Small Airway Patency Research Articles

FOT Technique Applied for Monitoring of COVID-19 Pneumonia Reveals Small Airways Involvement.

The fact that some SARS-CoV-2 pneumonia patients benefit from changing body position, and some from continuous positive airways pressure (CPAP), indicates the functional character of hypoxia. We hypothesize that such effects could be explained by the closure of small airways. To prove the hypothesis, we evaluated the patency of small airways in 30 oxygen-dependent, spontaneously breathing patients with SARS-CoV-2 pneumonia during their hospital stay using the FOT method and then compared the results with data obtained three months later. During the acute period, total resistance (R5) and peripheral resistance (R5-20) rose above the upper limit of normal (ULN) in 28% and 50% of all patients, respectively. Reactance indices X5, AX and Fres exceeded ULN in 55%, 68% and 66% of cases. Significant correlations were observed between PaO2/FiO2, the time spent in the hospital and R5, X5, AX and Fres. After 3 months, 18 patients were re-examined. During the hospital stay, 11 of them had risen above the upper limit of normal (ULN), for both resistance (R5-20) and reactance (X5, AX) values. Three months later, ULN for R5-20 was exceeded in only four individuals, but ULN for X5 and AX was exceeded in five individuals. Lung function examination revealed a combined restrictive/obstructive ventilatory failure and reduced CO transfer factor. We interpret these changes as lung tissue remodeling due to the process of fibrosis. We conclude that during acute period of SARS-CoV-2 pneumonia, dilated pulmonary blood vessels and parenchymal oedema induce functional closure of small airways, which in turn induce atelectasis with pulmonary right-to-left shunting, followed by the resulting hypoxemia.

Effects of Medication Use on Small Airway Function and Airway Inflammation in Patients with Clinically Controlled Asthma

To observe effects of medication use on small airway function, airway inflammation and acute exacerbations in patients with clinically controlled asthma. Forced expiratory flow over the middle half of the forced expiratory curve (FEF25%-75%), percentage of eosinophil, concentrations of eosinophil cationic protein (ECP) and interleukin (IL)-5 in induced sputum were assessed in patients with clinically controlled asthma who were given oral anti-inflammatory agents alone or in combination with inhaled therapy and inhaled therapy alone. Subsequently, acute exacerbations were compared between two groups during the 24-week follow-up period. FEF25%-75% in 43 patients with clinically controlled asthma given oral anti-inflammatory agents alone or in combination with inhaled therapy was significantly higher than that in 49 patients given inhaled therapy alone. Meanwhile, the percentage of eosinophils and levels of IL-5 and ECP in patients with clinically controlled asthma given oral anti-inflammatory agents alone or in combination with inhaled therapy were significantly lower than those in patients given inhaled therapy alone. Additionally, the patients with clinically controlled asthma given inhaled therapy were likely to have more acute exacerbation than the patients given oral anti-inflammatory agents alone or in combination with inhaled therapy during the 24-week follow-up period. Systemic anti-inflammatory agents may have a greater effect on parameters reflecting small airway patency and reducing acute exacerbations, presumably secondary to reduction in airway inflammation.

Pressure pulsations enhance penetration index in COPD.

This study was done in order to evaluate the effect of a novel pressure pulsation device (Pulsehaler™, Respinova Ltd., Israel) on the deposition pattern of inhaled aerosol in the lungs of COPD patients. Fifteen COPD patients were recruited to undergo spirometry and SPECT-CT lung scan following nebulization of radioactively labeled albuterol in saline solution with a jet nebulizer ("NEB") and with a combined Pulsehaler™/jet nebulizer ("PH + NEB") treatment. Central and peripheral segments of the coronal and transverse SPECT scans were evaluated for total counts and for the ratios between peripheral counts and central counts (penetration Index, "PI"). There was a significant improvement in FEV1 from before to after albuterol treatment in the PH + NEB group (151ml ± 187, p < 0.008), but not in the NEB only group (66ml ± 125, p = 0.06). FVC, FEF25-75, FEV1%, FVC%, FEF25, FEF50, and FEF75 also improved significantly in the PH + NEB group but not the NEB group. There were significant improvements seen between treatments for FEF25-75 (PH + NEB > NEB, p = 0.0176), FEF75 (PH + NEB > NEB, p = 0.0028), but not for the other spirometry measures. Borg scores also were improved significantly improved in PH + NEB vs NEB (p = 0.0006). Total lung deposition and total body deposition were lower in the PH + NEB treatments vs the NEB treatments. However, PI values were 3.08 ± 0.67 times greater on average with the PH + NEB (p = 0.026) as compared to NEB only. The magnitude of the increased penetration index observed in this study indicates that pressure pulsations should be further explored as means to improve drug delivery into the distal small airways of the bronchial tree. Effects of the pressure pulsations on small airway patency could be the mechanism by which the effect was achieved.

