Pulmonary Airway Resistance Research Articles

Effects of cyanate on pulmonary epithelial cells and pulmonary function in mice

To investigate the injury of cyanate on the pulmonary function and morphology of C57/BL6N mice. Forty male C57/BL6N mice were randomly divided into two groups: normal control group (20 mice) and cyanate group (20 mice). Mice were exposed to 100 mmol/L cyanate feeding for 4 weeks, and pulmonary Raw (Resistance in Air Way) was measured at the beginning and end of the experiment. The mice were sacrificed at the end of the fourth week of the experiment, and the lung tissues were collected for pathological observation and molecular detection of E-Cadherin and Fibronectin. Well-growing A549 cells in logarithmic growth phase were treated with cyanate at the concentrations of 0, 0.25, 0.5 and 1 mmol/L for 24 h, and the cell viability was detected by CCK8 method; reactive oxygen species ROS fluorescent probe (DCFH-DA) was used to detect the changes of ROS levels, and expressions of E-Cadherin and Fibronectin in cells and pulmonary tissues were detected by Western blot. At the beginning of the experiment, the pulmonary airway resistance values of the mice in the normal control group and the cyanate group were (1.82±0.76)cmH2O/(L·s) and (1.85±0.78)cmH2O/(L·s), respectively, with no significant difference. Four weeks later, the pulmonary airway resistance value of mice in the cyanate group was increased to (4.86±0.87)cmH2O/(L·s) (P＜0.01). The HE staining showed that, compared with the normal control group, the injured alveolar structure, the thickened tracheal wall and the significantly proliferated pulmonary interstitial tissue were observed in the cyanate group. The Masson staining showed that elastic fibers were deposited around the trachea of mice in the cyanate group. The results of CCK8 assay for the viability of A549 cells showed that 0.5 mmol/L cyanate exposure could reduce the viability (P＜0.01). The immunofluorescence staining showed that cyanate could increase ROS level in A549 cells by producing green fluorescence in a concentration-dependent manner. The results of Western blotting showed that 0.5 mmol/L of cyanate treatment on A549 cells could reduce the expression of E-Cadherin (P＜0.01) with increasing concentration of cyanate. The expression level of Fibronectin in A549 cells was increased with the increasing cyanate concentration, and there was a significant difference (P＜0.01) on 1 mmol/L cyanate. Western blot results of lung showed the decreasing expression of E-Cadherin (P＜0.01) and increasing expression of Fibronectin (P＜0.01) in cyanate mice. Pathological concentrations of cyanate can induce the proliferation of pulmonary interstitial tissue, fibrous deposition, and increased pulmonary airway resistance in mice, which may be related to damaged pulmonary epithelial cell viability, enhanced ROS production, and induced pathologic changes of extracellular matrix by cyanate.

Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC

BackgroundOxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential.MethodsWe aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592).ResultsMosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model.ConclusionInhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

HDAC6 Activates ERK in Airway and Pulmonary Vascular Remodeling of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a multisystemic respiratory disease that is associated with progressive airway and pulmonary vascular remodeling due to the increased proliferation of bronchial smooth muscles cells (BSMCs) and pulmonary arterial smooth muscle cells (PASMCs) and the overproduction of extracellular matrix (e.g., collagen). Cigarette smoke (CS) and several mediators, such as PDGF (platelet-derived growth factor) and IL-6, play critical roles in COPD pathogenesis. HDAC6 has been shown to be implicated in vascular remodeling. However, the role of airway HDAC6 signaling in pulmonary vascular remodeling in COPD and the underlying mechanisms remain undetermined. Here, we show that HDAC6 expression is upregulated in the lungs of patients with COPD and a COPD animal model. We also found that CS extract (CSE), PDGF, and IL-6 increase the protein levels and activation of HDAC6 in BSMCs and PASMCs. Furthermore, CSE and these stimulants induced deacetylation and phosphorylation of ERK1/2 and increased collagen synthesis and BSMC and PASMC proliferation, which were outcomes that were prevented by HDAC6 inhibition. Inhibition of ERK1/2 also diminished the CSE-, PDGF-, and IL-6-caused elevation in collagen levels and cell proliferation. Pharmacologic HDAC6 inhibition with tubastatin A prevented the CS-stimulated increases in the thickness of the bronchial and pulmonary arterial wall, airway resistance, emphysema, and right ventricular systolic pressure and right ventricular hypertrophy in a rat model of COPD. These data demonstrate that the upregulated HDAC6 governs the collagen synthesis and BSMC and PASMC proliferation that lead to airway and vascular remodeling in COPD.

