<0.05 each). TAT‐FAKWT, but not TAT‐FAKpMUT inhibited both responses (p<0.05). Endothelial F‐actin was markedly higher after TAT‐FAKWT than after TAT‐FAKpMUT infusion (p<0.05). LPS‐induced mortality in 5 days was 80% for untreated or TAT‐FAKpMUT infused mice. However, TAT‐FAKpWT infusion decreased the mortality to 25% (p<0.05). Our findings indicate that purified FAK can be effectively given by intravenous injection. TAT‐FAKWT, given well after the initiation of LPS‐induced ALI, markedly increased survival. The protective effect was due to FAK's Y925 residue that is likely responsible for enhancing cortical F‐actin, thereby strengthening the endothelial barrier (PMID:23033075). We propose that intravenous delivery of TAT‐FAKpWT might be effective therapy for ALI (HL36024).Support or Funding InformationNIH: HL36024This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The effects of aging and exercise on lung mechanics, surfactant and alveolar macrophages
Authors: MCCAIG LYNDA , Pape Cynthia , Gill Sean , Veldhuizen Ruud 
Published: June 2021

IntroductionIt has been well established that advancing age leads to changes to the respiratory system and an associated susceptibility to lung diseases. Furthermore, exercise may counteract this pulmonary disease susceptibility. To start to investigate the underlying processes of these effects we explored the baseline characteristics due to aging and exercise on lung mechanics and on two important components of a healthy pulmonary environment, alveolar macrophage function and the pulmonary surfactant system. It was hypothesized that aging would impact lung mechanics, macrophage polarization and the status of the surfactant system, and that these changes would be mitigated by exercise.Experimental approach: Male C57BL/6 mice were housed from 2–3 to 22 months, for the aged group, or until 4 months of age for young control mice. Mice in both the young and aged groups were randomized to either voluntarily running exercise or non‐exercise for a 2 month period. Mice were euthanized and lung mechanics were analyzed using a Flexivent ventilator. Subsequently, the lungs were lavaged to obtain pulmonary surfactant and alveolar macrophages. Pulmonary surfactant was analyzed for surfactant pool sizes and activity whereas alveolar macrophages were examined for a response to pro‐and anti‐inflammatory stimuli.ResultsChanges in lung mechanics, such as increased compliance and decreased airway resistance, were observed in the aged cohorts. These changes were not affected by exercise.The quantity as well as the biophysical activity of the pulmonary surfactant system was unaffected by either aging or exercise. More alveolar macrophages were recovered from exercising aged mice as compared to both the young and non‐exercising groups.Support or Funding InformationWestern Strategic Support, Lawson Internal Research FundsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High Resolution Evaluation of Human Airway Cell Diversity Towards Understanding the Cellular Composition and Function of the Distal Human Airways
Authors: Basil Maria Ciocca , Zacharias William , Katzen Jeremy , Carl Justine , Li Shanru , Morley Michael , Englehardt John , Cantu Edward , Morrisey Edward 
Published: June 2021

The mammalian lung is a complex organ comprised of epithelial cells, supporting stroma, and capillaries, which combine to allow the lung to perform its principle function of gas exchange. Our understanding of the cellular and molecular mechanisms that drive lung development and repair is based almost entirely on the study of murine models. While the human lung has many similarities to its murine counterpart, it also contains additional complexity. Distinctive structures, such as the respiratory bronchioles – the most distal portion of the human respiratory tree – are not present in small mammals. The cellular composition and function of these distal human airways are not well understood, but this region of the human lung is involved in many pathological processes, including subsets of interstitial lung disease, chronic lung allograft rejection, and COPD. There is a need to better define the nature of these human‐specific lung epithelial lineages. In this study, we utilized single cell RNA‐seq technology, combined with high resolution imaging, to characterize epithelial cells from distal respiratory airways and proximal conducting airway across postnatal development. Functional relationship between these cell types were assessed with induced pluriportent stem cell assays and in vitro organoid systems. The airway epithelium of the distal terminal and respiratory bronchioles represent a distinct cellular subset. The identification and analysis of these cells provides insight into the unique organization of the human lung, as well as the role these populations play in human disease.Support or Funding Information5T32HL007586‐32This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dexamethasone Improves Neuromuscular Junction Recovery From Ischemia‐Reperfusion Injury Induced by Tourniquet Application in Mouse Hindlimb
Authors: Tu Huiyin , Zhang Dongze , Wadman Michael C , Li Yu‐Long 
Published: June 2021

