scholarly journals Role of Aquaporin Water Channels in Airway Fluid Transport, Humidification, and Surface Liquid Hydration

2001 ◽  
Vol 117 (6) ◽  
pp. 573-582 ◽  
Author(s):  
Yuanlin Song ◽  
Sujatha Jayaraman ◽  
Baoxue Yang ◽  
Michael A. Matthay ◽  
A.S. Verkman
Keyword(s):  
Knockout Mice ◽  
Fluid Transport ◽  
Upper Airway ◽  
Lower Airway ◽  
Wild Type ◽  
Upper Airways ◽  
Airway Epithelia ◽  
Airway Humidification ◽  
Surface Liquid

Several aquaporin-type water channels are expressed in mammalian airways and lung: AQP1 in microvascular endothelia, AQP3 in upper airway epithelia, AQP4 in upper and lower airway epithelia, and AQP5 in alveolar epithelia. Novel quantitative methods were developed to compare airway fluid transport–related functions in wild-type mice and knockout mice deficient in these aquaporins. Lower airway humidification, measured from the moisture content of expired air during mechanical ventilation with dry air through a tracheotomy, was 54–56% efficient in wild-type mice, and reduced by only 3–4% in AQP1/AQP5 or AQP3/AQP4 double knockout mice. Upper airway humidification, measured from the moisture gained by dry air passed through the upper airways in mice breathing through a tracheotomy, decreased from 91 to 50% with increasing ventilation from 20 to 220 ml/min, and reduced by 3–5% in AQP3/AQP4 knockout mice. The depth and salt concentration of the airway surface liquid in trachea was measured in vivo using fluorescent probes and confocal and ratio imaging microscopy. Airway surface liquid depth was 45 ± 5 μm and [Na+] was 115 ± 4 mM in wild-type mice, and not significantly different in AQP3/AQP4 knockout mice. Osmotic water permeability in upper airways, measured by an in vivo instillation/sample method, was reduced by ∼40% by AQP3/AQP4 deletion. In doing these measurements, we discovered a novel amiloride-sensitive isosmolar fluid absorption process in upper airways (13% in 5 min) that was not affected by aquaporin deletion. These results establish the fluid transporting properties of mouse airways, and indicate that aquaporins play at most a minor role in airway humidification, ASL hydration, and isosmolar fluid absorption.

scholarly journals Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons

Gut ◽  
2018 ◽  
Vol 68 (8) ◽  
pp. 1406-1416 ◽  
Author(s):  
Nathalie Stakenborg ◽  
Evelien Labeeuw ◽  
Pedro J Gomez-Pinilla ◽  
Sebastiaan De Schepper ◽  
Raymond Aerts ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Postoperative Ileus ◽  
Intestinal Inflammation ◽  
Electrical Field Stimulation ◽  
Enteric Neurons ◽  
Postoperative Treatment ◽  
Wild Type ◽  
Clinical Recovery ◽  
Preoperative Administration

ObjectivesVagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive muscularis macrophages (mMφ) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5-HT4R) agonist prucalopride can mimic this effect in mice and human.DesignUsing Ca2+ imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mMφ activation evoked by ATP in jejunal muscularis tissue. Next, preoperative and postoperative administration of prucalopride (1–5 mg/kg) was compared with that of preoperative VNS in a model of POI in wild-type and α7nAChR knockout mice. Finally, in a pilot study, patients undergoing a Whipple procedure were preoperatively treated with prucalopride (n=10), abdominal VNS (n=10) or sham/placebo (n=10) to evaluate the effect on intestinal inflammation and clinical recovery of POI.ResultsEFS reduced the ATP-induced Ca2+ response of mMφ, an effect that was dampened by neurotoxins tetrodotoxin and ω-conotoxin and mimicked by prucalopride. In vivo, prucalopride administered before, but not after abdominal surgery reduced intestinal inflammation and prevented POI in wild-type, but not in α7nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased Il6 and Il8 expression in the muscularis externa and improved clinical recovery.ConclusionEnteric neurons dampen mMφ activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI.Trial registration numberNCT02425774.

scholarly journals Aquaporins in complex tissues. II. Subcellular distribution in respiratory and glandular tissues of rat