ILC3-derived acetylcholine promotes protease-driven allergic lung pathology

ILC3-derived acetylcholine promotes protease-driven allergic lung pathology

Lung function parameters in patients with gastroesophageal reflux without respiratory symptoms: a case-control study.

This research aimed to evaluate the effect of gastroesophageal reflux disease (GERD) on pulmonary volumes, airflows, and airway resistance in the patients without respiratory symptoms and compare them with the healthy subjects. GERD is the return of gastric content into the esophagus and beyond. GERD may play an essential role in the extraesophageal diseases, including chest pain, asthma, laryngitis, chronic cough, and sinusitis. The relation between GERD and airway involvement in asthma and also bronchoconstrictor effects of GERD are well recognized, but its impact on lung parameters in the patients with GERD without respiratory symptoms is unclear. In a case-control study, 78 GERD patients without pulmonary symptoms and 93 healthy subjects as control group were enrolled. The impulse oscillometry examined airway resistance. The body plethysmograph measured the pulmonary volumes and airflows. The mean age of GERD patients and the healthy subjects were 37.30±9.76 and 34.74±11.10, respectively. A total of 53.8% of patients and 67.7% of healthy subjects were male. The lung volumes measured by the body plethysmography were normal in both patients and healthy subjects. However, there was a significant difference between the groups in forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) (P=0.01) and maximal mid expiratory flow (MMEF) (P=0.008). Airway resistance at R5Hz was significantly higher in the case group than the control group (P=0.001). The results of the current study demonstrated that GERD patients have small airway disease even in the absence of respiratory symptoms.

Pulmonary Dead Space Fraction and Extubation Success in Children After Cardiac Surgery.

1) Determine the correlation between pulmonary dead space fraction and extubation success in postoperative pediatric cardiac patients; and 2) document the natural history of pulmonary dead space fractions, dynamic compliance, and airway resistance during the first 72 hours postoperatively in postoperative pediatric cardiac patients. A retrospective chart review. Cardiac ICU in a quaternary care free-standing children's hospital. Twenty-nine with balanced single ventricle physiology, 61 with two ventricle physiology. None. We collected data for all pediatric patients undergoing congenital cardiac surgery over a 14-month period during the first 72 hours postoperatively as well as prior to extubation. Overall, patients with successful extubations had lower preextubation dead space fractions and shorter lengths of stay. Single ventricle patients had higher initial postoperative and preextubation dead space fractions. Two-ventricle physiology patients had higher extubation failure rates if the preextubation dead space fraction was greater than 0.5, whereas single ventricle patients had similar extubation failure rates whether preextubation dead space fractions were less than or equal to 0.5 or greater than 0.5. Additionally, increasing initial dead space fraction values predicted prolonged mechanical ventilation times. Airway resistance and dynamic compliance were similar between those with successful extubations and those who failed. Initial postoperative dead space fraction correlates with the length of mechanical ventilation in two ventricle patients but not in single ventricle patients. Lower preextubation dead space fractions are a strong predictor of successful extubation in two ventricle patients after cardiac surgery, but may not be as useful in single ventricle patients.

Short-term effects of fine particulate matter exposure on pulmonary function in healthy young adults: a time series study

