Your browser doesn't support javascript.
loading
: 20 | 50 | 100
1 - 16 de 16
1.
BJA Open ; 9: 100256, 2024 Mar.
Article En | MEDLINE | ID: mdl-38318270

Background: Neutrophil-derived heparin-binding protein (HBP) plays a role in the pathophysiology of impaired endothelial dysfunction during inflammation. HBP has been suggested as a predictor of organ dysfunction and disease progression in sepsis. We investigated the effects of heparins on plasma concentrations of HBP in patients undergoing surgery. Methods: We studied three groups of patients receiving heparins during or after surgery. The vascular surgery group received 3000-7500 U, whereas the cardiac surgery group received 27 500-40 000 U. After major general surgery, the third group received 5000 U of low-molecular-weight heparin (LMWH) subcutaneously. Serial plasma HBP concentrations were measured after these treatments with two different methods: Axis-Shield ELISA and Joinstar FIC-Q100. In addition, plasma myeloperoxidase and syndecan-1 were measured in the cardiac surgery group. Results: During vascular surgery, heparin induced a six-fold increase in HBP within 2 min, from 3.6 (2.4-5.4) to 21.4 (9.0-35.4) ng ml-1 (P<0.001). During cardiac surgery, the higher dose of heparin elevated HBP concentrations from 5.3 (2.7-6.1) to 48.7 (38.4-70.1) ng ml-1 (P<0.0001) within 3 min. Patients receiving LMWH showed an increase from a baseline of 5.7 (3.7-12.1) ng ml-1 to a peak HBP concentration of 14.8 (9.5-18.1) ng ml-1 (P<0.0001) after 3 h. Plasma concentrations of myeloperoxidase, but not syndecan-1, also responded with a rapid increase after heparin. There was a strong correlation between the two methods for HBP analysis (r=0.94). Conclusions: Plasma concentrations of HBP increased rapidly and dose-dependently after heparin administration. Subcutaneous administration of LMWH increases plasma HBP, but to a lesser degree. Clinical trial registration: ClinicalTrials.gov identifier: NCT04146493.

2.
Front Immunol ; 13: 911744, 2022.
Article En | MEDLINE | ID: mdl-35874666

Surgery triggers a systemic inflammatory response that ultimately impacts the brain and associates with long-term cognitive impairment. Adequate regulation of this immune surge is pivotal for a successful surgical recovery. We explored the temporal immune response in a surgical cohort and its associations with neuroimmune regulatory pathways and cognition, in keeping with the growing body of evidence pointing towards the brain as a regulator of peripheral inflammation. Brain-to-immune communication acts through cellular, humoral and neural pathways. In this context, the vagal nerve and the cholinergic anti-inflammatory pathway (CAP) have been shown to modify peripheral immune cell activity in both acute and chronic inflammatory conditions. However, the relevance of neuroimmune regulatory mechanisms following a surgical trauma is not yet elucidated. Twenty-five male patients undergoing elective laparoscopic abdominal surgery were included in this observational prospective study. Serial blood samples with extensive immune characterization, assessments of heart rate variability (HRV) and cognitive tests were performed before surgery and continuing up to 6 months post-surgery. Temporal immune responses revealed biphasic reaction patterns with most pronounced changes at 5 hours after skin incision and 14 days following surgery. Estimations of cardiac vagal nerve activity through HRV recordings revealed great individual variations depending on the pre-operative HRV baseline. A principal component analysis displayed distinct differences in systemic inflammatory biomarker trajectories primarily based on pre-operative HRV, with potiential consequences for long-term surgical outcomes. In conclusion, individual pre-operative HRV generates differential response patterns that associate with distinct inflammatory trajectories following surgery. Long-term surgical outcomes need to be examined further in larger studies with mixed gender cohorts.