Changes in the ventilation function of the lungs during the formation of chronic obstructive pulmonary disease and its combination with lung cancer

Aim. To study the ventilation function of the lungs in patients with varying degrees of severity of chronic obstructive pulmonary disease (COPD) and in patients with COPD combined with lung cancer (LC), as well as to establish the features of its disorders using spirography and body plethysmography. Materials and methods . A clinical and functional study of 57 individuals was carried out with 10 healthy patients (control group), 30 patients with COPD and 17 patients in whom LC was combined with COPD using the Masterlab Pro diagnostic complex (Erich Jaeger, Germany). Results . In patients with early COPD, a decrease in MEF 75 (a ventilation parameter characterizing small airway patency) is the most informative. With the progression of bronchial obstruction, both restrictive and obstructive disorders, characterized by a decrease in FEV 1 , VC, a change in the structure of the total lung capacity in the form of an increase in the RV/TLC ratio such as an increase in the RV/TLC ratio and an increase in bronchial resistance were recorded. In patients with LC and mild COPD, pulmonary volumes, capacities, flow-volume loop and bronchial resistance parameters did not differ from patients with COPD with a similar bronchial obstruction. In patients with LC and more severe COPD, in contrast to patients suffering from a similar severity of COPD, a decrease in the patency of large, medium and small diameter bronchi (PEF, MEF 25 , MEF 50 , MEF 75 ) was detected, which indicated development of generalized bronchial obstruction. Conclusion . Modern diagnostics of pulmonary ventilation disorders in patients with LC and COPD should be aimed at identifying the disease, and drug therapy should target maximum leveling of reversible components of bronchial obstruction in order to increase the functional reserve of the respiratory system and reduce the risk of postoperative complications caused by COPD.

Effects of Intrathoracic Pressure changes on Diaphragmatic Blood Flow during Mechanical Ventilation

IntroductionAlthough mechanical ventilation (MV) is a life‐saving intervention, prolonged MV can lead to deleterious effects on diaphragm function, such as ventilator‐induced diaphragmatic dysfunction (VIDD) and vascular incompetence. Specifically, prolonged MV elicits time‐dependent reductions in diaphragm blood flow, induces vascular dysfunction, and limits the hyperemic response to contractions associated with weaning. During MV, positive‐end expiratory pressure (PEEP) is used to maintain small airway patency and mitigate alveolar damage; yet increased intrathoracic pressure with high levels of PEEP may impair diaphragm perfusion.PurposeTo test the following hypotheses: 1) Diaphragm blood flow during MV will be less with high vs. low‐peep, and 2) ablation of intrathoracic pressures (via pneumothorax (PTX)) will not alter diaphragm blood flow during MV vs. the low‐peep condition.MethodsFemale Sprague‐Dawley rats (~5 mo) were randomly divided into low PEEP (LP; 1cmH2O, n=7) or high PEEP (HP; 9 cmH2O, n=6) groups during mechanical ventilation. Blood flow, via the fluorescent microsphere technique, was determined during spontaneous breathing (SB) and 10 minutes after intubation and the onset of MV with LP or HP. Thereafter, for a third determination of diaphragm blood flow, the LP group underwent a surgical laparotomy (LAP; to determine effects of intrabdominal pressure on perfusion) and the HP group was subjected to a pneumothorax (PTX), with microsphere infusions occurring 10 minutes after the completion of surgery. Following the final fluorescent microsphere infusion, tissues were harvested for blood flow analysis. The diaphragm was sectioned into costal (ventral, medial, and dorsal) and crural portions to determine diaphragmatic blood flow distribution.ResultsCompared to SB, both LP and HP MV significantly reduced diaphragm medial costal blood flow (LP, 61.9 ± 7.5 vs 43.8 ± 4.9; HP, 46.2 ± 7.7 vs 21.8 ± 3.7 mL/100g/min; P≤0.05). HP MV significantly reduced blood flow to the ventral and medial costal diaphragm compared to LP MV (P≤0.05). In the HP MV+PTX condition, medial and dorsal costal blood flow was significantly increased versus HP MV (P≤0.05). LP MV + LAP did not significantly increase diaphragm blood flow compared to LP MV. Diaphragm perfusion during HP MV+PTX and LP MV were not different (P&gt;0.05).ConclusionThis study demonstrates that HP MV reduces diaphragmatic blood flow to a greater extent than LP MV. Following a PTX in the HP MV condition, diaphragmatic blood flow is not different compared to the LP MV condition, suggesting that the reductions in diaphragmatic blood flow with LP MV are independent of intrathoracic pressure changes, and due likely to diaphragm quiescence.Support or Funding InformationSupported by: NIH HL137156‐01A1