Objective: To explore the short-term effects of fine particulate matter (PM2.5) exposure on pulmonary function of healthy young adults in Beijing. Methods: In this time series study, twenty-four healthy young adults who living around Guanyuan area were investigated in Beijing. The follow-up study was lasted for 12 days in total from Nov. 28, 2016 to Dec. 9, 2016, and pulmonary spirometry and inpulse oscillometry parameters were measured daily. Air pollution data (including PM2.5, etc.) and meteorological data (temperature, humidity, etc.) were monitored based on Guanyuan monitoring site. The short-term effects of PM2.5 on pulmonary ventilation function and airway resistance of healthy young adults were analyzed by using generalized estimating equation (GEE). Results: In our study period, average daily concentration of PM2.5 were 100.7 μg/m(3). The single pollutant model showed that there were negative dose-response associations between PM2.5 concentration and forced vital capacity (FVC) and forced expiratory volume in one second (FEV(1)); and there were negatively correlated with daily mean level of PM2.5 lagged 0-1 days, and the strongest negative effect was in lag0. At lag0 day, each 10 μg/m(3) increase in PM2.5 concentration was associated with a significant decrease in FVC of 12.186 (95% CI: -15.573, -8.799) ml and in FEV(1) of 9.449 (95% CI: -13.265, -5.634) ml. Moreover, there were positive dose-response associations between PM2.5 concentration at lag0 to lag2 and peripheral resistance (Rp) , resonance frequency (Fres) and the fall in resistance between resistance at 5 Hz (R5) and resistance at 20 Hz (R20) (R(5-20)). And the strongest negative effect was in lag0. Each 10 μg/m(3) increase in PM2.5 concentration was associated with a significant increase in Rp of 2.444 (95% CI: 0.889, 3.999) Pa·L(-1)·s(-1) , Fres of 0.125 (95% CI: 0.082, 0.168) Hz and R(5-20) of 1.074 (95% CI: 0.444, 1.703) Pa·L(-1)·s(-1) at lag0 day. Conclusion: Short-term PM2.5 exposure has a negative and lagged effect on pulmonary function in healthy young adults.

Mutating the CX3C Motif in the G Protein Should Make a Live Respiratory Syncytial Virus Vaccine Safer and More Effective.

Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Through a CX3C chemokine motif (182CWAIC186) in the G protein, RSV binds to the corresponding chemokine receptor, CX3CR1. Since RSV binding to CX3CR1 contributes to disease pathogenesis, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A186, within the CX3C motif, mutating it to CX4C (182CWAIAC187), which is known to block binding to CX3CR1, might decrease disease. We studied the effect of the CX4C mutation in two strains of RSV (A2 and r19F) in a mouse challenge model. We included RSV r19F because it induces mucus production and airway resistance, two manifestations of RSV infection in humans, in mice. Compared to wild-type (wt) virus, mice infected with CX4C had a 0.7 to 1.2 log10-fold lower virus titer in the lung at 5 days postinfection (p.i.) and had markedly reduced weight loss, pulmonary inflammatory cell infiltration, mucus production, and airway resistance after challenge. This decrease in disease was not dependent on decrease in virus replication but did correspond to a decrease in pulmonary Th2 and inflammatory cytokines. Mice infected with CX4C viruses also had higher antibody titers and a Th1-biased T cell memory response at 75 days p.i. These results suggest that the CX4C mutation in the G protein could improve the safety and efficacy of a live attenuated RSV vaccine.IMPORTANCE RSV binds to the corresponding chemokine receptor, CX3CR1, through a CX3C chemokine motif (182CWAIC186) in the G protein. RSV binding to CX3CR1 contributes to disease pathogenesis; therefore, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A186, within the CX3C motif, mutating it to CX4C (182CWAIAC187), known to block binding to CX3CR1, might decrease disease. The effect of this mutation and treatment with the F(ab')2 form of the anti-RSV G 131-2G monoclonal antibody (MAb) show that mutating the CX3C motif to CX4C blocks much of the disease and immune modulation associated with the G protein and should improve the safety and efficacy of a live attenuated RSV vaccine.

Therapeutic Effect of Whole Lung Lavage on Pneumoconiosis

Pneumoconiosis as an occupational disease is a serious threat to the health of workers. Patients with pneumoconiosis are mainly engaged in dust-related work such as gold, coal, or iron mining, electric welding, or road work, and present with miliary nodules, fuse mass-like opacities, and cavity lesions on chest imaging. Clinical manifestations of pneumoconiosis include progressive chest tightness, dyspnoea, chest pain, coughing, expectoration, fever, and hypodynamia. Pneumoconiosis patients are prone to respiratory tract infections (including bacterial pneumonia and tuberculosis) because of poor disease resistance and will eventually lose the ability to work and fully function in daily life completely. Patients can lose their life because of complications such as pulmonary heart disease and respiratory failure. Disease prevention is the main method to control pneumoconiosis. We retrospectively analysed 516 cases of pneumoconiosis patients receiving whole lung lavage (WLL) procedure from May 2009–January 2015. The symptoms, pulmonary function, chest computed tomography manifestations, and living status were reviewed carefully. The improvement rate of chest tightness, chest pain, and dyspnoea was 99%, 90%, and 98%, respectively, 7 days after WLL procedure. The symptoms had improved in 235 patients at 3–6 months postoperatively. The therapeutic effect remained stable in 56 cases after 4–5 years. Chest tightness, chest pain, and dyspnoea were improved significantly, and pulmonary diffusion function and small airway resistance also improved. There was no progress in 62 patients 4–5 years postoperatively, as indicated by the chest computed tomography examination. Overall, WLL treatment is an effective method for treating pneumoconiosis.