Inflammation , Vagus Nerve , Heart Rate/physiology , Humans , Immunity, Innate , Inflammation/metabolism , Male , Prospective Studies , Vagus Nerve/physiology
3.
Respir Physiol Neurobiol ; 294: 103746, 2021 12.
Article En | MEDLINE | ID: mdl-34302993

The molecular mechanisms of obstructive sleep apnea (OSA), in particular the gene expression patterns in whole blood of patients with OSA, can shed more light on the underlying pathophysiology of OSA and suggest potential biomarkers. In the current study, we have enrolled thirty patients with untreated moderate-severe OSA together with 20 BMI, age, and sex-matched controls and 15 normal-weight controls. RNA-sequencing of whole blood and home sleep apnea testing were performed in the untreated state and after three and twelve months of continuous positive airway pressure (CPAP) treatment. Analysis of the whole blood transcriptome of the patients with OSA revealed a unique pattern of differential expression with a significant number of downregulated immune-related genes including many heavy and light chain immunoglobulins and interferon-inducible genes. This was confirmed by the gene ontology analysis demonstrating enrichment with the biological processes associated with various immune functions. Expression of these genes was recovered after three months of CPAP treatment. After 12 months of CPAP treatment, the overall gene expression profile returns to the initial, untreated level. In addition, we have confirmed the importance of choosing BMI-matched controls as a reference group as opposed to normal-weight healthy individuals based on the significantly different gene expression signatures between these two groups.


Continuous Positive Airway Pressure , Outcome Assessment, Health Care , Sleep Apnea, Obstructive/blood , Sleep Apnea, Obstructive/therapy , Transcriptome/physiology , Adult , Aged , Body Mass Index , Female , Gene Ontology , Humans , Longitudinal Studies , Male , Middle Aged , Sequence Analysis, RNA , Time Factors
4.
Acta Anaesthesiol Scand ; 65(9): 1276-1284, 2021 Oct.
Article En | MEDLINE | ID: mdl-34028012

BACKGROUND: Apnoeic oxygenation using Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) during general anaesthesia prolongs the safe apnoeic period. However, there is a gap of knowledge how THRIVE-induced hyperoxia and hypercapnia impact vital organs. The primary aim of this randomised controlled trial was to characterise oxidative stress and, secondary, vital organ function biomarkers during THRIVE compared to mechanical ventilation (MV). METHODS: Thirty adult patients, American Society of Anesthesiologists (ASA) 1-2, undergoing short laryngeal surgery under general anaesthesia were randomised to THRIVE, FI O2 1.0, 70 L min-1 during apnoea or MV. Blood biomarkers for oxidative stress, malondialdehyde and TAC and vital organ function were collected (A) preoperatively, (B) at procedure completion and (C) at PACU discharge. RESULTS: Mean apnoea time was 17.9 (4.8) min and intubation to end-of-surgery time was 28.1 (12.8) min in the THRIVE and MV group, respectively. Malondialdehyde increased from 11.2 (3.1) to 12.7 (3.1) µM (P = .02) and from 9.5 (2.2) to 11.6 (2.6) µM (P = .003) (A to C) in the THRIVE and MV group, respectively. S100B increased from 0.05 (0.02) to 0.06 (0.02) µg L-1 (P = .005) (A to C) in the THRIVE group. No increase in TAC, CRP, leukocyte count, troponin-T, NTproBNP, creatinine, eGFRcrea or NSE was demonstrated during THRIVE. CONCLUSION: While THRIVE and MV was associated with increased oxidative stress, we found no change in cardiac, inflammation or kidney biomarkers during THRIVE. Further evaluation of stress and inflammatory response and cerebral and cardiac function during THRIVE is needed.


