Effects of continuous positive airway pressure on exhaled transforming growth factor-ß and vascular endothelial growth factor in patients with obstructive sleep apnea.

BACKGROUND: Both transforming growth factor ß (TGF-ß) and vascular endothelial growth factor (VEGF) are master regulators of airway remodeling; however, their pathological roles in obstructive sleep apnea (OSA) remain unclear. The aim of the present study was to evaluate the expression of TGF-ß and VEGF protein in the serum and exhaled breath condensate (EBC) before and after continuous positive airway pressure (CPAP) treatment in OSA patients. METHODS: Forty patients with moderate to severe OSA requiring CPAP and 20 healthy subjects were prospectively recruited. The concentrations of TGF-ß and VEGF protein in the serum and EBC were evaluated by enzyme-linked immunosorbent assay. All OSA patients underwent a sleep study that was repeated 3 months after receiving CPAP therapy. RESULTS: Protein concentrations of TGF-ß and VEGF in the serum did not differ between healthy controls and OSA patients before CPAP treatment. There was also no difference in the serum protein concentrations of TGF-ß and VEGF of the OSA patients before and after CPAP treatment. However, both the TGF-ß and VEGF protein concentrations in the EBC were higher in the OSA patients than those in control subjects, and recovered to normal levels after CPAP. CONCLUSIONS: Successful treatment of OSA by CPAP can restore the TGF-ß and VEGF protein concentrations in the EBC.

Effects of aminophylline on airway epithelial-mesenchymal transition in brown Norway rats after repeated allergen challenge.

Purpose: Chronic asthma is characterized by airway inflammation and remodeling. The aim of this study is to evaluate the effects of aminophylline on airway epithelial-mesenchymal transition (EMT). Materials and methods: Two experimental groups of brown Norway rats that were repeatedly challenged with aerosolized ovalbumin (OA) were given oral aminophylline (OA-aminophylline group) or saline only (OA-saline group). A third group was challenged by saline as a control. The rats were anesthetized and pulmonary function were performed. Immuno-histochemical staining of epithelial markers (zonula occludens-1 (ZO-1)) and mesenchymal markers (vimentin) in the airway were performed. The protein expressions of ZO-1, E-cadherin, vimentin, fibronectine, TGF-ß1, SMAD 2/3, JNK, and p38 MAPK were examined by western blot. Results: Aminophylline had beneficial effects on airway inflammation, and airway remodeling in the OA-aminophylline group compared to the OA-saline group. The OA-saline group had decreased ZO-1 but increased vimentin according to immuno-histochemical staining. The protein expression indicated decreases in ZO-1 and E-cadherin but increases in vimentin, fibronectine, TGF-ß1, SMAD 2/3, JNK, and p38 MAPK in comparison to the other two groups. The OA-aminophylline group had higher ZO-1 but lower vimentin in immuno-histochemical staining compared to the OA-saline group. The protein expression showed higher ZO-1 and E-cadherin but lower vimentin, fibronectine, TGF-ß1, SMAD 2/3, JNK, and p38 MAPK when compared to the OA-saline group. Conclusions: Ovalbumin increases airway remodeling and airway EMT. Aminophylline is effective in preventing airway remodeling and airway EMT in Brown Norway rats after repeated allergen challenge.

Effect of oral appliance on circulating leukocyte telomere length and SIRT1 in obstructive sleep apnea.

OBJECTIVES: The increased cardiovascular risk seen in patients with obstructive sleep apnea (OSA) may be due to combination of oxidative stress, systemic inflammation and damage to leukocyte telomere length (LTL) seen with aging. Another molecule, Sirtuin 1 (SIRT1), a histone/protein deacetylase, regulates endothelial nitric oxide synthase and is involved in different aspects of cardiovascular disease, aging and stress resistance. The aim of this study was to evaluate the effects of mandibular advancement device (MAD) on the circulating LTL and SIRT1 protein level in peripheral blood mononuclear cells (PBMCs) in patients with OSA. MATERIALS AND METHODS: Forty patients with moderately severe to severe OSA who desired MAD and 20 healthy controls were prospectively enrolled. The LTL was measured by quantitative polymerase chain reaction while SIRT1 protein levels in PBMC was assessed using a Sirtuin 1 ELISA Kit. All study subjects underwent baseline sleep study, with OSA patients having repeat testing at 3 months after MAD. RESULTS: Compared to healthy subjects, patients with OSA at baseline had lower LTL and SIRT1 protein levels in PBMC. After 3 months of MAD, 24 OSA patients, designated as MAD responders, median (range) LTL increased from (0.556 [0.393-0.748]) to (0.708 [0.533-0.893]) and SIRT1 protein levels in PBMC increased from 0.58 ± 0.23 pg/µg of total protein to 0.95 ± 0.26 pg/µg of total protein. For the 16 MAD unresponsive patients, LTL and SIRT1 protein levels remained low. CONCLUSIONS: Successful treatment of OSA with MAD can restore LTL and SIRT1 protein levels in PBMC. CLINICAL RELEVANCE: LTL and SIRT1 protein levels in PBMC can be improved following effective treatment of OSA using MAD.