Air pollution and pulmonary health: Effects of short-term indoor air quality intervention with portable air purifier

Introduction: Chronic ambient air pollution exposure is known to adversely affect health outcomes. While it will take a long time to improve the outdoor air quality in China, using an indoor air purifier can produce immediate reductions in indoor air pollution. This study aims to investigate the impacts of overnight use of an indoor air purifier on cardiopulmonary health. Methods: Seventy-two healthy non-smoking students were recruited into a randomized, double-blind crossover study. Between November to December 2015, each subject received 2 overnight 13-19-hour interventions consisting of a True filtration and a Sham filtration (purifiers with or without a HEPA filter and an active carbon filter) with a 2-week washout period in-between. Cardiopulmonary health parameters were assessed through spirometry for lung function, impulse oscillometry (IOS) for airway resistance and elastance, Vicorder for arterial stiffness, and biomarkers of inflammation, oxidative stress, and hemostasis. Results: The median outdoor PM2.5 level during the study was 47 µg/m3 (Q1-Q3 range: 30.7 µg/m3, 70.0 µg/m3). A preliminary analysis was done using a mixed effect linear model with the subject as the random effect. Pulmonary health impacts of True and Sham filtrations were compared as reflected in the change of each biomarker from “before” to “after” intervention. Compared to Sham filtration, True filtration was shown to significantly lower pulmonary impedance (Z5) by 0.16 (P=0.048) and airway resistance R10 by 0.138 (P=0.043). No significant changes in other impulse oscillometry measurements (R5-R20, X5, Fres), exhaled nitric oxide, and spirometry parameters (including FEV1, FVC, FEV1/FVC, and PEF) were observed. Conclusion: Under a moderate level of ambient air pollution, overnight use of an air purifier significantly reduces pulmonary impedance and airway resistance at 10Hz. Further analysis of the targeted molecular biomarkers is underway.

Effect of Ultrafiltration on Pulmonary Function and Interleukins in Patients Undergoing Cardiopulmonary Bypass.

To evaluate the effect of ultrafiltration on interleukins, TNF-α levels, and pulmonary function in patients undergoing coronary artery bypass grafting (CABG). Prospective, randomized, controlled trial. University hospital. Forty patients undergoing CABG were randomized into a group assigned to receive ultrafiltration (UF) during cardiopulmonary bypass (CPB) or into another group (control) that underwent the same procedure but without ultrafiltration. Interleukins and TNF-α levels, pulmonary gas exchange, and ventilatory mechanics were measured in the preoperative, intraoperative, and postoperative periods. Interleukins and TNF-α also were analyzed in the perfusate of the test group. There were increases in IL-6 and IL-8 at 30 minutes after CPB and 6, 12, 24, and 36 hours after surgery, along with an increase in TNF-α at 30 minutes after CPB and 24, 36, and 48 hours after surgery in both groups. IL-1 increased at 30 minutes after CPB and 12 hours after surgery, while IL-6 increased 24 and 36 hours after surgery in the UF group. The analysis of the ultrafiltrate showed the presence of TNF-α and traces of IL-1β, IL-6, and IL-8. There were alterations in the oxygen index, alveolar-arterial oxygen difference, deadspace, pulmonary static compliance and airway resistance after anesthesia and sternotomy, as well as in airway resistance at 6 hours after surgery in both groups, with no difference between them. Ultrafiltration increased the serum level of IL-1 and IL-6, while it did not interfere with gas exchange and pulmonary mechanics in CABG.