Insufflation , Administration, Intranasal , Adult , Airway Management , Biomarkers , Humans , Oxidative Stress , Respiration, Artificial
5.
Front Immunol ; 12: 824696, 2021.
Article En | MEDLINE | ID: mdl-35116043

Surgical interventions rapidly trigger a cascade of molecular, cellular, and neural signaling responses that ultimately reach remote organs, including the brain. Using a mouse model of orthopedic surgery, we have previously demonstrated hippocampal metabolic, structural, and functional changes associated with cognitive impairment. However, the nature of the underlying signals responsible for such periphery-to-brain communication remains hitherto elusive. Here we present the first exploratory study that tests the hypothesis of extracellular vesicles (EVs) as potential mediators carrying information from the injured tissue to the distal organs including the brain. The primary goal was to investigate whether the cargo of circulating EVs after surgery can undergo quantitative changes that could potentially trigger phenotypic modifications in the target tissues. EVs were isolated from the serum of the mice subjected to a tibia surgery after 6, 24, and 72 h, and the proteome and miRNAome were investigated using mass spectrometry and RNA-seq approaches. We found substantial differential expression of proteins and miRNAs starting at 6 h post-surgery and peaking at 24 h. Interestingly, one of the up-regulated proteins at 24 h was α-synuclein, a pathogenic hallmark of certain neurodegenerative syndromes. Analysis of miRNA target mRNA and corresponding biological pathways indicate the potential of post-surgery EVs to modify the extracellular matrix of the recipient cells and regulate metabolic processes including fatty acid metabolism. We conclude that surgery alters the cargo of circulating EVs in the blood, and our results suggest EVs as potential systemic signal carriers mediating remote effects of surgery on the brain.


Biomarkers , Extracellular Vesicles/metabolism , Wounds and Injuries/metabolism , Animals , Chemical Fractionation , Chromatography, Liquid , Disease Models, Animal , Disease Susceptibility , Extracellular Vesicles/ultrastructure , Mice , MicroRNAs/genetics , Proteome , Proteomics/methods , RNA, Messenger/genetics , Surgical Procedures, Operative/adverse effects , Tandem Mass Spectrometry , Wounds and Injuries/blood , Wounds and Injuries/etiology
6.
Exp Physiol ; 105(9): 1634-1647, 2020 09.
Article En | MEDLINE | ID: mdl-32652583

NEW FINDINGS: What is the central question of this study? Are carotid bodies (CBs) modulated by the damage-associated molecular patterns (DAMPs) and humoral factors of aseptic tissue injury? What are the main findings and their importance? DAMPs (HMGB1, S100 A8/A9) and blood plasma from rats subjected to tibia surgery, a model of aseptic injury, stimulate the release of neurotransmitters (ATP, dopamine) and TNF-α from ex vivo rat CBs. All-thiol HMGB1 mediates upregulation of immune-related biological pathways. These data suggest regulation of CB function by endogenous mediators of innate immunity. ABSTRACT: The glomus cells of carotid bodies (CBs) are the primary sensors of arterial partial O2 and CO2 tensions and moreover serve as multimodal receptors responding also to other stimuli, such as pathogen-associated molecular patterns (PAMPs) produced by acute infection. Modulation of CB function by excessive amounts of these immunomodulators is suggested to be associated with a detrimental hyperinflammatory state. We have hypothesized that yet another class of immunomodulators, endogenous danger-associated molecular patterns (DAMPs), released upon aseptic tissue injury and recognized by the same pathogen recognition receptors as PAMPs, might modulate the CB activity in a fashion similar to PAMPs. We have tested this hypothesis by exposing rat CBs to various DAMPs, such as HMGB1 (all-thiol and disulfide forms) and S100 A8/A9 in a series of ex vivo experiments that demonstrated the release of dopamine and ATP, neurotransmitters known to mediate CB homeostatic responses. We observed a similar response after incubating CBs with conditioned blood plasma obtained from the rats subjected to tibia surgery, a model of aseptic injury. In addition, we have investigated global gene expression in the rat CB using an RNA sequencing approach. Differential gene expression analysis showed all-thiol HMGB1-driven upregulation of a number of prominent pro-inflammatory markers including Il1α and Il1ß. Interestingly, conditioned plasma had a more profound effect on the CB transcriptome resulting in inhibition rather than activation of the immune-related pathways. These data are the first to suggest potential modulation of CB function by endogenous mediators of innate immunity.