Impulse Oscillometry Discerns the Peripheral Airway Response to an Inhaled Bronchodilator between Obese and Nonobese Children

IntroductionImpulse oscillometry (iOS) is a useful tool to distinguish between central and peripheral airway resistance. For example, iOS has shown that peripheral airway resistance is greater in children with versus those without obesity, despite no difference in FEV1. Considering the added peripheral airway resistance in children with obesity, we sought to determine if iOS can detect potential differences in the peripheral airway response to an inhaled bronchodilator (BD) between children with and those without obesity.MethodsTwenty‐four children with and eleven without obesity, ages 8–12yrs, completed iOS and spirometry testing before and 15mins after the administration of four puffs of an inhaled BD (Ventolin®, 90μg). A mixed models ANOVA (group by pre‐to‐post‐BD) was used to determine differences in FEV1, plethysmographic airway resistance (Raw) and specific Raw (sRaw), and iOS parameters associated with airway resistance. These parameters include resistance at 5 Hz, 10 Hz (R5 and R10: total airway resistance), 20 Hz (R20: large airway resistance), and the difference between R5 and R20 (R5–20: peripheral airway resistance). Reactance at 5 Hz (X5: total airway elastic recoil) and the area under the reactance‐frequency curve (AX: index of small airway patency) were also measured using iOS.ResultsThere was no difference in FEV1 (% pred) or FEV1/FVC between groups and none of our participants showed a positive BD response based on the conventional method of a ≥12% increase in FEV1. Compared with children without obesity, children with obesity presented a greater baseline R5 (7.28 ± 1.20 vs. 5.42 ± 1.44 cmH2O·L−1·s−1; p=0.001), R10 (6.04 ± 1.12 vs. 4.58 ± 1.07 cmH2O·L−1·s−1; p=0.002), R20 (4.76 ± 0.95 vs. 3.94 ± 0.79 cmH2O·L−1·s−1; p=0.025), R5–20 (2.52 ± 0.64 vs. 1.49 ± 0.75 cmH2O·L−1·s−1; p&lt;0.001), and AX (7.65 ± 5.59 vs. 3.75 ± 1.97 cmH2O·L−1; p=0.008), with no difference in X5 (−1.19 ± 0.77 vs. −1.19 ± 0.33 cmH2O·L−1; p=0.667). A group by pre‐to‐post‐BD interaction was found for R5 (p=0.033) and R10 (p=0.024). Both R5 and R10 decreased to a greater extent with BD in children with obesity versus children without obesity (R5: −20.8 ± 9.5% vs. −12.8 ± 15.2%; R10: −21.6 ± 8.6% vs. −14.5 ± 13.1%). In all children (n=35), Raw, sRaw, and all iOS parameters, except for X5, decreased with the BD (p&lt;0.05).ConclusionIn addition to greater central and peripheral airway resistance in children with obesity, iOS also detected a greater peripheral airway response to a BD in children with obesity. Although no established criteria exist for children ages 8–12yrs, the American Thoracic Society defines an airway response in preschool children as a 20–40% decrease in R5 and a 15–30% decrease in R10. Based on these criteria, our finding that R5 and R10 dropped by 20.8% and 21.6% in children with obesity indicates potential peripheral airway hyperresponsiveness in children with obesity. However, further research is warranted to establish the meaning of, or normal criteria for, peripheral airway responsiveness in prepubescent children.Support or Funding InformationNIH R01 HL136643, Texas Health Presbyterian Hospital Dallas, King Charitable Foundation Trust, and Dr. Pepper Snapple.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pulmonary function, white blood corpuscles &amp; haemoglobin levels in asymptomatic light smokers and non-smokers