Pulmonary C‐Fibers (PCFs) Are Essential for Airway Inflammation (AI) and Hyperreactivity (AHR) Induced by Respiratory Syncytial Virus (RSV) Infection

RSV infection causes acute AI and AHR with the peak response occurring at ~5th day postinfection (PID 5) in humans and animals. Owing to the critical role of PCFs in regulating pulmonary inflammation and airway resistance, we tested the contribution of PCFs to these RSV‐induced disorders. These RSV‐induced disorders are reportedly dependent on increased IFN‐γ in our previous study. IFN‐γ could activate C‐fibers and the latter affect the production of the former. Thus, we asked whether PCFs were required in IFN‐γ upregulation by RSV and the IFN‐γ‐mediated AI and AHR. RSV and mock were instilled intranasally in PCF‐intact (CON) and PCF‐degenerated (KPCF) mice. On PID 5, we measured specific airway resistance (sRaw) in awake state and collected lung tissues after euthanasia for detecting BALF inflammatory cells, the lung viral titration, substance P (SP), IFN‐γ and its transcription factor (T‐bet) gene expressions. Compared with CON, KPCF mice showed significant decreases in: (1) weight loss and RSV titer in the lungs; (2) total cells and macrophages in BALF with little change in lymphocytes; (3) inflammatory cells infiltrated in the lungs; (4) the sRaw response to aerosol of methacholine (3.125 ‐ 50 mg/ml); and (5) SP. In addition, the augmented IFN‐γ and T‐bet by RSV infection was not significantly different between the two groups of mice. However, recombinant IFN‐γ (ip) induced AHR in the CON, but not KPCF mice. Our results suggest that PCFs play an important role in RSV replication, the RSV‐induced AI and AHR. Moreover, PCFs were required for IFN‐γ‐promoted AI and AHR (Supported by HL119683).

Respiratory toxicity of repeated exposure to particles produced by traffic and sugar cane burning

We compared the toxicity of subchronic exposure to equivalent masses of particles from sugar cane burning and traffic. BALB/c mice received 3 intranasal instillations/week during 1, 2 or 4 weeks of either distilled water (C1, C2, C4) or particles (15μg) from traffic (UP1, UP2, UP4) or biomass burning (BP1, BP2, BP4). Lung mechanics, histology and oxidative stress were analyzed 24h after the last instillation. In all instances UP and BP groups presented worse pulmonary elastance, airway and tissue resistance, alveolar collapse, bronchoconstriction and macrophage influx into the lungs than controls. UP4, BP2 and BP4 presented more alveolar collapse than UP1 and BP1, respectively. UP and BP had worse bronchial and alveolar lesion scores than their controls; BP4 had greater bronchial lesion scores than UP4. Catalase was higher in UP4 and BP4 than in C4. In conclusion, biomass particles were more toxic than those from traffic after repeated exposures.

Nasal versus oronasal raised volume forced expirations in infants—A real physiologic challenge

Raised volume rapid thoracoabdominal compression (RTC) generates forced expiration (FE) in infants typically from an airway opening pressure of 30 cm H(2)O (V(30)). We hypothesized that the higher nasal than pulmonary airway resistance limits forced expiratory flows (FEF(%)) during (nasal) FE(n), which an opened mouth, (oronasal) FE(o), would resolve. Measurements were performed during a brief post-hyperventilation apnea on 12 healthy infants aged 6.9-104 weeks. In two infants, forced expiratory (FEFV) flow volume (FV) curves were generated using a facemask that covered the nose and a closed mouth, then again with a larger mask with the mouth opened. In other infants (n = 10), the mouth closed spontaneously during FE. Oronasal passive expiration from V(30) generated either the inspiratory capacity (IC) or by activating RTC before end-expiration, the slow vital capacity ((j) SVC). Peak flow (PF), FEF(25), FEF(50), FEF(25-75), FEV(0.4), and FEV(0.5) were lower via FE(n) than FE(o) (P < 0.05), but the ratio of expired volume at PF and forced vital capacity (FVC) as percent was higher (P < 0.05). FEF(75), FEF(85), FEF(90), FVC as well as the applied jacket pressures were not different (P > 0.05). FEFV curves generated via FE(o) exhibited higher PF than FV curves of IC (P < 0.05); PF of those produced via FE(n) were not different from FV curves of IC (P > 0.05) but lower than those of (j) SVC (P < 0.05). In conclusion, the higher nasal than pulmonary airways resistance unequivocally affects the FEFV curves by consistently reducing PF and decreases mid-expiratory flows. A monitored slightly opened mouth and a gentle anterior jaw thrust are physiologically integral for raised volume RTC in order to maximize the oral and minimize nasal airways contribution to FE so that flow limitation would be in the pulmonary not nasal airways.