Alarmins/metabolism , Carotid Body/metabolism , Neurotransmitter Agents/metabolism , Wounds and Injuries/metabolism , Adenosine Triphosphate/metabolism , Animals , Calgranulin A , Calgranulin B , Dopamine/metabolism , Gene Expression , HMGB1 Protein , Male , Rats , Rats, Sprague-Dawley , Tibia/surgery
7.
PLoS One ; 15(1): e0220020, 2020.
Article En | MEDLINE | ID: mdl-31971939

BACKGROUND: In a previous study we found a significant correlation between dystocia and hyponatraemia that developed during labour. The present study examined a possible causal relationship. In vitro studies often use area under the curve (AUC) determined by frequency and force of contractions as a measure of myometrial contractility. However, a phase portrait plot of isometric contraction, obtained by plotting the first derivate of contraction against force of contraction, could indicate that bi-or multiphasic contractions might be less effective compared to the smooth contractions. MATERIAL AND METHODS: Myometrial biopsies were obtained from 17 women undergoing elective caesarean section at term. Each biopsy was divided into 8 strips and mounted isometrically in a force transducer. Seven biopsies were used in the first part of the study when half of the strips were immersed in the hyponatraemic study solution S containing Na+ 120 mmol/L and observed for 1 hour, followed by 1 hour in normonatraemic control solution C containing Na+ 136 mmol/L, then again in S for 1 hour, and finally 1 hour in C. The other half of the strips were studied in reverse order, C-S-C-S. The remaining ten biopsies were included in the second part of the study. Response to increasing doses of oxytocin (OT) in solutions S and C was studied. In the first part of the study we calculated AUC, and created phase portrait plots of two different contractions from the same strip, one smooth and one biphasic. In both parts of the study we registered frequency and force of contractions, and described appearance of the contractions. RESULTS: First part of the study: Mean (median) contractions per hour in C: 8.7 (7.6), in S 14,3 (13). Mean (SD) difference between groups 5.6 (4.2), p = 0.018. Force of contractions in C: 11.8 (10.2) mN, in S: 10.8 (9.2) mN, p = 0.09, AUC increased in S; p = 0.018. Bi-/multiphasic contractions increased from 8% in C to 18% in S, p = 0.001. All changes were reversible in C. Second part of the study: Frequency after OT 1.65 x 10-9 M in C:3.4 (2.9), in S: 3.8 (3.2), difference between groups: p = 0.48. After OT 1.65 x 10-7 M in C: 7.8 (8.9), increase from previous OT administration: p = 0.09, in S: 8.7 (9.0), p = 0.04, difference between groups, p = 0.32. Only at the highest dose of OT dose was there an increase in force of contraction in S, p = 0.05, difference between groups, p = 0.33. Initial response to OT was more frequently bi/multiphasic in S, reaching significance at the highest dose of OT(1.65 x 10-7 M), p = 0.015. when almost all contractions were bi/multiphasic. CONCLUSION: Hyponatraemia reversibly increased frequency of contractions and appearance of bi-or multiphasic contractions, that could reduce myometrial contractility. This could explain the correlation of hyponatraemia and instrumental delivery previously observed. Contractions in the hyponatraemic solution more frequently showed initial multiphasic contractions when OT was added in increasing doses. Longer lasting labours carry the risk both of hyponatraemia and OT administration, and their negative interaction could be significant. Further studies should address this possibility.


