Ching-Chi Lin

Obstructive sleep apnea syndrome and bronchial hyperreactivity

This study was designed to investigate the prevalence of bronchial hyperreactivity (BH) in patients with obstructive sleep apnea syndrome (OSAS), heavy snorers, and light snorers; its correlation with OSAS severity; and its response to nasal CPAP therapy. Forty-eight age- and sex-matched subjects were selected on the basis of preentry sleep studies: Group I consisted of 16 patients with OSAS (hypopnea-apnea index (HAI) = 35 ± 9); group II consisted of 16 cases of heavy snorers without OSAS; and group III, a control group, consisted of 16 subjects with only mild snoring. All 48 patients had normal pulmonary function (simple spirometry) prior to study entry and had no history of asthma or allergies. The prevalence of BH was prospectively assessed by giving each subject a methacholine challenge test (MCT). Patients with a positive MCT were treated with 2–3 months of nasal CPAP treatment, after which they had a second MCT. Four of 16 patients in group I had BH on MCT (PD20 = 88, 103, 109, 162 D.U.), whereas none of the group II or III subjects demonstrated BH. There was no correlation between BH and the severity of the OSAS. The 4 patients with BH in group I showed an increase in PD20M after 2–3 months of nasal CPAP treatment. In conclusion, BH may occur in patients with OSAS. It is unrelated to the severity of the OSAS, and nasal constant positive airway pressure (CPAP) therapy can decrease the hyperreactivity to methacholine in these patients.

Work of breathing and respiratory drive in obesity

Obesity, particularly severe central obesity, affects respiratory physiology both at rest and during exercise. Reductions in expiratory reserve volume, functional residual capacity, respiratory system compliance and impaired respiratory system mechanics produce a restrictive ventilatory defect. Low functional residual capacity and reductions in expiratory reserve volume increase the risk of expiratory flow limitation and airway closure during quiet breathing. Consequently, obesity may cause expiratory flow limitation and the development of intrinsic positive end expiratory pressure, especially in the supine position. This increases the work of breathing by imposing a threshold load on the respiratory muscles leading to dyspnoea. Marked reductions in expiratory reserve volume may lead to ventilation distribution abnormalities, with closure of airways in the dependent zones of the lungs, inducing ventilation perfusion mismatch and gas exchange abnormalities. Obesity may also impair upper airway mechanical function and neuromuscular strength, and increase oxygen consumption, which in turn, increase the work of breathing and impair ventilatory drive. The combination of ventilatory impairment, excess CO2 production and reduced ventilatory drive predisposes obese individuals to obesity hypoventilation syndrome.

Cardiopulmonary exercise testing in obstructive sleep apnea syndrome

To investigate whether cardiac dysfunction or abnormal measurements on cardiopulmonary exercise testing (CPET) are present in patients with obstructive sleep apnea syndrome (OSAS) and what factors are responsible for exercise limitation in these patients. We enrolled 20 patients with moderate or severe OSAS in the OSA group and 20 subjects without OSAS in the control group. All subjects underwent a sleep study and cardiac evaluation by radionuclide scanning and CPET. There was no difference in left ventricular ejection fraction (VEF) between the two groups, but the OSA group had a lower right VEF. Patients in the OSA group had a lower VO2(peak), VO2(peak/kg) and workpeak than the control group. The OSA group had a higher breathing reserve and a greater decrease in anaerobic threshold (AT) and oxygen pulse. In conclusion, patients with moderate to severe OSAS had abnormal CPET results. These abnormalities may be due to cardiac disease, pulmonary vascular disease, or possible lack of fitness.

Work of Breathing in Eucapnic and Hypercapnic Sleep Apnea Syndrome

Background: Upper airways in patients with obstructive sleep apnea syndrome (OSAS) are more likely narrower than those of normal subjects, a factor in increasing the work of breathing (WOB) in these individuals. Objectives: To evaluate WOB while sitting and while supine, both awake and during stage 2 sleep, in patients with hypercapnic or eucapnic OSAS. Method: Twenty normal control subjects without OSAS, 20 patients with eucapnic moderate or severe OSAS and another 8 patients with hypercapnic severe OSAS were studied. WOB was measured by esophageal manometry with the subjects seated and then with the subjects supine, both while awake and during stage 2 sleep. Results: In both the control and the eucapnic group, WOB was normal in the sitting position. When the eucapnic subjects lay supine, their WOB increased, both while awake and asleep. In contrast, the hypercapnic subjects had an abnormally high WOB both sitting and supine, whether awake or asleep. Conclusion: WOB was increased in subjects with hypercapnic OSAS in both the sitting and supine positions. While eucapnic individuals with OSAS have increased WOB when supine, it is normal when they are sitting upright.