Context: Smoking, a risk factor for several diseases has also been reported as the largest preventable cause of morbidity and mortality globally. Tobacco smoking is associated with a decrease in lung function in smokers when compared to non-smokers. Aims: To study and compare pulmonary function, WBC count and Hb levels in asymptomatic light smokers and non-smokers. Settings and Design: Case control study. Methods and Material: Patient relatives or subjects who had come for health check with a known history of smoking and apparently asymptomatic were recruited as our study subjects (n = 49). Healthy volunteers were also recruited from patient relatives. Subjects without any known history of smoking were selected as controls (n = 50). Statistical analysis used: Data was analysed using SPSS V-19. P value ≤0.05 was considered significant. Results: A statistically significant difference was found in total leucocyte count in smokers (P = 0.004) when compared to non-smokers. There was also a statistically significant increase in absolute neutrophil (P = 0.021), monocyte (P = 0.004) and eosinophil (P = 0.075) counts in smokers. FEV1/FVC (P = 0.005) and FEF 75 (P = 0.027) was significantly higher in non-smokers when compared to smokers. No significant difference was observed in haemoglobin concentration and differential leucocyte count, pulse rate, systolic pressure, diastolic pressure and rate pressure product among the two groups. Conclusions: The present study gives ample evidence for the damage to the respiratory system along with activation of immune system as evident from a significant lowering of small airway patency and increased white cell counts

Pathophysiology and Prevention of Intraoperative Atelectasis: A Review of the Literature.

Atelectasis is a common problem in the perioperative setting, affecting a significant number of surgical patients receiving general anesthesia. Absorption, compression, and reduced surfactant are the three mechanisms implicated in the etiology of atelectasis. Interventions designed to minimize the risk of intraoperative atelectasis such as positioning, positive end-expiratory pressure, and administration of the least amount of fraction of inspired oxygen can be used to maintain patency of small airways and ultimately improve gas exchange in the surgical patient.

The Utility of Forced Expiratory Flow between 25% and 75% of Vital Capacity in Predicting Childhood Asthma Morbidity and Severity

Objectives. The forced expiratory volume in 1 second (FEV1) felt to be an objective measure of airway obstruction is often normal in asthmatic children. The forced expiratory flow between 25% and 75% of vital capacity (FEF25–75) reflects small airway patency and has been found to be reduced in children with asthma. The aim of this study was to determine whether FEF25–75 is associated with increased childhood asthma severity and morbidity in the setting of a normal FEV1, and to determine whether bronchodilator responsiveness (BDR) as defined by FEF25–75 identifies more childhood asthmatics than does BDR defined by FEV1. Methods. The Boston Children’s Hospital Pulmonary Function Test database was queried and the most recent spirometry result was retrieved for 744 children diagnosed with asthma between 10 and 18 years of age between October 2000 and October 2010. Electronic medical records in the 1 year prior and the 1 year following the date of spirometry were examined for asthma severity (mild, moderate, or severe) and morbidity outcomes for the three age, race, and gender-matched subgroups: Group A (n = 35) had a normal FEV1, FEV1/forced vital capacity (FVC), and FEF25–75; Group B (n = 36) had solely a diminished FEV1/FVC; and Group C (n = 37) had a normal FEV1, low FEV1/FVC, and low FEF25–75. Morbidity outcomes analyzed included the presence of hospitalization, emergency department visit, intensive care unit admission, asthma exacerbation, and systemic steroid use. Results. Subjects with a low FEF25–75 (Group C) had nearly 3 times the odds ratio (OR) (OR = 2.8, p < .01) of systemic corticosteroid use and 6 times the OR of asthma exacerbations (OR = 6.3, p > .01) compared with those who had normal spirometry (Group A). Using FEF25–75 to define BDR identified 53% more subjects with asthma than did using a definition based on FEV1. Conclusions. A low FEF25–75 in the setting of a normal FEV1 is associated with increased asthma severity, systemic steroid use, and asthma exacerbations in children. In addition, using the percent change in FEF25–75 from baseline may be helpful in identifying BDR in asthmatic children with a normal FEV1.