Culture Media/pharmacology , Myometrium/drug effects , Oxytocin/pharmacology , Sodium/pharmacology , Uterine Contraction/drug effects , Adult , Area Under Curve , Biopsy , Cesarean Section , Culture Media/chemistry , Dystocia/metabolism , Dystocia/physiopathology , Female , Humans , Hyponatremia/metabolism , Hyponatremia/physiopathology , Isometric Contraction/drug effects , Models, Biological , Myometrium/metabolism , Pilot Projects , Pregnancy , Tissue Culture Techniques
8.
Adv Exp Med Biol ; 1071: 25-33, 2018.
Article En | MEDLINE | ID: mdl-30357730

How hypoxia regulates gene expression in the human carotid body (CB) remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the impact of important post-transcriptional regulators, such as non-coding RNAs, and in particular miRNAs is not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied. Analysis of the hypoxia-regulated miRNAs shows that they target biological pathways with upregulation of functions related to cell proliferation and immune response and downregulation of cell differentiation and cell death functions. Comparative analysis of the human CB miRNAome with the global miRNA expression patterns of a large number of different human tissues showed that the CB miRNAome had a unique profile which reflects its highly specialized functional status. Nevertheless, the human CB miRNAome is most closely related to the miRNA expression pattern of brain tissues indicating that they may have the most similar developmental origins.


Carotid Body/physiology , Hypoxia , MicroRNAs/genetics , Gene Expression Regulation , Humans , In Vitro Techniques
9.
Exp Cell Res ; 352(2): 412-419, 2017 03 15.
Article En | MEDLINE | ID: mdl-28238835

The carotid body (CB) is the key sensing organ for physiological oxygen levels in the body. Under conditions of low oxygen (hypoxia), the CB plays crucial roles in signaling to the cardiorespiratory center in the medulla oblongata for the restoration of oxygen homeostasis. How hypoxia regulates gene expression in the human CB remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the identity and impact of important post-transcriptional regulators such as non-coding RNAs, and in particular miRNAs are not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied. Analysis of the hypoxia-regulated miRNAs shows that they target biological pathways with upregulation of functions related to cell proliferation and immune response and downregulation of cell differentiation and cell death functions. Comparative analysis of the human CB miRNAome with the global miRNA expression patterns of a large number of different human tissues showed that the CB miRNAome had a unique profile which reflects its highly specialized functional status. Nevertheless, the human CB miRNAome is most closely related to the miRNA expression pattern of brain tissues indicating that they may have the most similar developmental origins.


Carotid Body/metabolism , Hypoxia/metabolism , MicroRNAs/genetics , Oxygen/metabolism , Adult , Aged , Aged, 80 and over , Cell Hypoxia , Cells, Cultured , Humans , Hypoxia/genetics , Male , MicroRNAs/metabolism , Middle Aged
10.
Anesthesiology ; 125(4): 700-15, 2016 10.
Article En | MEDLINE | ID: mdl-27483127

BACKGROUND: In contrast to general anesthetics such as propofol, dexmedetomidine when used for sedation has been put forward as a drug with minimal effects on respiration. To obtain a more comprehensive understanding of the regulation of breathing during sedation with dexmedetomidine, the authors compared ventilatory responses to hypoxia and hypercapnia during sedation with dexmedetomidine and propofol. METHODS: Eleven healthy male volunteers entered this randomized crossover study. Sedation was administered as an intravenous bolus followed by an infusion and monitored by Observer's Assessment of Alertness/Sedation (OAA/S) scale, Richmond Agitation Sedation Scale, and Bispectral Index Score. Hypoxic and hypercapnic ventilatory responses were measured at rest, during sedation (OAA/S 2 to 4), and after recovery. Drug exposure was verified with concentration analysis in plasma. RESULTS: Ten subjects completed the study. The OAA/S at the sedation goal was 3 (3 to 4) (median [minimum to maximum]) for both drugs. Bispectral Index Score was 82 ± 8 and 75 ± 3, and the drug concentrations in plasma at the sedation target were 0.66 ± 0.14 and 1.26 ± 0.36 µg/ml for dexmedetomidine and propofol, respectively. Compared with baseline, sedation reduced hypoxic ventilation to 59 and 53% and the hypercapnic ventilation to 82 and 86% for dexmedetomidine and propofol, respectively. In addition, some volunteers displayed upper airway obstruction and episodes of apnea during sedation. CONCLUSIONS: Dexmedetomidine-induced sedation reduces ventilatory responses to hypoxia and hypercapnia to a similar extent as sedation with propofol. This finding implies that sedation with dexmedetomidine interacts with both peripheral and central control of breathing.