Effect of Treatment by Nasal Continuous Positive Airway Pressure on Serum High Mobility Group Box-1 Protein in Obstructive Sleep Apnea

BACKGROUND Serum levels of high mobility group box-1 protein (HMGB1) are increased in a variety of inflammatory disorders. Obstructive sleep apnea syndrome (OSAS) is associated with inflammation secondary to chronic intermittent hypoxia, but HMGB1 levels in treated and untreated OSAS have not been evaluated. METHODS Twenty healthy subjects and 30 subjects with moderately severe or severe OSAS who desired nasal continuous positive airway pressure (CPAP) treatment were enrolled. Serum levels of HMGB1 and nitric oxide derivative (NO(x)) from peripheral blood samples were measured, and all subjects underwent a sleep study. These studies were repeated 2 months after nasal CPAP treatment in the patients with OSAS. RESULTS In OSAS before nasal CPAP treatment, the serum level of HMGB1 was higher but that of NO(x) was lower than those levels of normal subjects. The HMGB1 levels correlated negatively with NO(x) levels in subjects with OSAS. After nasal CPAP treatment, the HMGB1 and NO(x) returned to normal levels. CONCLUSION Elevated HMGB1 levels and reduced NO(x) levels in patients with OSAS normalized after nasal CPAP treatment.

Pulmonary function changes and immunomodulation of Th 2 cytokine expression induced by aminophylline after sensitization and allergen challenge in brown Norway rats.

BACKGROUND AND OBJECTIVE Evidence has shown that aminophylline has bronchoprotective, anti-inflammatory, and immunomodulatory effects. Our purpose was to evaluate the effect of different doses of aminophylline on the late-phase reaction, bronchial hyperresponsiveness (BHR) and T cell-related cytokine mRNA expression in brown Norway rats induced by ovalbumin (OA) sensitization. METHODS Forty rats were equally divided into four groups. Groups I, II, and III animals were sensitized and subsequently provoked with OA. Aminophylline 25 mg/kg was given intraperitoneally to the group I animals and 5 mg/kg to group II animals. Group III animals received intraperitoneal normal saline. Group IV breathed aerosolized saline as a control. After OA provocation, the animals were anesthetized. Pulmonary function tests were performed at baseline and after varying doses of acetylcholine. Thereafter, bronchoalveolar lavage was performed and the lungs were examined histologically. Total RNA was extracted from lung tissue and reverse transcriptase-polymerase chain reaction was performed using primers for interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, interferon-gamma, inducible nitric oxide synthase, and beta-actin. RESULTS Group III had worse pulmonary function tests, more severe BHR, and more severe lung inflammation, higher IL-4 and IL-10 cytokine levels in bronchoalveolar lavage fluid, and higher IL-4, IL-5, IL-6, IL-10, tumor necrosis factor-alpha and inducible nitric oxide synthase mRNA expression than the other three groups. Expression of IL-2 and interferon-gamma was significantly reduced in group III. CONCLUSIONS Both low and high dose aminophylline are effective in preventing late-phase bronchoconstriction, BHR, and an inflammatory response. Aminopylline decreases T helper cell 2-related cytokine mRNA expression but increases T helper cell 1-related cytokines mRNA expression.