1997 ◽  
Vol 273 (5) ◽  
pp. C1549-C1561 ◽  
Author(s):  
Søren Nielsen ◽  
Landon S. King ◽  
Birgitte Mønster Christensen ◽  
Peter Agre
Keyword(s):  
Plasma Membranes ◽  
Fluid Transport ◽  
Water Movement ◽  
Upper Airway ◽  
Apical Plasma Membrane ◽  
Type I ◽  
Basal Cells ◽  
Basolateral Membranes ◽  
Surface Liquid ◽  
Columnar Cells

The molecular pathways for fluid transport in pulmonary, oral, and nasal tissues are still unresolved. Here we use immunocytochemistry and immunoelectron microscopy to define the sites of expression of four aquaporins in the respiratory tract and glandular epithelia, where they reside in distinct, nonoverlapping sites. Aquaporin-1 (AQP1) is present in apical and basolateral membranes of bronchial, tracheal, and nasopharyngeal vascular endothelium and fibroblasts. AQP5 is localized to the apical plasma membrane of type I pneumocytes and the apical plasma membranes of secretory epithelium in upper airway and salivary glands. In contrast, AQP3 is present in basal cells of tracheal and nasopharyngeal epithelium and is abundant in basolateral membranes of surface epithelial cells of nasal conchus. AQP4 resides in basolateral membranes of columnar cells of bronchial, tracheal, and nasopharyngeal epithelium; in nasal conchus AQP4 is restricted to basolateral membranes of a subset of intra- and subepithelial glands. These sites of expression suggest that transalveolar water movement, modulation of airway surface liquid, air humidification, and generation of nasopharyngeal secretions involve a coordinated network of aquaporin water channels.

scholarly journals Effect of Targeted Deletion of the Heme Oxygenase-2 Gene on Hemoglobin Toxicity in the Striatum

2005 ◽  
Vol 25 (11) ◽  
pp. 1466-1475 ◽  
Author(s):  
Yan Qu ◽  
Jing Chen ◽  
Luna Benvenisti-Zarom ◽  
Xin Ma ◽  
Raymond F Regan
Keyword(s):  
Heme Oxygenase ◽  
Knockout Mice ◽  
Protein Oxidation ◽  
Gene Deletion ◽  
Wild Type ◽  
Cell Culture Study ◽  
Targeted Deletion ◽  
Rate Limiting Step ◽  
Diphenyltetrazolium Bromide

The heme oxygenase (HO) enzymes catalyze the rate-limiting step in the breakdown of heme to iron, carbon monoxide, and biliverdin. A prior cell culture study demonstrated that deletion of HO-2, the isoform constitutively expressed in neurons, attenuated hemoglobin (Hb) neurotoxicity. The present study tested the hypothesis that HO-2 gene deletion is cytoprotective in a model of Hb toxicity in vivo. Stereotactic injection of 6 μL stroma-free Hb (SFHb) into the striatum significantly increased protein oxidation in wild-type mice at 24 to 72 h, as detected by an assay for carbonyl groups. At 72 h, carbonylation was increased 2.5-fold compared with that in the contralateral striatum. In HO-2 knockout mice, protein oxidation was not increased at 24 h, and was increased by only 1.7-fold at 72 h. Similarly, striatal lipid peroxidation, as detected by the malondialdehyde assay, was significantly greater in the SFHb-injected striata of wild-type mice than in knockout mice. Striatal cell viability, determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was 45.0%±6.3% of that in contralateral striata in wild-type mice at 72 h; it was increased to 85%±8% in knockouts. Heme oxygenase-2 gene deletion did not alter weight loss or mortality after SFHb injection. Baseline striatal HO-1 expression was similar in knockout and wild-type mice; induction after SFHb injection occurred more rapidly in the latter. These results suggest that HO-2 gene deletion protects striatal cells from the oxidative toxicity of Hb in vivo. Pharmacologic or genetic strategies that target HO-2 may be beneficial after central nervous system hemorrhage, and warrant further investigation.