Dexmedetomidine/pharmacology , Hypnotics and Sedatives/pharmacology , Hypoxia/physiopathology , Propofol/pharmacology , Respiration/drug effects , Adolescent , Adult , Cross-Over Studies , Humans , Hypercapnia/physiopathology , Male , Reference Values , Young Adult
11.
Adv Exp Med Biol ; 860: 371-7, 2015.
Article En | MEDLINE | ID: mdl-26303502

Although animal carotid body oxygen sensing and signaling has been extensively investigated, the human carotid body remains essentially uncharacterized. Therefore, we aimed to study the human carotid body in terms of morphology, global and specific expression of sensing and signaling genes as well as inflammatory genes. The human carotid body response to brief or prolonged hypoxia was studied in carotid body slices from adult surgical patients and ACh, ATP and cytokine release was analyzed. We demonstrate that the human carotid body expresses key oxygen sensing and signaling genes in similarity with animal carotid bodies with a few diverging data. The human carotid body moreover shows enrichment of genes in the inflammatory response and releases pro and anti-inflammatory cytokines in response to prolonged hypoxia. In response to acute hypoxia the human carotid body releases ACh and ATP and we thus translate previous findings in animal models to human tissue. We conclude that by releasing pro- and anti-inflammatory cytokines during hypoxia the human carotid body displays a structural and functional capacity to participate in sensing and mediating systemic inflammation.


Carotid Body/physiology , Hypoxia/physiopathology , Inflammation/physiopathology , Adult , Aged , Aged, 80 and over , Cytokines/metabolism , Female , Humans , Hypoxia/immunology , Male , Middle Aged , Oxygen/metabolism , Sleep Apnea, Obstructive/etiology , Transcriptome
12.
Exp Physiol ; 99(8): 1089-98, 2014 Aug.
Article En | MEDLINE | ID: mdl-24887113

Studies on experimental animals established that the carotid bodies are sensory organs for detecting arterial blood O2 levels and that the ensuing chemosensory reflex is a major regulator of cardiorespiratory functions during hypoxia. However, little information is available on the human carotid body responses to hypoxia. The present study was performed on human carotid bodies obtained from surgical patients undergoing elective head and neck cancer surgery. Our results show that exposing carotid body slices to hypoxia for a period as brief as 5 min markedly facilitates the release of ACh and ATP. Furthermore, prolonged hypoxia for 1 h induces an increased release of interleukin (IL)-1ß, IL-4, IL-6, IL-8 and IL-10. Immunohistochemical analysis revealed that type 1 cells of the human carotid body express an array of cytokine receptors as well as hypoxia-inducible factor-1α and hypoxia-inducible factor-2α. Taken together, these results demonstrate that ACh and ATP are released from the human carotid body in response to hypoxia, suggesting that these neurotransmitters, as in several experimental animal models, play a role in hypoxic signalling also in the human carotid body. The finding that the human carotid body releases cytokines in response to hypoxia adds to the growing body of information suggesting that the carotid body may play a role in detecting inflammation, providing a link between the immune system and the nervous system.