Effects of nasal CPAP on exhaled SIRT1 and tumor necrosis factor-α in patients with obstructive sleep apnea.

Exhaled breath condensate (EBC) has been used to examine airway inflammation and oxidative stress. This study aimed to evaluate if there were abnormal Sirtuin 1 (SIRT1) protein and tumor necrosis factor (TNF)-α levels in EBC and to determine if these levels could be improved after nasal continuous positive airway pressure (CPAP) treatment. Thirty-five patients with moderately severe to severe obstructive sleep apnea syndrome (OSAS) who wanted nasal CPAP treatment and 20 healthy controls were prospectively enrolled. The EBC SIRT1 protein levels and EBC TNF-α protein levels were assessed by ELISA. All patients underwent sleep studies that were repeated 3 months after nasal CPAP treatment in patients with OSAS. Results showed that in OSAS before nasal CPAP treatment, the EBC SIRT1 protein levels were lower than that in normal subjects, whereas the EBC TNF-α protein levels were higher. After nasal CPAP treatment, the EBC SIRT1 levels increased and EBC TNF-α levels decreased. In conclusion, successful treatment of OSAS by nasal CPAP can normalize the levels of EBC SIRT1 and EBC TNF-α.

Effect of Nasal CPAP on SIRT1 and Endothelial Function in Obstructive Sleep Apnea Syndrome.

BACKGROUND: Sirtuin 1 (SIRT1), a histone/protein deacetylase, has been implicated in aging, metabolism, and stress resistance. SIRT1 regulates endothelial nitric oxide (NO) synthase, restores NO availability, and is involved in different aspects of cardiovascular disease. The aim of this study was to evaluate any abnormalities with regard to SIRT1 protein level in the blood, SIRT1 activity, and impaired endothelial function in patients with obstructive sleep apnea syndrome (OSAS). We also investigated whether or not OSAS patients who received nasal continuous positive airway pressure (CPAP) treatment showed improvements in the levels of SIRT1. METHODS: Thirty-five patients with moderately severe to severe OSAS who requested nasal CPAP treatment and 20 healthy controls were prospectively enrolled. The SIRT1 protein levels in blood and its activity, and the serum levels of nitric oxide derivative (NO x ) were assessed. All subjects participated in sleep studies, which were repeated 3 months after nasal CPAP treatment in the patients with OSAS. RESULTS: In the patients with OSAS, the level of SIRT1 in the blood, its activity, and that of NO x was lower than those of normal subjects before nasal CPAP treatment. After nasal CPAP treatment, the level of SIRT1 in the blood and its activity increased from 0.55 ± 0.32 pg/µg of total protein and 3085.53 ± 1071.57 arbitrary fluorescence units (AFUs)/µg of total protein to 1.13 ± 0.43 pg/µg of total protein and 5344.65 ± 1579.71 AFUs/µg of total protein. The serum levels of NO x in the patients with OSAS increased from 16.36 ± 5.78 to 25.94 ± 5.17 µM. CONCLUSIONS: Successful treatment for OSAS with nasal CPAP can restore blood levels of the SIRT1 protein and its activity and serum levels of NO x .

Effect of oral appliance on endothelial function in sleep apnea.

