bluuebunny/crossref_metadata_2025_split huggingface dataset:
Obesity Prevention by Calorie Restraint Using the Bathroom Scale Model Prevents Hypertension for Life in Nonhuman Primates
Authors: Hansen Barbara Caleen , Linden Ellen H , Newcomb Jennifer D. 
Published: November 2023

Obesity prevention via application of the “bathroom scale” model of long term calorie restriction/calorie titration in nonhuman primates (NHPs) prevents the slow motion development of features of the metabolic syndrome, specifically dyslipidemia, and now hypertension. This has enabled time‐linked analysis of the natural history of emergent features in the search for mechanisms underlying the metabolic syndrome. The present study is a follow on of the first defining of normal NHP blood pressure (BP) (121.8 ± 1.6/63.5 ±1.1 mmHg systolic/diastolic respectively), with a Mean Arterial Pressure (MAP) of 85.6 ± 1.1 mmHg, as measured by the GE pro 100V2 instrument. We sought to determine the consequences of obesity, type 2 diabetes, and obesity prevention on the progression of hypertension. BP levels were found to be highly similar to those hypertension levels defined by the American Heart Association JNC7 report in humans, however, mean diastolic BP was significantly lower in NHPs relative to reported normal human levels. (63.5 vs ~ 80), albeit that the 80 is not the mean of normal but rather a threshold above which is abnormal, with mean of normal in humans undefined. We have found progressive increases in hypertension in NHPs with increasing body weight over the adult monkey range 7 to 25 kg (r=0.01, p=0.006). We also examined 1) the relationship of developing hypertension to T2DM onset/dx in 64 monkeys, 2) to the consequences of long‐term diabetes with and without obesity, and 3) then determined the relationship of diabetes prevention by calorie restriction (CR) to hypertension (N=7). Long term CR of NHPs for ~ 23+ years from early adulthood through old age entirely prevented all levels of hypertension compared to ad libitum fed controls (N=192), and in fact CR significantly lowered blood pressure levels (CR: SBP 116.5, DBP 58.2 & MAP 82.9 mm Hg; ad lib controls: SBP 131.3, DBP 66.6 & MAP 92.3 mm Hg). CR monkeys showed 11, 12 and 10% lower systolic, diastolic and mean arterial BPs respectively (p's<0.01). Elderly CR monkeys had a non‐significant difference in BP compared to the above referenced normal adults of similar weight with no CR. In addition systolic BP defined a greater prevalence of hypertension in adult NHPs (67%) compared to diastolic BP (21%) in adult rhesus monkeys. The life time prevalence of T2DM in nonhuman primates appears, based on current long term data, to be approximately 65%. Despite their similar prevalence, the overlap of diabetes and hypertension is not fully concordant, although both relate to obesity in NHPs. Non‐similar trajectories suggest separate underlying regulatory mechanisms. In conclusion, this large animal model naturally develops in middle age all features of human hypertension, including the high prevalence and wide range of severity, together with associations with obesity, age and diabetes.Support or Funding InformationNational Institute on Aging HHSN263200800022C
IL‐1β Participates in Sensitization of Bronchopulmonary C‐fibers Induced by Prenatal Nicotinic Exposure (PNE) in Rat Pups
Authors: Zhao Lei , Zhuang Jianguo , Xu Fadi 
Published: November 2023

Maternal smoking during pregnancy has the highest risk for inducing sudden infant death syndrome (SIDS) characterized by cardiorespiratory failure including aggravated apnea. We recently found that PNE promoted hypoxia‐induced central apnea by sensitizing the bronchopulmonary C‐fibers (PFCs), i.e., prolonged PCF firing and apneic response to right atrial bolus injection of capsaicin, a selective stimulant to PCFs (Zhuang et al., AJP 2015), but the relevant mechanisms have not been fully understood. IL‐1β is a potent stimulant to PCFs and its concentration in serum is substantially increased in the majority of SIDS victims (Vennemann et al., Int J Legal Med. 2012). Thus we asked whether PNE increased IL‐1β release into the lungs and IL‐1 type I receptor (IL1R1) expression in nodose/jugular (N/J) ganglion, especially the vagal pulmonary C‐neurons, and if so, whether the prolonged apneic response to capsaicin by PNE would be shortened by pretreatment of IL‐1Ra (an IL1R1 antagonist). To this end, we collected BALF to detect gene and protein levels of IL‐1β released into the airways and lungs, harvested N/J ganglion for determining IL1R1 gene and protein expression, and extracted vagal pulmonary C‐neurons retrograde‐traced by DiI for analysis of IL1R1 mRNA. Subsequently, in anesthetized and spontaneously breathing pups, we compared the respiratory responses to atrial bolus injection of capsaicin before and after IL‐1R1 blockade. Our results showed that PNE obviously elevated IL‐1β in BALF, and upregulated IL1R1 gene and protein expression of N/J ganglion, particularly IL1R1 mRNA in pulmonary C neurons. Moreover, the PNE‐induced prolongation of the apneic response to capsaicin was significantly shortened by ~55% after IL‐1R1 blockade. Our results suggest that PNE promotes IL‐1β release into the lungs and IL1R1 expression in vagal pulmonary C‐neurons to sensitize PCFs, contributing to the prolongation of the PCF‐mediated apnea.Support or Funding InformationSupported by HL119683 and HL107462
Short‐Term Modulation of the Ventilatory Response to Exercise is Preserved in Obstructive Sleep Apnea
Authors: Bernhardt Vipa , Bassett J Todd , Moran Raksa B , Marines‐Price Rubria , Mitchell Gordon S , Lee Won Y , Babb Tony G 
Published: November 2023