Acetylcholine/metabolism , Adenosine Triphosphate/metabolism , Carotid Body/metabolism , Carotid Body/physiopathology , Hypoxia/metabolism , Hypoxia/physiopathology , Interleukins/metabolism , Adult , Aged , Aged, 80 and over , Basic Helix-Loop-Helix Transcription Factors/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Middle Aged , Neurotransmitter Agents/metabolism , Oxygen/metabolism , Receptors, Cytokine/metabolism , Reflex/physiology
13.
Free Radic Biol Med ; 65: 1257-1264, 2013 Dec.
Article En | MEDLINE | ID: mdl-24084579

Antibacterial nitrogen oxides including nitric oxide are formed from nitrite under acidic conditions. In a continuous-flow model of the urinary bladder we used the retention cuff of an all-silicone Foley catheter as a depot for export of nitrogen oxides. The cuff was filled with sodium nitrite (50mM) and an acidic buffer solution (pH 3.6) and the growth of nine common uropathogens in the surrounding artificial urine was measured along with biofilm formation on the catheter surface. In experiments with control catheters (NaCl) bacteria grew readily and biofilm developed within hours in five of nine strains. In contrast, with test catheters bacterial counts were markedly reduced and biofilm formation by Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter cloace was prevented, whereas Escherichia coli and Staphylococcus aureus were unaffected. We conclude that antibacterial nitrogen oxides generated in the retention cuff of a urinary catheter diffuse into urine and prevent the growth of urinary pathogens and biofilm formation. Although promising, future studies will reveal if this novel approach can be clinically useful for the prevention of catheter-associated urinary tract infections.


Bacteria/drug effects , Biofilms/growth & development , Drug Delivery Systems/methods , Nitrogen Oxides/pharmacology , Urinary Catheters/microbiology , Anti-Bacterial Agents , Anti-Infective Agents/pharmacology , Bacteria/growth & development , Biofilms/drug effects , Cysteine/analogs & derivatives , Cysteine/biosynthesis , Microbial Sensitivity Tests , S-Nitrosothiols , Sodium Nitrite/chemistry , Urinary Bladder/microbiology , Urinary Catheterization/instrumentation , Urine/microbiology
14.
J Physiol ; 590(16): 3807-19, 2012 Aug 15.
Article En | MEDLINE | ID: mdl-22615433

The carotid body (CB) is the key oxygen sensing organ. While the expression of CB specific genes is relatively well studied in animals, corresponding data for the human CB are missing. In this study we used five surgically removed human CBs to characterize the CB transcriptome with microarray and PCR analyses, and compared the results with mice data. In silico approaches demonstrated a unique gene expression profile of the human and mouse CB transcriptomes and an unexpected upregulation of both human and mouse CB genes involved in the inflammatory response compared to brain and adrenal gland data. Human CBs express most of the genes previously proposed to be involved in oxygen sensing and signalling based on animal studies, including NOX2, AMPK, CSE and oxygen sensitive K+ channels. In the TASK subfamily of K+ channels, TASK-1 is expressed in human CBs, while TASK-3 and TASK-5 are absent, although we demonstrated both TASK-1 and TASK-3 in one of the mouse reference strains. Maxi-K was expressed exclusively as the spliced variant ZERO in the human CB. In summary, the human CB transcriptome shares important features with the mouse CB, but also differs significantly in the expression of a number of CB chemosensory genes. This study provides key information for future functional investigations on the human carotid body.


Carotid Body/metabolism , Inflammation/metabolism , Oxygen/metabolism , Transcriptome/physiology , Adult , Aged , Animals , Female , Gene Expression Regulation/physiology , Humans , Male , Mice , Middle Aged , Polymerase Chain Reaction , Potassium Channels/metabolism , Protein Array Analysis , Signal Transduction
15.
Anesthesiology ; 113(6): 1270-9, 2010 Dec.
Article En | MEDLINE | ID: mdl-20980909