Protease inhibitor nafamostat mesilate attenuates complement activation and improves function of xenografts in a discordant lung perfusion model

Anti-complement activity of nafamostat mesilate (FUT-175) is strong including its variety of pharmacological effects. The effect of FUT-175 for xenografts in an ex vivo guinea pig-to-rat lung perfusion model was evaluated. Heparinized Lewis rat blood was used to perfuse the lungs in three groups (n = 6 each). Group I used Lewis rat left lung for donor, Group X used guinea pig left lung for donor, and Group XF used guinea pig left lung for donor, which was perfused with Lewis rat blood with 0.2 mg/ml of FUT-175. Complement activity causing 50% hemolysis (CH50) in the perfusion blood and pulmonary function either before or during perfusion were serially measured. Pathological assessments of the lungs were also carried out after perfusion. The duration of satisfactory pulmonary function was significantly increased in Group XF. Complement activity causing 50% hemolysis in Group XF decreased more significantly compared to Group X. FUT-175 suppressed both the increase in pulmonary arterial pressure and airway resistance, and the decrease in dynamic lung compliance. In Group X, pathology showed intra-alveolar hemorrhage, perivascular edema, and medial thickening with endothelial swelling of the pulmonary arteries. In Group XF, less changes were observed compared to Group X. Group X showed deposition of IgM, IgG, and C3 at the endothelium of arteries, which was fewer in Group XF, and even fewer in Group I. This study suggests that FUT-175 inhibited complement activation and improved lung xenograft function. FUT-175 ameliorates hyperacute rejection in a guinea pig-to-rat ex vivo xenogeneic lung perfusion model.

D-4F, an apoA-1 mimetic, decreases airway hyperresponsiveness, inflammation, and oxidative stress in a murine model of asthma

Asthma is characterized by oxidative stress and inflammation of the airways. Although proinflammatory lipids are involved in asthma, therapies targeting them remain lacking. Ac-DWFKAFYDKVAEKFKEAFNH(2) (4F) is an apolipoprotein (apo)A-I mimetic that has been shown to preferentially bind oxidized lipids and improve HDL function. The objective of the present study was to determine the effects of 4F on oxidative stress, inflammation, and airway resistance in an established murine model of asthma. We show here that ovalbumin (OVA)-sensitization increased airway hyperresponsiveness, eosinophil recruitment, and collagen deposition in lungs of C57BL/6J mice by a mechanism that could be reduced by 4F. OVA sensitization induced marked increases in transforming growth factor (TGF)β-1, fibroblast specific protein (FSP)-1, anti-T15 autoantibody staining, and modest increases in 4-hydroxynonenal (4-HNE) Michael's adducts in lungs of OVA-sensitized mice. 4F decreased TGFβ-1, FSP-1, anti-T15 autoantibody, and 4-HNE adducts in the lungs of the OVA-sensitized mice. Eosinophil peroxidase (EPO) activity in bronchial alveolar lavage fluid (BALF), peripheral eosinophil counts, total IgE, and proinflammatory HDL (p-HDL) were all increased in OVA-sensitized mice. 4F decreased BALF EPO activity, eosinophil counts, total IgE, and p-HDL in these mice. These data indicate that 4F reduces pulmonary inflammation and airway resistance in an experimental murine model of asthma by decreasing oxidative stress.

Impact of Ambient Air Pollution on the Respiratory Health of Children With Sickle Cell Anemia in Atlanta, Georgia