BackgroundThe ventilatory response to exercise is temporarily augmented in response to environmentally (e.g., breathing apparatus) or physiologically altered conditions (e.g., respiratory disease), maintaining constant relative arterial PCO2 regulation from rest to exercise; this augmentation is called short‐term modulation (STM) of the ventilatory response to exercise. Obesity and/or obstructive sleep apnea could affect the exercise ventilatory response and STM capacity due to the additional mechanical or ventilatory load on the respiratory system and/or the repetitive intermittent hypoxia during sleep. We hypothesized that: 1) the exercise ventilatory response is augmented in obese OSA patients compared with otherwise healthy obese adults, and 2) the capacity for STM with added dead space is diminished in obese OSA patients.MethodsNine obese adults with OSA (age: 39 ± 6 yr, BMI: 40 ± 5 kg/m2, AHI: 25 ± 24 events/hr [range 6–73], mean ± SD) and 8 obese adults without OSA (age: 38 ± 10 yr, BMI: 37 ± 6 kg/m2, AHI: 1 ± 2) completed three, 20‐min bouts of constant‐load submaximal cycling exercise (8 min rest, 6 min at 10 and 30 W) with or without added external dead space (200 or 400 ml; 20 min rest between bouts). Steady state measurements were made of O2, CO2, minute ventilation ( E) and end‐tidal PCO2 (PETCO2). The exercise ventilatory response was defined as the slope of the E‐ CO2 relationship (Δ E/Δ CO2).ResultsIn control (i.e. no added dead space), the exercise ventilatory response was not significantly different between non‐OSA and OSA groups (slope: 30.5 ± 4.2 and 30.5 ± 3.8, p > 0.05); PETCO2 did not differ from rest to exercise in either group (p > 0.05). In the trials with added external dead space, no significant differences between groups were observed. Δ E/Δ CO2 increased with increasing dead space (p < 0.05); PETCO2 increased with increasing dead space and exercise intensity (interaction p < 0.05); however, the change in PETCO2 from rest to exercise remained small (<2 mmHg) in both groups, demonstrating STM.ConclusionsContrary to our hypotheses: 1) the exercise ventilatory response is not different between obese OSA patients and otherwise healthy obese adults, and 2) the capacity for STM with added dead space is not different between groups. Thus, the capacity for STM is preserved in OSA.Support or Funding InformationKing Charitable Foundation Trust, Texas Health Presbyterian Hospital, NIH Grant R01 HL096782
Influence of electrical and natural stimulation of pharyngeal/laryngeal sensory afferents on the swallow motor pattern
Authors: King Suzanne , Bolser Donald C. , Rose Melanie J. , Poliacek Ivan , Shen Tabitha Y. , Musselwhite M. Nicholas , Pitts Teresa 
Published: November 2023