Cyclic Adenosine Monophosphate Stimulation of Mucociliary Activity in the Upper Airways in Vivo

1995 ◽  
Vol 104 (5) ◽  
pp. 388-393 ◽  
Author(s):  
Anders Cervin ◽  
Sven Lindberg ◽  
Jan Dolata ◽  
Ulf Mercke
Keyword(s):  
Upper Airway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Airway Disease ◽  
Maxillary Artery ◽  
Dibutyryl Camp ◽  
Upper Airways ◽  
Maximum Increase ◽  
Xanthine Derivatives

Xanthine derivatives are known to accelerate mucociliary transport in the lower airways, probably by preventing degradation of cyclic adenosine monophosphate (cAMP) and thereby increasing its intracellular concentration. The purpose of this study was to investigate the effects of cAMP on mucociliary activity in the upper airways. The effect on the mucociliary activity in the rabbit maxillary sinus of the xanthine derivatives theophylline and enprophylline was compared to that of the cAMP analog dibutyryl cAMP. The compounds were administered into the maxillary artery, and the response was recorded with a photoelectric technique. Infusions of theophylline (1.0 and 10 mg/kg) increased mucociliary activity (22.8% ± 5.9%, n = 6, and 21.6% ± 4.9%, n = 7, p < .05, respectively). Infusions of enprophylline (1.0 and 10.0 mg/kg) accelerated mucociliary activity (at the highest dosage tested, 24.3% ± 4.1%). Infusions of dibutyryl cAMP (0.1 and 1.0 mg/kg) stimulated mucociliary activity, with the maximum increase (20.1% ± 3.0%, n = 13, p < .05) being observed at a dosage of 0.1 mg/kg. The infused substances increased mucociliary activity within 1 minute after the start of the infusion, the duration of the response being approximately 20 minutes for theophylline, 22 minutes for enprophylline, and 12 minutes for dibutyryl cAMP. The present results support the view that cAMP is involved in regulating mucociliary activity in the upper airways. It remains to be elucidated whether xanthines such as theophylline and enprophylline are beneficial in upper airway disease in which mucociliary function is impaired (eg, chronic sinusitis).

scholarly journals Villin and actin in the mouse kidney brush-border membrane bind to and are degraded by meprins, an interaction that contributes to injury in ischemia-reperfusion

2011 ◽  
Vol 301 (4) ◽  
pp. F871-F882 ◽  
Author(s):  
Elimelda Moige Ongeri ◽  
Odinaka Anyanwu ◽  
W. Brian Reeves ◽  
Judith S. Bond
Keyword(s):  
Brush Border ◽  
Knockout Mice ◽  
Brush Border Membrane ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Kidney ◽  
Cytoskeletal Proteins ◽  
Kidney Tubules ◽  
Wild Type

Meprins, metalloproteinases abundantly expressed in the brush-border membranes (BBMs) of rodent proximal kidney tubules, have been implicated in the pathology of renal injury induced by ischemia-reperfusion (IR). Disruption of the meprin β gene and actinonin, a meprin inhibitor, both decrease kidney injury resulting from IR. To date, the in vivo kidney substrates for meprins are unknown. The studies herein implicate villin and actin as meprin substrates. Villin and actin bind to the cytoplasmic tail of meprin β, and both meprin A and B are capable of degrading villin and actin present in kidney proteins as well as purified recombinant forms of these proteins. The products resulting from degradation of villin and actin were unique to each meprin isoform. The meprin B cleavage site in villin was Glu744-Val745. Recombinant forms of rat meprin B and homomeric mouse meprin A had Km values for villin and actin of ∼1 μM (0.6–1.2 μM). The kcat values varied substantially (0.6–128 s−1), resulting in different efficiencies for cleavage, with meprin B having the highest kcat/ Km values (128 M−1·s−1 × 106). Following IR, meprins and villin redistributed from the BBM to the cytosol. A 37-kDa actin fragment was detected in protein fractions from wild-type, but not in comparable preparations from meprin knockout mice. The levels of the 37-kDa actin fragment were significantly higher in kidneys subjected to IR. The data establish that meprins interact with and cleave villin and actin, and these cytoskeletal proteins are substrates for meprins.