BACKGROUND: Hypoxia is a common cause of adverse events in the postoperative period, where respiratory depression due to residual effects of drugs used in anesthesia is an important underlying factor. General anesthetics and neuromuscular blocking agents reduce the human ventilatory response to hypoxia. Although the carotid body (CB) is the major oxygen sensor in humans, critical oxygen sensing and signaling pathways have been investigated only in animals so far. Thus, the aim of this study was to characterize the expression of key genes and localization of their products involved in the human oxygen sensing and signaling pathways with a focus on receptor systems and ion channels of relevance in anesthesia. METHODS: Six CBs were removed unilaterally from patients undergoing radical neck dissection. The gene expression and cell-specific protein localization in the CBs were investigated with DNA microarrays, real-time polymerase chain reaction, and immunohistochemistry. RESULTS: We found gene expression of the oxygen-sensing pathway, heme oxygenase 2, and the K channels TASK (TWIK-related acid sensitive K channel)-1 and BK (large-conductance potassium channel). In addition, we show the expression of critical receptor subunits such as γ-aminobutyric acid A (α2, ß3, and γ2), nicotinic acetylcholine receptors (α3, α7, and ß2), purinoceptors (A2A and P2X2), and the dopamine D2 receptor. CONCLUSIONS: In unique samples of the human CB, we here demonstrate presence of critical proteins in the oxygen-sensing and signaling cascade. Our findings demonstrate similarities to, but also important differences from, established animal models. In addition, our work establishes an essential platform for studying the interaction between anesthetic drugs and human CB chemoreception.


Anesthesia , Carotid Body/physiology , Gene Expression/physiology , Oxygen Consumption/genetics , Oxygen Consumption/physiology , Signal Transduction/genetics , Signal Transduction/physiology , Adult , Aged , Anesthetics, Inhalation , Female , Gene Expression/genetics , Humans , Immunohistochemistry , Male , Methyl Ethers , Microarray Analysis , Middle Aged , Neck Dissection , Patch-Clamp Techniques , Potassium Channels/genetics , Potassium Channels/physiology , RNA/biosynthesis , RNA/isolation & purification , Receptors, Cholinergic/genetics , Receptors, Cholinergic/physiology , Receptors, Dopamine/genetics , Receptors, Dopamine/physiology , Receptors, GABA/genetics , Receptors, GABA/physiology , Receptors, Purinergic/genetics , Receptors, Purinergic/physiology , Respiration, Artificial , Reverse Transcriptase Polymerase Chain Reaction , Sevoflurane
16.
Respir Physiol Neurobiol ; 172(3): 122-8, 2010 Jul 31.
Article En | MEDLINE | ID: mdl-20452469

We have characterized the mouse carotid body (CB) with special attention to nicotinic, purinergic and dopaminergic receptors as well as the TASK-1 K(+)-channel. Mouse CB sections were stained immunohistochemically and visualized using fluorescent and confocal microscopy. The CB type 1 cells contained the alpha3 (n=8), alpha4 (n=7), alpha7 (n=4) and beta2 (n=3) nicotinic acetylcholine receptor (nAChR) subunits, the ATP-receptors P2X(2) (n=15) and P2X(3) (n=9), the dopamine D(2) receptor (n=9) and the TASK-1 K(+)-channel (n=7). Here we report the presence of alpha3, alpha4, alpha7 and beta2 nAChR subunits, the D(2) receptor and the TASK-1 K(+)-channel in the mouse CB. Also, we confirm the presence of the P2X(2) and P2X(3) receptors in mouse CB. Thus, we have localized nicotinergic, purinergic and dopaminergic receptors and the TASK-1 K(+)-channel on a protein level in one species. Our data are in line with the theory that the CB chemoreceptor cell hosts an orchestra of receptor systems that ultimately modulate the response to hypoxia.


Carotid Body/metabolism , Nerve Tissue Proteins/metabolism , Potassium Channels, Tandem Pore Domain/metabolism , Receptors, Dopamine/metabolism , Receptors, Nicotinic/metabolism , Receptors, Purinergic/metabolism , Animals , Glial Fibrillary Acidic Protein/metabolism , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Neurofilament Proteins/metabolism , Receptors, Dopamine/drug effects , Receptors, Nicotinic/drug effects , Receptors, Purinergic/drug effects , Receptors, Purinergic P2/drug effects , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X , Reverse Transcriptase Polymerase Chain Reaction , Tubulin/metabolism , Tyrosine 3-Monooxygenase/metabolism
...