Targeting small airways in asthma: improvement in clinical benefit?

Disease control is not achieved in a substantial proportion of patients with asthma. Recent advances in aerosol formulations and delivery devices may offer more effective therapy. This review will focus on the importance and potential clinical benefit of targeting the lung periphery in adult asthma by means of ultra-fine aerosols. Ultra-fine formulations of inhaled corticosteroids (ICS) have improved lung deposition up to at least 50%, primarily in the peripheral airways. Ultra-fine formulations of ICS provide equivalent asthma control to non-ultra-fine ICS at approximately half the daily dose, with no increased risk of systemic effects. Clinical studies of adults with asthma have shown a greater effect of ultra-fine ICS, compared with non-ultra-fine ICS, on quality of life, small airway patency, and markers of pulmonary and systemic inflammation, but no difference with regard to conventional clinical indices of lung function and asthma control. Asthma patients treated with ultra-fine ICS, compared with non-ultra-fine ICS, have at least similar chance of achieving asthma control at a lower daily dose. Further clinical studies are needed to explore whether treatment with ultra-fine formulations of ICS will change the natural history of asthma and prevent airway remodelling in both the large and small airways.

Comparison of Effectiveness in Ciclesonide and Fluticasone Propionate on Small Airway Function in Mild Asthma

Inhaled corticosteroids (ICS) are the mainstay of asthma treatment, but conventional ICS may have limited effectiveness in inflammation and patency of small airways. Ciclesonide is delivered and deposited in the peripheral region of the lung as a small particle corticosteroid. The aim of the study is to compare the effects of ciclesonide with fluticasone propionate on small airway function in asthma. Thirty mild persistent asthma patients treated with 200 microg of fluticasone propionate were randomized to receive either ciclesonide 200 microg once daily or fluticasone propionate 100 microg twice daily for 8 weeks. Small airway function was assessed by impulse oscillometry (IOS) and percentage of eosinophil induced sputum. We observed that ciclesonide significantly improved IOS measured resistance of small airways (R5-R20; p<0.05), distal reactance (X5; p<0.01), reactance area (AX; p<0.01), and decreased late-phase sputum eosinophil level (p<0.01) compared with fluticasone propionate. There were no significant changes in spirometry indices in either group during the study. These findings suggest that ciclesonide improves small airway function and inflammation compared with fluticasone propionate in mild asthma. This study provides evidence that IOS and late-phase induced sputum allows detection of changes in the small airways that can not be detected by spirometry.

Effect of the inhaled corticosteroid mometasone on small airway patency in patients with asthma

The inflammation in asthma involves both the large and the small airways. This study was designed to examine whether mometasone delivered from a dry powder inhaler would improve those parameters thought to reflect patency and obstruction of the small airways (diameter <2 mm). Subjects with mild to moderate asthma, only receiving short-acting beta-agonists, underwent baseline assessment, and then were randomized to receive for 12 weeks either mometasone 400 micrograms once daily in the evening or matching placebo. Outcomes assessed included clinical measures and measures of airway responsiveness and inflammation included methacholine sensitivity (concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second [FEV(1)] [PC(20)]), exhaled nitric oxide, serum ECP, and sputum eosinophils. Pulmonary function was assessed by spirometry, plethysmography, and forced oscillometry. Measures of small airway patency included single breath nitrogen washout and air trapping on expiratory high-resolution computed tomography. Results were available on 12 adult subjects who received mometasone and 14 subjects who received placebo. Among tests reflecting small airway patency, the forced expiratory flow between 25 and 75% of vital capacity was significantly improved by mometasone compared with placebo (+9% versus -6%; p = 0.006 and the closing volume over forced vital capacity (FVC; -2% versus 0%; p = 0.05). Other results significantly favoring mometasone over placebo included FEV(1), FVC, PC(20), and A.M. and P.M. peak expiratory flows, and albuterol use. Mometasone delivered by a dry powder inhaler improved asthma control and pulmonary function in tests reflecting both large and small airways.