Tourniquet‐induced ischemia‐reperfusion (IR) injuries impede long‐term recovery of skeletal muscle contraction. The neuromuscular junction (NMJ) is an important factor to influence skeletal muscle contractile function. Here, we observed the effect of dexamethasone (Dex) on morphological and functional recovery of the NMJ from tourniquet‐induced IR injuries in mouse hindlimb.Unilateral hindlimb of C57/BL6 mice were subjected to 3 hours of ischemia by placing a rubber band and followed different periods of reperfusion (1 week, 2 weeks, 4 weeks, and 6 weeks). Dex treatment (1 mg/kg/day, i.p.) began on the day of IR induction and lasted for 7 days. After 3 hours of ischemia and different periods of reperfusion, NMJs in the gastrocnemius muscle showed significantly the morphological and functional damage. In the gastrocnemius muscle, TNFα and IL‐1β (two inflammatory cytokines) were increased after 1, 2 and 6 weeks of tourniquet‐induced IR. Treatment with Dex inhibited the elevation of TNFα and IL‐1β, mitigated fragmentation of nicotinic acetylcholine receptor (nAChR) clusters, promoted re‐innervation of nAChR clusters, and increased nerve‐stimulated end plate potentials (EPPs).The data suggested that tourniquet‐related IR induced serious skeletal muscle inflammation for a long period. Dex treatment for 1 week inhibits IR‐caused inflammation in the early period of IR, and improves the morphological and functional recovery of the NMJ from tourniquet‐induced IR injuries.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Oxytocinergic Neurons in the Hypothalamic Paraventricular Nucleus Stimulate Brown Adipose Tissue Thermogenesis through Rostral Medullary Raphe
Authors: Fukushima Akihiro , Nakamura Kazuhiro 
Published: June 2021

Hypothalamic neurons in the paraventricular nucleus (PVN) produce several neuropeptides, including oxytocin and vasopressin, and send their axons to various brain regions. These PVN neurons have been considered to serve neuroendocrine and autonomic functions, and many studies have demonstrated the involvement of oxytocin in social and emotional behaviors (e.g. maternal and sexual behaviors, and stress responses). Although these behaviors are accompanied with autonomic responses, it is unclear how oxytocin modulates the activities of the autonomic nervous system. To investigate the roles of PVN oxytocinergic neurons in the central regulation of autonomic function, in this study, we first performed neural tract tracing in rats from PVN oxytocinergic neurons to the rostral medullary raphe region (rMR), which contains sympathetic premotor neurons controlling brown adipose tissue (BAT) thermogenesis. In the rMR, oxytocin‐immunoreactive fibers, but not vasopressin‐immunoreactive fibers, were distributed, and oxytocin‐containing terminals were apposed to tryptophan hydroxylase‐expressing (i.e., serotonergic) neurons, potentially BAT sympathetic premotor neurons. Retrograde tracing from the rMR with cholera toxin b‐subunit (CTb) labeled a portion of oxytocinergic neurons in the caudal PVN, but not in the supraoptic nucleus, suggesting that the PVN is a major source of oxytocinergic fibers in the rMR. Then, we performed in vivo BAT sympathetic nerve recording combining optogenetic stimulation of the PVN‐derived oxytocinergic axon terminals in the rMR. Recombinant adeno‐associated viral vectors were injected into the PVN to express the engineered channel rhodopsin variant, ChIEF, under the oxytocin promoter. We confirmed that most of PVN neurons expressing ChIEF‐mCherry contained oxytocin and that their axon fibers were densely distributed in the rMR. Optogenetic stimulation of these fibers evoked BAT sympathetic nerve activities as well as increased expired CO2 and heart rate. Similar thermogenic and cardiac responses were elicited by nanoinjection of oxytocin into the rMR, and these responses were blocked by prior injection of the oxytocin receptor antagonist, L‐368,899 into the rMR. In addition, oxytocin injection into the rMR also potentiated NMDA‐evoked BAT sympathetic nerve activities. These findings indicate that PVN oxytocinergic neurons stimulate thermogenic sympathetic outflow to BAT through activation of rMR neurons. This oxytocinergic pathway may play an important role in emotion‐related autonomic responses.Support or Funding InformationThis work was supported by JSPS KAKENHI Grant Numbers JP16H05128, JP15H05932, JP26118508 (KN) and by AMED under Grant Number JP18gm5010002 (KN)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.