OBJECTIVES: This study evaluated the effects of mandibular advancement device (MAD) on serum levels of nitric oxide derivatives and endothelial function by endothelium-dependent flow-mediated dilation (FMD) in obstructive sleep apnea syndrome (OSAS). METHODS: Thirty patients with moderately severe-to-severe OSAS who desired MAD and 15 healthy controls were prospectively enrolled. FMD was measured by high-resolution B-mode ultrasonography, while serum NO x level from peripheral blood samples was measured by ELISA. All subjects participated in the sleep studies, which were repeated 2 months after MAD in OSAS patients. RESULTS: Serum NO x level and FMD were lower in patients with OSAS than in controls prior to MAD. Serum NO x levels in 19 of 30 patients with OSAS, the designated MAD responders, increased from 11.8 ± 5.8 µM pre-MAD to 22.7 ± 4.9 µM post-MAD. The FMD increased from 5.9 ± 4.6 pre-MAD to 10.5 ± 4.8 post-MAD. For the 11 unresponsive patients, serum NO x and FMD remained impaired after MAD. CONCLUSIONS: Successful treatment of OSAS with MAD can restore serum levels of NO x and FMD. CLINICAL RELEVANCE: Endothelial function can be improved following effective treatment of OSAS using MAD.

Effect of uvulopalatopharyngoplasty on leptin and endothelial function in sleep apnea.

OBJECTIVES: This study evaluated the effects of uvulopalatopharyngoplasty (UPPP) on serum leptin levels and endothelial function in patients with obstructive sleep apnea syndrome (OSAS). METHODS: Fifteen healthy subjects and 35 patients with moderate to severe OSAS who desired UPPP were prospectively enrolled. The serum levels of leptin and nitric oxide derivative (NOx) from their peripheral blood samples were measured by enzyme-linked immunosorbent assay. All subjects participated in sleep studies, which were repeated 3 months after UPPP in the patients with OSAS. RESULTS: Before UPPP, the patients with OSAS had a higher serum level of leptin and a lower NOx level than did the control subjects. The serum leptin levels in the 17 of the 35 patients with OSAS who were surgical responders decreased from 24.2 ± 6.1 ng/mL before operation to 15.9 ± 6.0 ng/mL after operation. The serum NOx levels in these 17 patients increased from 18.5 ± 7.5 µmol/L before operation to 27.3 ± 8.2 µmol/L after operation. In the 18 patients who were unresponsive to surgery, the serum leptin and NOx levels remained impaired after the UPPP. CONCLUSIONS: Successful treatment of OSAS with UPPP leads to the normalization of serum leptin and NOx levels.

Upregulation of endocan by Epstein-Barr virus latent membrane protein 1 and its clinical significance in nasopharyngeal carcinoma.

Endocan (or called Esm-1) has been shown to have tumorigenic activities and its expression is associated with poor prognosis in various cancers. Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV)-encoded oncoprotein and has been shown to play an important role in the pathogenesis of EBV-associated nasopharyngeal carcinoma (NPC). To further understand the role of LMP1 in the pathogenesis of NPC, microarray analysis of LMP1-regulated genes in epithelial cells was performed. We found that endocan was one of the major cellular genes upregulated by LMP1. This induction of endocan by LMP1 was confirmed in several epithelial cell lines including an NPC cell line. Upregulation of endocan by LMP1 was found to be mediated through the CTAR1 and CTAR2 domains of LMP1 and through the LMP1-activated NF-κB, MEK-ERK and JNK signaling pathways. To study whether endocan was expressed in NPC and whether endocan expression was associated with LMP1 expression in NPC, the expression of endocan and LMP1 in tumor tissues from 42 NPC patients was evaluated by immunohistochemistry. Expression of endocan was found in 52% of NPC specimens. Significant correlation between LMP1 and endocan expression was observed (p<0.0001). Moreover, NPC patients with endocan expression were found to have a shorter survival than NPC patients without endocan expression (p=0.0104, log-rank test). Univariate and Multivariate analyses revealed that endocan was a potential prognostic factor for NPC. Finally, we demonstrated that endocan could stimulate the migration and invasion ability of endothelial cells and this activity of endocan was dependent on the glycan moiety and the phenylalanine-rich region of endocan. Together, these studies not only identify a new molecular marker that may predict the survival of NPC patients but also provide a new insight to the pathogenesis of NPC.

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.

Effects of erlotinib on pulmonary function and airway remodeling after sensitization and repeated allergen challenge in Brown-Norway rats.