Effect of the Inhaled Corticosteroid Mometasone Furoate on Small Airway Patency in Patients with Asthma

Effect of the Inhaled Corticosteroid Mometasone Furoate on Small Airway Patency in Patients with Asthma

Physiology of the small airways: A gender difference?

Small airways are affected in asthma, but gender differences have not been investigated. This study aims to assess whether gender differences exist in the extent of small airway involvement in asthma. Sixteen patients with mild-to-moderate asthma (seven males, median (range) age 39 (19-56) years, FEV(1)%predicted 89% (62-120), PC(20) Methacholine (MCh) 0.4 mg/mL (0.1-4.2)) participated in the study. MCh-induced air trapping at end-expiratory CT scans, alveolar and bronchial exhaled Nitric Oxide (eNO), Single-Breath N(2) closing volume, FEF(25-75%), FEF(50%) and % change in FVC at PC(20) adenosine-5'-monophosphate (AMP) and at PC(20)MCh were evaluated. Multiple regression analyses evaluated whether gender, body mass index and age were explanatory variables for the severity of air trapping. Males had significantly larger MCh-induced increases in low attenuation areas on CT than females, 6% (1-9) versus 2% (-1-7), p=0.012. Males had significantly more signs of MCh-induced air trapping in the non-dependent lung lobes than females. Male gender was the sole factor explaining higher values of MCh-induced signs of air trapping. Females had higher bronchial eNO values than males, 4 nL/s (2-7) versus 2 nL/s (1-4), p=0.04. Small airway involvement in asthma as reflected by MCh-induced air trapping at CT was significantly larger in males than females even in this relatively small group. Bronchial eNO, reflecting partially small airway inflammation, was higher in females than males. These data suggest that the small airways are affected differently in males and females with asthma. Males exhibit small airway involvement by attenuated small airway patency and females by small airway inflammation.

Ciclesonide improves measures of small airway involvement in asthma

Ciclesonide is delivered as a small-particle inhaled corticosteroid and improves lung function and airway hyperresponsiveness. The objective of the present study was to assess whether ciclesonide can specifically improve small airway function in asthma. A total of 16 mild-to-moderate asthma patients (seven males; median (range) age 39 (19-56) yrs and forced expiratory volume in one second (FEV(1)) 89 (62-120)% predicted) were randomised to 5 weeks' treatment with placebo or 320 mug ciclesonide once daily. The following small airway parameters were assessed: mean forced expiratory flow between 25 and 75% of forced vital capacity (FVC), percentage fall in FVC at provocative dose of adenosine-5'-monophosphate and of methacholine (MCh) causing a 20% fall in FEV(1), expiratory lung volume on computed tomography (CT) scan after MCh challenge, single-breath nitrogen closing volume and alveolar exhaled nitric oxide (eNO). Seven subjects received placebo and nine received ciclesonide. Both alveolar eNO and CT measurements of expiratory lung volume after MCh challenge decreased significantly with ciclesonide (median (range) decrease 4.4 (54.8-1.4) ppb and 59 (1,569- -117) mL, respectively), and compared with placebo (-0.4 (7.3- -3.4) ppb and -121 (20- -236) mL respectively). Ciclesonide did not significantly improve other small airways parameters. Inflammation and patency of small airways, reflected by alveolar exhaled nitric oxide and air trapping on computed tomography scan, both improve with ciclesonide even in this small number of patients. This indicates that ciclesonide exerts anti-inflammatory effects on small airways.