Comparison of upper and lower airway responses of two sensitized rat strains to inhaled antigen

1992 ◽  
Vol 73 (4) ◽  
pp. 1608-1613 ◽  
Author(s):  
L. J. Xu ◽  
S. Sapienza ◽  
T. Du ◽  
S. Waserman ◽  
J. G. Martin
Keyword(s):  
Upper Airway ◽  
Brown Norway ◽  
Lower Airway ◽  
Sprague Dawley ◽  
Pulmonary Resistance ◽  
Upper Airways ◽  
Tracheal Pressure ◽  
Airway Response ◽  
Airway Responses ◽  
Inbred Rat

The purpose of the study was to investigate the relationships between upper airways responses and pulmonary responses of two strains of highly inbred rats to inhaled antigen. To do this we measured the upper and lower airways resistance for 60 min after challenge of Brown-Norway rats (BN; n = 13) and an inbred rat strain (MF; n = 11), derived from Sprague-Dawley, with aerosolized ovalbumin (OA). Rats were actively sensitized with OA (1 mg sc) using Bordetella pertussis as an adjuvant. Two weeks later the animals were anesthetized and challenged. Tracheal pressure, esophageal pressure, and airflow were measured, from which total pulmonary resistance was partitioned into upper airway and lower pulmonary resistance (RL). The peak upper airway response to inhaled OA was similar in BN (1.89 +/- 0.66 cmH2O.ml-1.s; n = 7) and MF (2.85 +/- 0.68 cmH2O.ml-1.s; n = 6). The lower airway response to OA challenge was substantially greater in BN, and RL changed from 0.07 +/- 0.01 to 0.34 +/- 0.13 (n = 6; P < 0.05). The MF did not have any significant increase in RL after challenge; the baseline RL was 0.12 +/- 0.02 and only reached a peak value of 0.15 +/- 0.05 (n = 5; P = NS). Lower airway responsiveness of BN (n = 10) to serotonin, an important mediator early allergic airway responses, was similar to MF (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals IL-17 Activates the IL-6/STAT3 Signal Pathway in the Proliferation of Hepatitis B Virus-Related Hepatocellular Carcinoma

2017 ◽  
Vol 43 (6) ◽  
pp. 2379-2390 ◽  
Author(s):  
Zongqiang Hu ◽  
Ding Luo ◽  
Dongdong Wang ◽  
Linjie Ma ◽  
Yingpeng Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Knockout Mice ◽  
Hepg2 Cells ◽  
Wild Type ◽  
B Virus ◽  
And Migration ◽  
Proliferation And Migration

Background/Aims: We performed this study to determine the role of IL-17 in the immune microenvironment of hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). Methods: HepG2 cells were treated with IL-17, STAT3 inhibitor S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb). Cell proliferation and migration were compared using the Cell Counting kit-8 (CCK-8) and Transwell assays, respectively. Real-time quantitative PCR (RT-qPCR), Western Blot, ELISA, immunofluorescence and histological staining were used for determining the expression levels of IL-17, IL-6, MCP-1, CCL5, VEGF, STAT3 and p-STAT3. HCC xenograft models were constructed in wild type and IL-17 knockout mice to clarify the effects of IL-17 on HCC in vivo. Results: Exogenous IL-17 enhanced the proliferation and migration of HepG2 cells, and it activated the phosphorylation of STAT3. RT-qPCR and ELISA showed that IL-17 promoted the expression of IL-6. The CCK-8 and Transwell assays showed that S31-201 or IL-6 mAb remarkably reversed the promotion effects of proliferation and migration by exogenous IL-17 in HepG2 cells. Additionally, IL-6 could promote the phosphorylation of STAT3, while IL-6 mAb acted as an inhibitor, and exogenous IL-17 could neutralize the inhibitory effects of IL-6 mAb. In vivo, compared to the wild type mice, the tumor volume, weight, density and size were decreased in IL-17 knockout mice. Additionally, the expression levels of p-STAT3, IL-6, MCP-1, CCL5 and VEGF decreased in IL-17 knockout mice. Conclusions: IL-17 can enhance the proliferation of HepG2 cells in vitro and in vivo via activating the IL-6/STAT3 pathway. Therefore, the IL-17/IL-6/STAT3 signaling pathway is a potential therapeutic target for HBV-related HCC.