Effect of erythromycin on bronchial hyperreactivity and inflammation in ovalbumin-sensitized brown Norway rats

To evaluate the effect of erythromycin on bronchial hyperreactivity, inflammation, and T-cell related cytokine mRNA expression in rats sensitized to ovalbumin, three experimental groups of 10 brown Norway rats each were sensitized by breathing aerosolized ovalbumin. From day 1 to day 15, one group was given oral erythromycin 80 mg/kg/day, another group oral erythromycin 20mg/kg/day, and the third group oral saline only. A fourth control group of 10 rats breathed aerosolized saline. After sensitization, the three experimental groups were provoked by breathing ovalbumin, with the controls again breathing saline. The rats were then anesthetized and paralyzed, and pulmonary function tests were performed at baseline and after varying doses of acetylcholine. Bronchoalveolar lavage (BAL) fluid and lung tissues were examined for expression of mRNA for T-cell cytokines. Our results showed that erythromycin had no beneficial effects on pulmonary function and lung inflammation in the two erythromycin-treated experimental groups compared with the saline experimental group. Th2-related cytokines and their mRNA expression in the three experimental groups were higher than in controls but did not differ among the experimental groups. In conclusion, erythromycin does not prevent bronchial hyperreactivity or an inflammatory response in ovalbumin-sensitized rats.

Effect of uvulopalatopharyngoplasty on endothelial function in obstructive sleep apnea

Objectives: This study evaluates the effects of uvulopalatopharyngoplasty (UPPP) on serum levels of nitric oxide derivatives (NOx) and endothelial function by endothelium dependent flow-mediated dilation (FMD) in obstructive sleep apnea syndrome (OSAS). Study Design: Prospective study. Subjects and Methods: Fifteen healthy subjects and 30 subjects with moderately severe to severe OSAS who desired UPPP were prospectively enrolled. FMD was measured by high-resolution B-mode ultrasonography; serum level of NOx from peripheral blood samples was also measured. All subjects participated in sleep studies. These studies were repeated 3 months after UPPP in OSAS patients. Results: For healthy patients, there was no difference in serum level of NOx and FMD between baseline and 3 months later. The serum levels of NOx in 14 of 30 patients with OSAS – designated surgical responders – increased from 13.9 ± 5.5 μM preoperation to 28.9 ± 8.2 μM postoperatively. FMD increased from 5.2 ± 5.0 preoperatively to 10.0 ± 4.7 postoperatively. For the 16 unresponsive patients, serum NOx and FMD remained impaired after UPPP. Conclusion: Successful treatment of OSAS with UPPP leads to restoration of FMD and normal serum levels of NOx.

Effects of Zileuton on Airway Smooth Muscle Remodeling after Repeated Allergen Challenge in Brown Norway Rats

Background: Chronic asthma is characterized by airway inflammation and remodeling. Objective: This study aimed to evaluate the effects of zileuton on bronchial hyperresponsiveness, airway inflammation and airway smooth muscle (ASM) remodeling. Methods: Two experimental groups of brown Norway rats sensitized and repeatedly challenged with aerosolized ovalbumin (OA) were given oral zileuton (OA-zileuton group) and oral saline only (OA-saline group). A third, control group was sensitized and challenged by saline. The rats were anesthetized and paralyzed. Pulmonary function tests were performed at baseline and after varying doses of acetylcholine. Bronchoalveolar lavage fluid and lung tissues were examined. Results: Zileuton had beneficial effects on pulmonary function, airway inflammation and ASM remodeling in the OA-zileuton group compared to the OA-saline group. Zileuton inhibited an OA-stimulated increase in ASM by inhibiting hypertrophy, hyperplasia and increased extracellular matrix via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, thereby reducing cyclin D1 expression and attenuating bronchial hyperresponsiveness. Conclusion: OA increases airway inflammation and ASM mass. Zileuton effectively prevents bronchial hyperresponsiveness, airway inflammation and ASM remodeling in sensitized rats through the PI3K/Akt pathway, which reduces cyclin D1 expression.

Effect of uvulopalatopharyngoplasty on work of breathing during wakefulness in obstructive sleep apnea syndrome

Objectives: We evaluated the effects of uvulopalatopharyngoplasty (UPPP) on the work of breathing (WOB) in obstructive sleep apnea syndrome (OSAS). Methods: Fifteen healthy subjects and 30 subjects with OSAS who desired UPPP were prospectively enrolled. All underwent measurement of WOB while awake as well as in a sleep study. These studies were repeated 3 months after UPPP in the patients with OSAS. Results: In OSAS before UPPP, the WOB while supine was increased above that of normal subjects. After UPPP, the WOB while supine remained elevated in those whose OSAS did not respond to surgery, and it returned to normal levels in patients whose OSAS improved after UPPP. Conclusions: Abnormal WOB in patients with OSAS returns to normal if UPPP results in amelioration of OSAS.