Combined activities of secretory phospholipases and eosinophil lysophospholipases induce pulmonary surfactant dysfunction by phospholipid hydrolysis

Surfactant dysfunction is implicated in small airway closure in asthma. Increased activity of secretory phospholipase A(2) (sPLA(2)) in the airways is associated with asthma exacerbations. Phosphatidylcholine, the principal component of pulmonary surfactant that maintains small airway patency, is hydrolyzed by sPLA(2). The lysophosphatidylcholine product is the substrate for eosinophil lysophospholipases. To determine whether surfactant phospholipid hydrolysis by the combined activities of sPLA(2)s and eosinophil lysophospholipases induces surfactant dysfunction. The effect of these enzymes on surfactant function was determined by capillary surfactometry. Thin layer chromatography was used to correlate enzyme-induced changes in surfactant phospholipid composition and function. Phosphatidylcholine and its hydrolytic products were measured by using mass spectrometry. Eosinophils express a 25-kd lysophospholipase and group IIA sPLA(2). Phospholipase A(2) alone induced only a small decrease in surfactant function, and 25-kd lysophospholipase alone degraded lysophosphatidylcholine but had no effect on surfactant function. The combined actions of sPLA(2) and lysophospholipase produced dose-dependent and time-dependent losses of surfactant function, concomitant with hydrolysis of phosphatidylcholine and lysophosphatidylcholine. Lysates of AML14.3D10 eosinophils induced surfactant dysfunction, indicating these cells express all the necessary lipolytic activities. In contrast, lysates of blood eosinophils required exogenous phospholipase A(2) to induce maximal surfactant dysfunction. The combined activities of sPLA(2)s and eosinophil lysophospholipases are necessary to degrade surfactant phospholipids sufficiently to induce functional losses in surfactant activity as reported in asthma. The phospholipases and lysophospholipases expressed by eosinophils or other airway cells may represent novel therapeutic targets for blocking surfactant degradation, dysfunction, and peripheral airway closure in asthma.

Montelukast improves regional air-trapping due to small airways obstruction in asthma

Quantitative image analysis of high-resolution computed tomography (HRCT) performed at residual volume, before and after methacholine, is a sensitive method of detecting small airways involvement in asthma and response to therapy targeted to the small airways. Since an oral anti-leukotriene reaches the small airways via the circulation, the present authors hypothesised that treatment with montelukast would lead to improved small airway patency. A double-blind crossover study compared the effect of montelukast versus placebo for 4 weeks in 16 mild-to-moderate steroid-naïve asthmatics. Small airways function was evaluated by HRCT at residual volume before and after methacholine to assess regional air-trapping and airways hyperresponsiveness, as well as by physiological studies of small airways. Montelukast treatment resulted in significantly less regional air-trapping on HRCT on the pre-methacholine images when compared with placebo, as well as improvement in total quality of life scores and symptom sub-scores. However, montelukast treatment had no effect on increases in regional air-trapping on HRCT in response to methacholine. No differences were noted in global measures of small airways physiology between placebo and montelukast. In conclusion, distal airways disease improves in asthmatic subjects treated with montelukast. This improvement can be detected with high-resolution computed tomography, but not with conventional physiological studies.

Effect of surfactant deficiency and surfactant replacement on airway patency in the piglet lung

We investigated the effect of surfactant deficiency on airway patency and the effectiveness of surfactant replacement as either an instilled liquid bolus, a non-hygroscopic aerosol or a hygroscopic aerosol. Small airway patency was assessed in isolated piglet lungs by passing a continuous flow of gas though a cannulated airway. Occlusion was assessed by measuring increases in pressure in the cannula that resulted from airway obstruction. In surfactant-deficient conditions the amount of airway closure increased approximately three-fold. However, administration of exogenous surfactant as an instilled liquid bolus, non-hygroscopic aerosol or a hygroscopic aerosol decreased airway closure such that it was statistically similar to that recorded prior to induction of surfactant deficiency, although the instilled and hygroscopic aerosol surfactant both appeared superior to the non-hygroscopic aerosol. These experiments showed that pulmonary surfactant does have a role in maintaining airway patency and that airway closure induced by surfactant deficiency could be reduced by administration of surfactant in any of the aforementioned forms.