scholarly journals Ficolins Promote Fungal Clearance in vivo and Modulate the Inflammatory Cytokine Response in Host Defense against Aspergillus fumigatus

2016 ◽  
Vol 8 (6) ◽  
pp. 579-588 ◽  
Author(s):  
Ninette Genster ◽  
Elisabeth Præstekjær Cramer ◽  
Anne Rosbjerg ◽  
Katrine Pilely ◽  
Jack Bernard Cowland ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Host Defense ◽  
Knockout Mice ◽  
Fungal Infections ◽  
Inflammatory Cells ◽  
Lectin Pathway ◽  
Wild Type ◽  
Opportunistic Fungal Pathogen

Aspergillus fumigatus is an opportunistic fungal pathogen that causes severe invasive infections in immunocompromised patients. Innate immunity plays a major role in protection against A. fumigatus. The ficolins are a family of soluble pattern recognition receptors that are capable of activating the lectin pathway of complement. Previous in vitro studies reported that ficolins bind to A. fumigatus, but their part in host defense against fungal infections in vivo is unknown. In this study, we used ficolin-deficient mice to investigate the role of ficolins during lung infection with A. fumigatus. Ficolin knockout mice showed significantly higher fungal loads in the lungs 24 h postinfection compared to wild-type mice. The delayed clearance of A. fumigatus in ficolin knockout mice could not be attributed to a compromised recruitment of inflammatory cells. However, it was revealed that ficolin knockout mice exhibited a decreased production of proinflammatory cytokines in the lungs compared to wild-type mice following A. fumigatus infection. The impaired clearance and cytokine production in ficolin knockout mice was independent of complement, as shown by equivalent levels of A. fumigatus-mediated complement activation in ficolin knockout mice and wild-type mice. In conclusion, this study demonstrates that ficolins are important in initial innate host defense against A. fumigatus infections in vivo.

scholarly journals Reassortment between Avian H5N1 and Human H3N2 Influenza Viruses in Ferrets: a Public Health Risk Assessment

2009 ◽  
Vol 83 (16) ◽  
pp. 8131-8140 ◽  
Author(s):  
Sara Jackson ◽  
Neal Van Hoeven ◽  
Li-Mei Chen ◽  
Taronna R. Maines ◽  
Nancy J. Cox ◽  
...  
Keyword(s):  
Upper Airway ◽  
Influenza Viruses ◽  
Upper Respiratory Tract ◽  
Upper Airways ◽  
Nasal Secretions ◽  
H5 Subtype ◽  
H3n2 Influenza ◽  
Human Viruses ◽  
Reassortant Viruses

ABSTRACT This study investigated whether transmissible H5 subtype human-avian reassortant viruses could be generated in vivo. To this end, ferrets were coinfected with recent avian H5N1 (A/Thailand/16/04) and human H3N2 (A/Wyoming/3/03) viruses. Genotype analyses of plaque-purified viruses from nasal secretions of coinfected ferrets revealed that approximately 9% of recovered viruses contained genes from both progenitor viruses. H5 and H3 subtype viruses, including reassortants, were found in airways extending toward and in the upper respiratory tract of ferrets. However, only parental H5N1 genotype viruses were found in lung tissue. Approximately 34% of the recovered reassortant viruses possessed the H5 hemagglutinin (HA) gene, with five unique H5 subtypes recovered. These H5 reassortants were selected for further studies to examine their growth and transmissibility characteristics. Five H5 viruses with representative reassortant genotypes showed reduced titers in nasal secretions of infected ferrets compared to the parental H5N1 virus. No transmission by direct contact between infected and naïve ferrets was observed. These studies indicate that reassortment between H5N1 avian influenza and H3N2 human viruses occurred readily in vivo and furthermore that reassortment between these two viral subtypes is likely to occur in ferret upper airways. Given the relatively high incidence of reassortant viruses from tissues of the ferret upper airway, it is reasonable to conclude that continued exposure of humans and animals to H5N1 alongside seasonal influenza viruses increases the risk of generating H5 subtype reassortant viruses that may be shed from upper airway secretions.

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