O-29C4-4 Background/Aims: Children with sickle cell disease (SCD) comprise a potentially susceptible, yet largely unstudied, sub-group. SCD is an inherited, autosomal recessive blood disorder and is one of the most prevalent genetic disorders in the United States. The aim of the pilot study is to determine if elevated concentrations of personal exposures to air pollutants are associated with adverse respiratory health effects in children with SCD. To our knowledge, this is the first panel study in the United States, examining these potential associations in this population. Methods: We conducted a panel study of 7 homozygous children with SCD in Atlanta, GA from 2008–2009. Repeated measurements of 24-hour integrated personal exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were collected for 2 seasons, with 12 samples per season. Before and after each sampling period, children underwent an assessment of their pulmonary inflammatory response, airway resistance, and respiratory symptoms. Lung function data were also collected at the beginning and end of each week. Results: The mean age of the participants was 9 years (range: 7–12 years). Preliminary 24- hour mean personal PM2.5 and NO2 exposure concentrations were 15.0 ± 25.5 μg/m3 and 0.23 ± 0.14 ppm, respectively. Exhaled nitric oxide measurements for all participants ranged from <5 to 57.5 ppb. Overall, daily NO2 concentrations were strong (r = 0.77) and positively correlated with exhaled nitric oxide measurements made after the sampling period. Exhaled nitric oxide was negatively correlated with PM2.5. When examined by child, correlations were moderate-to-strong (r < 0.80) but varied by pollutant. Conclusion: The initial findings suggest that associations exist between children's exhaled nitric oxide levels and exposures to PM2.5 and NO2. Complete analysis, including lung function and other markers of airway inflammation and resistance will also be presented to help elucidate the variability and the strength of this association among the children.

Oral contraceptive pills decrease pulmonary airway resistance in healthy north Indian women

Oral contraceptive pills (OCPs) are hormonal pills used by females to prevent conception; they are a combination of estrogen and progestin. There is, however, compelling evidence that throughout the reproductive life of a woman, her airways are subject to the influence of the cyclical variations in sex hormones which occur in relation to circadian rhythms. The present study has been designed to investigate the effects of OCPs on airway resistance in terms of spirometric parameters in OCP users and nonusers. A total of 100 women (age: 20-40 years) ware selected for the present study. The subjects were provided with a one-month supply of OCPs. The constituents per tablet of MALA-N used were levonorgestrel 0.15 mg and ethinylestradiol 0.03 mg. Peak expiratory flow rate (PEFR), forced expiratory flow in expiring 25-75% air (FEF 25-75), forced expiratory volume percentage in one second (FEV1% or FEV1/FVC), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) were recorded. In our study, the FEF 25-75and PEFR increased significantly in OCP users, showing that these hormone pills decrease the resistance offered by small bronchioles.

The effects of inhalation salbutamol administration on systemic and pulmonary hemodynamic, pulmonary mechanics and oxygen balance during general anaesthesia in the horse