Electrical stimulation of the superior laryngeal nerve (ES‐SLN) is a method that is a mainstay to study swallow. Although its efficiency in evoking a swallow motor response has been well proven, it is a deterministic stimulus that is unlike natural stimulation (mechanical/chemical) of the diverse afferent beds lying in aerodigestive tract. We hypothesized that swallowing muscle activity induced by injection of water into the oropharynx would contrast those produced by ES‐SLN. Swallow was evoked in anesthetized spontaneously breathing cats via injection of a 3cc bolus of water, unilateral ES‐SLN (5 and 20Hz), or a combination of 5Hz ES‐SLN with water. Electromyography (EMG) activity (duration, amplitude) was measured concurrently in thyrohyoid, thyropharyngeus (ThPh), mylohyoid, geniohyoid, cricopharyngeus, parasternal, and posterior cricoarytenoid muscles. Significant stimulus‐related effects were observed in ThPh when a stimulus was presented individually, as indicated by increases in mean amplitude with 5Hz ES‐SLN compared to water alone. No differences were found between ES‐SLN (either frequency) compared to a combination of ES‐SLN with water. Additionally, an inverse relationship was apparent between the frequency of the ES‐SLN and the amplitude of ThPh activity. Current results suggest: a) stimulus modality influences the motor pattern of the pharyngeal phase of swallow in an anesthetized animal model and b) frequency dependence of afferent feedback on the spatiotemporal features of some, but not all, swallow‐related motor outputs. Supported by HL 111215, HL 103415, P30‐GM103507.Support or Funding InformationSupported by HL 111215, HL 103415, P30‐GM103507.
The exploration of novel systemic biomarkers of chronic obstructive pulmonary disease with different levels of the severity
Authors: Ishihara Yoko , Nakao Motoyuki 
Published: November 2023

IntroductionThe burden of chronic obstructive pulmonary disease (COPD) is glowing worldwide. COPD is characterized by progressive airflow limitation associated with lung and systemic inflammation, and is caused mainly by cigarette smoking and second‐hand smoke. The present study assessed serum cytokine/chemokine profiles in outpatient with COPD, and in the subject free of respiratory diseases. The purpose of this study is to find out useful biomarker of COPD.MethodSubjects were recruited at the hospital, clinic and healthcare center in Yamaguchi, Nagasaki and Kumamoto prefecture, Japan. 48 patients with COPD and age‐ and sex‐matched control subjects were involved in this study. Serum samples were analyzed using MAGPIX system magnetic‐bead based multi‐analyte (29 analyte) panels.ResultIn the subjects, 35 patients with bronchial asthma occurred with COPD was included. The prevalence of comorbidities such as hypertension and diabetes were not significantly different except for allergic rhinitis, which was only found in the patients group. When compared with the control group, IL‐6, IL‐15, TNFβ, and IP‐10 (CXCL10/interferon‐γ‐inducible protein 10) levels were significantly higher in the patient group. IL‐6 and IL‐15 was not detected in the control group, and TNFβ was only found one subject in the control group. Interestingly, EGF levels were significant higher in the control group than in the patients group although EGF level has been reported to be increased in COPD patients. When the subjects were stratified by the severity of COPD, only IP‐10 showed positive association with the severity of COPD. Current or ex‐smoking also increased IP‐10 levels in the patient group although the difference was not significant because of small sample number of never smokers in the patient group. When the subjects were divided by smoking status, IP‐10 levels in current or ex‐smokers were higher than those in never‐smokers but the difference was not significant.ConclusionsResults obtained in this study showed that differential expression of biomarkers is present in the patients with COPD, and in the control subjects. Large part of these biomarkers showed higher levels by the presence of COPD or experience of smoking. IP‐10 levels were also influenced by the smoking experience, however, the significance was only found in the patient group. These results suggest that serum IP‐10 is one of the promising candidates for novel biomarker of COPD and its severity.Support or Funding InformationThis study was supported by Grants‐in‐Aid for Scientific Research (B) 20406001, 23406001 and (C) 26340053, and a “MEXT‐Supported Program for the Strategic Research Foundation at Private Universities” from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Blocking of EDA‐Fibronectin Attenuates Airway Hyperresponsivenss in a Murine Model of Acute and Chronic Allergen‐Induced Airway Remodeling
Authors: Assayag Miri , Berkman Neville 
Published: November 2023