Erlotinib, an EGFR tyrosine kinase inhibitor, can inhibit the proliferation and survival of cancer cells. It has been widely used to treat non-small cell lung cancer. This study aimed to evaluate the effects of erlotinib on bronchial hyperresponsiveness, airway inflammation, and airway remodeling in sensitized, ovalbumin-challenged rats. Two experimental groups of Brown-Norway rats were sensitized and repeatedly challenged by breathing aerosolized ovalbumin. Since Day 1, one group was given oral erlotinib (OA-erlotinib group) while the other group was given only oral saline (OA-saline group). The control group was sensitized and challenged using saline. All were anesthetized and paralyzed, and pulmonary function tests conducted at baseline and after provocation with varying doses of acetylcholine. Lung tissues were examined for airway inflammation, airway remodeling, and Th2-related cytokine mRNA expression. Results showed that the OA-erlotinib group had better pulmonary function and less airway inflammation, Th2-related cytokines and their mRNA expression, and airway remodeling compared to the OA-saline group. In conclusion, erlotinib effectively prevents bronchial hyperreactivity, airway inflammation, Th2-related cytokine mRNA expression, and airway remodeling after sensitization and repeated allergen challenge in Brown-Norway rats.

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.

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 (NO(x)) 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 NO(x) 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 NO(x) and FMD between baseline and 3 months later. The serum levels of NO(x) in 14 of 30 patients with OSAS - designated surgical responders - increased from 13.9 +/- 5.5 microM preoperation to 28.9 +/- 8.2 microM 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 NO(x).

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 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 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.

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.

Oral airway resistance during wakefulness in eucapnic and hypercapnic sleep apnea syndrome.

The purpose of this study was to evaluate whether there was an abnormal increase of upper airway resistance in the sitting and supine positions in hypercapnic obstructive sleep apnea syndrome (OSAS) patients compared with eucapnic OSAS or normal controls as measured by impulse oscillometry (IOS) while awake. Twenty subjects without OSAS served as controls (group I), and 20 patients with moderate or severe eucapnic OSAS (group II) and another eight hypercapnic severe OSAS patients (group III) were studied. Group II was further divided into two subgroups. Group IIa consisted of 14 subjects whose BMI was less than 35 and group IIb of six subjects whose BMI was greater than 35. All subjects also had an overnight sleep study. Oral airway resistance (AR) (including impedance (Zrs), resistance (R) and reactance (X)) was measured by impulse oscillometry (IOS) (MasterScreen IOS, VIASYS Healthcare GmbH, Germany) in the upright (seated) position and then in the supine position while awake. The results demonstrated that in both group I and group II, Zrs was normal in the sitting position. However, there was a high Zrs in the supine position for group II patients. In contrast, in group III patients, there was a high Zrs in both the sitting and supine positions. In conclusion, upper airway resistance was increased both sitting and supine in the hypercapnic OSAS patients; this would presumably increase the work of breathing and might explain why these subjects were hypercapnic while awake, while eucapnic OSAS patients and normal controls were not. Secondly, the increased upper airway resistance in the supine position in the eucapnic OSAS patients may contribute to their OSAS.

Maximal forced expiratory maneuver to measure airway obstruction in allergen challenged mice.

Our purpose was to develop a method of using a maximal forced expiratory maneuver (MFEM) for the study of bronchoconstriction and bronchial hyperreactivity (BHR) induced in mice by ovalbumin (OA) inhalation challenge. Eight mice (group I) were sensitized and then provocated with OA. Pulmonary function testing (PFT) at baseline and after varying doses of acetylcholine challenge was performed. Eight weight-matched normal mice served as controls (group II). Pulmonary functions include MFEM, dynamic respiratory system compliance (Crs) and respiratory system resistance (Rrs). The results showed that mice treated with OA had worse PFTs than normal controls, characterized by lower MFEF 50%, FEV0.1 and Crs but higher Rrs. The OA-sensitized mice also had more severe bronchoconstriction in response to acetylcholine, characterized by greater decreases in MFEF 50%, FEV0.1 and Crs but a higher Rrs than the controls. There was a good correlation between PD20MFEF50%Ach and PD20FEV0.1Ach with PD20CrsAch and PD20RrsAch. In conclusion, the MFEM can be used to evaluate airway obstruction and BHR induced in mice by allergen challenge.

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.