This research aimed to determine the effect of aerosolized salbutamol administration on systemic and pulmonary hemodynamic, pulmonary mechanics and oxygen balance in healthy horses during general anaesthesia. Six healthy Thoroughbreds (body weight range 471&amp;ndash;587 kg) underwent two general anaesthesias in dorsal recumbency with and without aerosolized salbutamol administration in randomized order with a one month washout period. The anaesthesia was induced by 1.1 mg/kg of xylazine, 0.02 mg/kg of diazepam and 2.2 mg/kg of ketamine, maintained with isoflurane in oxygen and air and horses were mechanically ventilated. Measurement of arterial and pulmonary arterial blood pressures, cardiac output and arterial and mixed venous blood gas analysis was carried out. Spirometry was performed using a Horse-lite. After achieving a steady state, baseline (T&lt;sub&gt;0&lt;/sub&gt;) values of cardiac output, systemic and pulmonary arterial blood pressures, heart rate, dynamic compliance, airway resistance and arterial and mixed venous blood gas values and pH were recorded in both groups. In the S-group (salbutamol), 2 &amp;micro;g/kg of aerosolized salbutamol were administered synchronously with inspirium into the tracheal tube. In both groups data were recorded at 15, 30, 45 and 60 min (T&lt;sub&gt;15&lt;/sub&gt;, T&lt;sub&gt;30&lt;/sub&gt;, T&lt;sub&gt;45&lt;/sub&gt;, T&lt;sub&gt;60&lt;/sub&gt;) after the baseline. PaO&lt;sub&gt;2&lt;/sub&gt;/FiO&lt;sub&gt;2&lt;/sub&gt; ratio, oxygen consumption (VO&lt;sub&gt;2&lt;/sub&gt;), oxygen delivery (DO&lt;sub&gt;2&lt;/sub&gt;), pulmonary shunt values were calculated. Data were tested for normality and compared within each group: T&lt;sub&gt;0&lt;/sub&gt; value with T&lt;sub&gt;15&lt;/sub&gt;, T&lt;sub&gt;30&lt;/sub&gt;, T&lt;sub&gt;45&lt;/sub&gt;, T&lt;sub&gt;60&lt;/sub&gt; values using Wilcoxon's test with Bonferoni correction (significance level 0.0125). For each time point, comparisons were made between the S- and C-groups (control) using Wilcoxon's test. In the S-group, there was a significant increase in values (mean &amp;plusmn; SD) of cardiac output (l/min), T&lt;sub&gt;0&lt;/sub&gt; (38 &amp;plusmn; 7), a peak at T&lt;sub&gt;15&lt;/sub&gt; (64 &amp;plusmn; 25.5), significantly higher values persisted throughout the period of anaesthesia; heart rate (beats/min), T&lt;sub&gt;0&lt;/sub&gt; (32 &amp;plusmn; 2), T&lt;sub&gt;15&lt;/sub&gt; (40 &amp;plusmn; 6), T&lt;sub&gt;30&lt;/sub&gt; (38 &amp;plusmn; 5); DO&lt;sub&gt;2&lt;/sub&gt; (l/min), T&lt;sub&gt;0&lt;/sub&gt; (5.8 &amp;plusmn; 0.8), a peak at T&lt;sub&gt;15&lt;/sub&gt; (9.6 &amp;plusmn; 3.2), significantly higher values persisted until the end of anaesthesia and VO&lt;sub&gt;2&lt;/sub&gt; (l/min), T&lt;sub&gt;0&lt;/sub&gt; (1.1 &amp;plusmn; 0.5), T&lt;sub&gt;30&lt;/sub&gt; (1.6 &amp;plusmn; 0.7) and T&lt;sub&gt;45&lt;/sub&gt; (1.8 &amp;plusmn; 0.5). In the C-group, there was a significant decrease in values of PaO&lt;sub&gt;2&lt;/sub&gt;/FiO&lt;sub&gt;2&lt;/sub&gt; ratio from T&lt;sub&gt;0&lt;/sub&gt; (176 &amp;plusmn; 67) to a minimum at T&lt;sub&gt;60&lt;/sub&gt; (114 &amp;plusmn; 36) and in DO&lt;sub&gt;2&lt;/sub&gt; from T&lt;sub&gt;0&lt;/sub&gt; (6 &amp;plusmn; 2.3) to a minimum at T&lt;sub&gt;60&lt;/sub&gt; (4.3 &amp;plusmn; 1.2). A comparison of the S- and C-groups did not reveal any difference in the baseline data. Subsequently, significantly higher values of cardiac output, heart rate, DO&lt;sub&gt;2&lt;/sub&gt;, and the PaO&lt;sub&gt;2&lt;/sub&gt;/FiO&lt;sub&gt;2 &lt;/sub&gt;ratio were found in the S-group compared to the C-group. Pulmonary arterial blood pressure was significantly lower in the S-group. Aerosolized salbutamol administration in healthy horses during general anaesthesia caused hemodynamic changes which resulted in an elevation of oxygen delivery. It can have a positive effect on arterial oxygenation, but the effect varies between individuals.

Alterações da função pulmonar após tratamento cirúrgico de cardiopatias congênitas com hiperfluxo pulmonar

Analysis of pulmonary status of pediatric patients in the postoperative phase of cardiac surgery. To assess pulmonary compliance and airway resistance in patients with congenital heart disease and pulmonary hyperflow submitted to surgical treatment with the use of extracorporeal circulation. Thirty-five patients were evaluated during surgery with measurements of static compliance and airway resistance at four different timepoints. Pulmonary measurements were performed non-invasively using end-inspiratory airway occlusion and specific mathematical formulas. The variables examined and related to pulmonary changes were: preoperative - age, weight, and relationship between systemic and pulmonary blood flow; intraoperative - perfusion times, anoxia times and minimum temperature; postoperative - time on mechanical ventilation and length of stay in the intensive care unit. Pulmonary compliance in all patients had an immediate and significant increase (P<0.001) at the end of surgery. Patients older than 30 months experienced a greater increase (P=0.0004). Those with more than 10 kg also had a greater increase (P=0.0006). In patients on extracorporeal circulation for more than 50 minutes, the increase in pulmonary compliance took longer to occur (P=0.04). Airway resistance was not significantly changed at the end of surgery (P=0.393). All patients experienced improved pulmonary compliance at the end of surgery, and this was significantly influenced by age, weight and time on extracorporeal circulation. Airway resistance, however, was not changed.