RationaleAirway remodeling refers to changes in the structural components of the airway wall such as subepithelial fibrosis, increased myofibroblasts and increased airway smooth muscle. Airway hyperresponsiveness (AHR) is a defining feature of asthma and may be attributable to the presence of airway remodeling. Fibronectin is a 440‐kd dimeric major ECM glycoprotein that plays a regulatory role during embryogenesis, wound healing and maintenance of tissue integrity. EDA‐FN is a splice variant of fibronectin. Increased levels of EDA‐FN were reported in the lungs of asthmatic patients and of allergen exposed mice. We have previously shown that EDA −/− mice exposed to chronic allergen challenge have attenuated airway fibrosis and AHR.AimTo determine whether blocking the EDA‐FN in‐vivo in wild type mice (genetically “intact”) attenuates the development of airway remodeling and airway hyperresponsiveness in a murine model of acute and chronic allergen‐induced “asthma”.MethodsBALB/c female mice (6 groups, 5–10/group) were exposed to saline (Sal) or ovalbumin (OVA) (intraperitoneal sensitization followed by inhalations on alternate days for 1 or 4 weeks). Three of the groups received intraperitoneal EDA‐FN blocking antibody (every 5 days) beginning prior to sensitization. AHR in response to methacholine (Flexivent), bronchoalveolar lavage (BAL) cell counts and histological evaluation (H&E, Masson Trichrome) was performed 24h after the last inhalation followed by collagen content and cytokine expression in the lung tissue.ResultsOVA treated mice showed a significant increase in AHR (airway resistance) in both the acute (relative to baseline: 4.12±0.48) and chronic (3.93±0.36) groups in comparison with saline treated mice (2±0.1) and this increase was abolished by EDA‐FN blocking antibody in acute OVA treated mice (2.76±0.24, p<0.03), but not in the chronic model (OVA 3.93±0.36 vs OVA+Ab EDA‐FN 4.06±0.35). OVA exposed mice had marked BAL eosinophilia (acute: 77.5±2.8% and chronic 57.5±2.8%) that was significantly lowered by anti EDA‐FN treatment (58.8±3% acute and 39.3±3.2% chronic, p<0.001 for both acute and chronic) while antibody treatment alone was similar to saline. Histologic evaluation also showed less peribronchial inflammation in the acute model in response to blocking antibody but no reduction in the chronic model. The increase in lung collagen content seen in response to chronic OVA‐exposure was completely abolished in the presence of anti EDA‐FN antibody (93.4±4.6 mg collagen/50 mg tissue vs. 56.3±2.9 mg collagen/50 mg tissue, p<0.001 compared to SAL 66±7.6 mg collagen/50 mg tissue).ConclusionsIn a murine model of allergen induced “asthma”, inhibition of EDA‐FN attenuates airway hyperresponsiveness, airway fibrosis and airway inflammation, however these effects vary, depending on chronicity of allergen and antibody exposure.Support or Funding InformationIsrael Science Foundation
Estrogen Interferes with Cigarette Smoke Exposure‐Induced Proliferation in Human Airway Smooth Muscle Cells
Authors: Wang Shengyu , Goorhouse Katelyn J , Freeman Michelle R , Pabelick Christina M , Prakash Y.S. , Sathish Venkatachalem 
Published: November 2023

IntroductionAsthma is acutely aggravated and chronically worsened by cigarette smoke (CS), as well as secondhand smoke exposure. In this regard, studies show significant differences between women vs. men in their response to the detrimental effects of CS, suggesting that female sex steroids (particularly estrogen) may be involved. Airway smooth muscle (ASM) cell proliferation and airway remodeling is a key feature of asthma and COPD. Surprisingly, there is little information regarding sex steroid effects on cigarette smoke‐induced changes of airway structure and function. In the current study, we hypothesize that estrogen interferes with CSE exposure‐induced proliferation, thereby contributing to airway smooth muscle remodeling.Methods and ResultsHuman ASM tissues (epithelium‐denuded) and isolated ASM cells were from lung samples of patients with known smoking histories undergoing thoracic surgery for non‐infectious, focal pathology. Exposure of human ASM to cigarette smoke extract (CSE, Kentucky research cigarette 1RF4) 1%CSE or 2%CSE for 24h significantly increased ASM proliferation (proliferation assay: Cell Titer Aueous One, and Cyquant). Exposure of physiological concentrations of 17‐β‐estradiol (E2, 1nM) did not alter ASM proliferation at baseline. Interestingly, E2 pre‐treatment (1 h prior to CSE exposure) significantly reduced CSE‐induced human ASM proliferation. This was further confirmed by Western blot analysis for proliferative markers PCNA and Cyclin E. In addition, to explore the mechanistic bases of differential effects of E2 on ASM proliferation under basal and CSE‐exposed conditions, the estrogen receptor profile in ASM tissue was screened in parallel for patients with and without smoking histories. Human ASM tissue from smokers samples showed substantial increased ERα and β expression compared to non‐smokers. Inhibition of ERα and β prevented the effects of estrogen on CSE‐induced increases in proliferation.ConclusionsCollectively, estrogen exposure decreased human ASM proliferation induced by CSE. ER expression and signaling is enhanced in CSE induced inflamed ASM, with a potential beneficial role in reducing remodeling with CS exposure. These results will lay the foundation for examining the role of estrogen signaling in pathogenesis of cigarette smoke‐induced airway remodeling and possible sex based therapeutic targets in smoking‐related diseases.Support or Funding InformationSupported by Flight Attendants Medical Research Institute (VS) and NIH R01 grant HL123494 (VS)
EP1 Receptor Agonists Augment Hyperoxia‐Induced Airway Hyperresponsiveness
Authors: Sopi Ramadan B , Neziri Burim , Mladenov Mitko , Vela Driton , Lajçi Njomza , Thaqi Qendrim , Bislimi Kemajl , Jakupaj Muharrem , Lajçi Azem 
Published: November 2023