Hydrofluoroalkane-134A Beclomethasone or Chlorofluorocarbon Fluticasone: Effect on Small Airways in Poorly Controlled Asthma

Inflammation in asthma extends into the small airways (< 2 mm diameter). Most inhaled corticosteroids are suspensions with a particle size > 2 mm. Therefore, inflammation in the small airways of patients with asthma may not be adequately treated with these preparations. Some inhaled corticosteroids, on the other hand, are compounded with alcohol, resulting in a solution producing an aerosol that has a mean particle diameter of < 2 mm. This study was designed to compare the addition of equivalent amounts of two inhaled corticosteroids (one a suspension and one a solution) to the treatment of patients with asthma, which was uncontrolled despite treatment with moderate to high doses of inhaled corticosteroids and usually additional controller medications. The study was performed with 30 patients, ≥ 18 years of age. Subjects were randomized in a single-blind fashion to receive, in addition to their current asthma therapy, either CFC-FP 220 µg each morning and 110 µg each evening (n = 10) or HFA-BDP 160 mcg twice daily (n = 20). Pre- and postbronchodilator spirometry, single breath nitrogen washout for closing volume and residual volume by plethysmography were assessed before and after 3 months of therapy. In the subjects who received HFA-BDP, the ratio of closing volume (CV) to vital capacity (VC) and residual volume (RV) decreased significantly (p = 0.0214 and 0.0433, respectively), whereas forced expiratory flow over 25–75% of the vital capacity (FEF25–75%), forced expiratory volume in 1 second (FEV1), and morning peak flow improved significantly (p = 0.0014, 0.0184, and 0.0321). Improvements from baseline of CV, CV/VC, and postbronchodilator FEF25–75%, were statistically significant in the HFA-BDP group compared with the CFC-FP group (p = 0.0049, 0.0194, and 0.0355, respectively). These preliminary findings suggest that the addition of HFA-BDP, compared with CFC-FP in patients with poorly controlled asthma despite receiving moderate to high doses of inhaled steroids, has a greater effect on parameters reflecting small airway patency presumably secondary to reduction in inflammation.

Clinical and functional responses to salbutamol inhaled via different devices in asthmatic patients with induced bronchoconstriction

This study aimed at evaluating changes in airway patency, lung volumes and perception of breathing discomfort intensity following salbutamol administration via the Diskus dry-powder inhaler (DPI) or a pressurized metered-dose inhaler with the Volumatic valved holding chamber (pMDI + Volumatic) in asthmatic patients with methacholine-induced bronchoconstriction. On six different study days, 18 patients inhaled methacholine until forced expiratory volume in 1 s (FEV(1)) decreased by approximately 35% of baseline. Following placebo, 200 and 400 microg of salbutamol through the pMDI + Volumatic or the Diskus, changes in FEV(1), volume-adjusted mean forced expiratory flow from 25 to 75% of the forced vital capacity (isoFEF(25-75)), lung volumes and breathing discomfort intensity, assessed by visual analogue scale (VAS) score, were repeatedly measured over a 60-min observation period. Induced bronchoconstriction was accompanied by obvious reductions in lung volumes and increases in VAS score. After salbutamol administration, FEV(1) and VAS score changes were similar in all experimental conditions. However, following 400 microg salbutamol via pMDI + Volumatic, isoFEF(25-75) values increased up to 4.48 l s(-1) (95% confidence interval 4.06, 4.90), a significantly (P < 0.01) higher value than those attained in all other experimental conditions. Independently of the salbutamol dose, lung volumes rose to significantly (P < 0.01) higher levels in pMDI + Volumatic than in Diskus trials. The low salbutamol dose via the pMDI + Volumatic and the high dose via the DPI increased isoFEF(25-75) and lung volumes to similar extents. Salbutamol via the pMDI + Volumatic provides greater isoFEF(25-75) and lung volume increases in asthmatic patients with induced bronchoconstriction; salbutamol-induced changes in VAS scores poorly reflect those in small airway patency. The lack of differences in FEV(1) increases observed after 200 and 400 microg salbutamol may reflect attainment of the flat portion of the dose-response curve using either device.