Neonatal hyperoxia is associated with airway hyperresponsiveness. It was shown that hyperoxia upregulates prostaglandin E2 synthesis, which has contrasting physiological effects depending on subtypes of receptors and other conditions. We tested the hypothesis that EP1 receptors are involved in airway hyperresponsiveness induced by hyperoxia. Tracheal cylinders were obtained from 12 days Wistar rat pups exposed to hyperoxia (≥ 95% O2) or room air for seven days. These cylinders were used to study contractile responses of airway smooth muscle evoked by methacholine (MCh, 10−8 – 10−4 M) or electrical field stimulation (EFS, 0.5 – 62 Hz) in absence or presence of EP1 agonists (17‐phenyl‐trinor‐PGE2 (analog of PGE2), 1 μM; or PGE2, 1 μM) or an EP1 antagonist (SC19920, 10 μM). MCh and EFS induced dose‐dependent and frequency‐dependent contractile responses of airway smooth muscle, respectively. The contractile responses were significantly higher in preparations obtained from animals exposed to hyperoxia as compared to those obtained from controls exposed to room air, and these enhanced contractile responses in hyperoxic tissues were augmented in presence of EP1 agonists (17‐PGE2 or PGE2), but significantly attenuated by the EP1 antagonist (SC19920). The results of this study revealed that PGE2 – EP1 receptor signaling pathway contributes to hyperoxia‐induced airway hyperresponsiveness and we speculate that the use of EP1 antagonists might be an effective therapeutic approach to reverse the hyperoxia‐induced enhanced contractile responses of airway smooth muscle.Support or Funding InformationSupported by MEST
PGE2 – EP3 Receptor Signaling Involves Rho‐kinase Pathway in Hyperoxia‐Induced Airway Hyperresponsiveness
Authors: Neziri Burim , Sopi Ramadan B , Dreshaj Ismail A , Beqiraj Qendresa , Cenaj Asllan , Kurtishi Ilir , Krasniqi Avdyl , Dreshaj Shemsedin , Jakupaj Muharrem 
Published: November 2023

Hyperoxic exposure is associated with airway hyperresponsiveness and it was shown that hyperoxia upregulates synthesis of prostaglandin E2 (PGE2), which induces contraction of airway smooth muscle via EP1 and EP3 receptors. It is not clear through which signaling pathway PGE2 exerts contractile effect on airway smooth muscle under hyperoxic conditions. Therefore, we hypothesized that under hyperoxic condition PGE2 induces contraction of airway smooth muscle via EP3 receptors by activating Rho‐kinase signaling pathway. Tracheal cylinders were obtained from 12 days Wistar rat pups exposed to hyperoxia (≥ 95% O2) or room air for seven days. These cylinders were used to study contractile responses evoked by EP3 agonist (sulprostone, 10−9 – 10−5 M); methacholine (MCh, 10−8 – 10−4 M) in absence or presence of an EP3 antagonist (L‐798106, 10 μM) or Rho‐kinase inhibitors (Y‐27632, 10 μM or fasudil, 10 μM).Both, sulprostone and MCh induced dose‐dependent contractile responses of airway smooth muscle, respectively. The contractile responses were significantly higher in preparations obtained from animals exposed to hyperoxia as compared to those obtained from room air controls. These enhanced contractile responses in hyperoxic tissues were reversed by pre‐incubating tissues with Y‐27632 or fasudil. EP3 antagonist also significantly attenuated contractile responses evoked by sulprostone. The results of this study revealed that PGE2 – EP3 receptor signaling involves Rho‐kinase pathway and we speculate that the use of Rho‐kinase inhibitors or EP3 antagonist could attenuate the contractile effects of PGE2 and this might be an effective therapeutic approach to reverse hyperoxia‐induced airway hyperresponsiveness.Support or Funding InformationSupported by MEST