Changes of 5-lipoxygenase pathway and proinflammatory mediators in cerebral cortex and lung tissue of sensitized rats.

AIM: To explore the change of 5-lipoxygenase (5-LO) pathway expression and proinflammatory mediators level of lung tissue and cerebral cortex, and the possible regulatory mechanism through central nervous 5-LO pathways to pulmonary inflammatory status in antigen repeated challenged rats. METHODS: Four groups of rats were treated as control, asthma model, asthma model treatment with dexamethasone (DXM, 0.5 mg/kg, i.p.) and ketotifen (5 mg/kg, i.g.). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, interferon (IFN)-gamma, and nitric oxide (NO) were detected by ELISA kits. The mRNA expression of 5-LO and LTA4-hydrolase (LTA4-H) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), and the protein content of 5-LO was measured by Western blot. RESULTS: Increase of TNF-alpha, IL-4, NO level, and decrease of IFN-gamma level in bronchoalveolar lavage fluid (BALF) and cerebral cortex in sensitized rats were shown after repeated antigen challenge. The expression of 5-LO and LTA4-H mRNA, and 5-LO protein levels were increased in lung tissue and cerebral cortex in asthma rats. In comparison with the asthma model, DXM significantly inhibited the increase of cytokine levels and the expression of 5-LO pathway enzyme (P<0.05). Ketotifen also inhibited the increase of TNF-alpha level and 5-LO pathway enzyme expression in lung and cerebral cortex, but had no effect on the level of NO, IL-4, and IFN-gamma. CONCLUSION: The correlative increase of 5-LO pathway enzyme expression and proinflammatory mediators of brain may have a regulatory effect on pulmonary inflammation in asthma.

[Effect of inhaled cyclosporin A on antigen-induced airway inflammation in asthmatic rats].

AIM: To investigate the effect of inhalation of cyclosporin (CsA) on antigen-induced airway inflammation in Sprague-Dawley rats. METHODS: Rats were sensitized with antigen (ovalbumin, OA). After two weeks, the sensitized rats were pretreated with aerosol CsA (5, 10, 20 g x L(-1)), once per day for 7 days. Then, the sensitized rats were challenged with OA (10 g x L(-1), once per day) for 2 days at day 20 after sensitization. The number of eosinophils in bronchoalveolar lavage fluid (BALF) and peripheral blood, histological changes of lung tissue, and TNF-alpha content in BALF were investigated. RESULTS: Inhalation of CsA significantly reduced the number of eosinophils in BALF and peripheral blood, inflammatory infiltration and tissue edema of lung tissue, decreased the content of TNF-alpha in BALF. CONCLUSION: Inhalation of CsA inhibited airway inflammation in rats, and the mechanism is related to inhibition of TNF-alpha release.

[Effects of cyclosporin A aerosol on airway hyperresponsiveness in rats].

AIM: To study cyclosporin A (CsA) aerosol for anti-airway hyperresponsiveness (AHR) in sensitized rats. METHODS: Sensitized Sprague-Dawley rats were given cyclosporin A (5, 20 g.L-1) and sodium cromoglycate (SCG, 20 g.L-1) by aerosol (5 min per day), dexamethasone (DXM, 0.5 mg.kg-1) i.p. once per day for 7 d before antigen challenge. The respiratory resistance(R(aw)) and lung dynamic compliance(Cdyn) of the rats induced by methacholine (Mch) were measured 24 h after ovalbumin(OA) challenge. The PC50 changes of R(aw) and PC25 changes of Cdyn were also investigated. RESULTS: Pretreatment with CsA, sodium cromoglycate and dexamethasone inhibited the increase of R(aw) and decrease of Cdyn caused by inhaling Mch. The value of R(aw) PC50 in the CsA(5 g.L-1) group 5.6 g.L-1, the CsA(20 g.L-1) group 6.4 g.L-1, the SCG group 8.3 g.L-1 and the DXM group 9.2 g.L-1, was significantly higher than that of the model group 1.9 g.L-1 (P < 0.05). The value of Cdyn PC25 in the CsA(5 g.L-1) group 4.3 g.L-1, the CsA(20 g.L-1) group 5.4 g.L-1, the SCG group 6.4 g.L-1 and the DXM group 6.2 g.L-1, was significantly higher than that of the model group 1.1 g.L-1 (P < 0.01). CONCLUSION: Anti-AHR of CsA by aerosol in animal model offered an experimental evidence for topical inhalation of CsA in treatment of asthma.

[A model for quantitative cigarette smoking and response of airways to cigarette smoke in guinea pigs].

OBJECTIVE: To establish an animal model for quantitative cigarette smoking and to determine the acute response of airways to cigarette smoke in guinea pigs. METHODS: The device for inhaling quantitative cigarette smoking was made, which was double pass and single-direction with the minimum dead space. The changes of airway resistance(R(L))and dynamic lung compliance(Cdyn) in guinea pigs exposed to compound air consisting of 75% cigarette smoke and 25% oxygen were observed. Exudation of Evans blue in pulmonary vessels was also determined after consecutive inhalation of 60 ml smoke. RESULT: The R(L) increased from the baseline of (0.21+/-0.05) cmH(2)O x ml(-1) x s to (0.37+/-0.13) cmH(2)O x ml(-1) x s after 10 consecutive breaths of cigarette smoke exposure(P<0.01). The Cdyn decreased to (61+/-19)% of baseline at the ninth to eleventh breaths (P<0.01). The exudations of Evans blue significantly increased in all measured parts of the airways such as lower trachea, main bronchi, proximal intrapulmonary airways and distal intrapulmonary airways (P<0.01). CONCLUSION: The model established in this study is useful for measuring the acute responses of airways induced by cigarette smoke in guinea pigs. Acute inhalation of cigarette smoke decreases dynamic lung compliance, increases airway resistance and vascular permeability of pulmonary vessels in guinea pigs.

Comparison of bronchodilating and antiinflammatory activities of oral formoterol and its (R,R)-enantiomers.

AIM: To compare the bronchodilating and antiinflammatory effects of oral racemic formoterol (rac-FMT) and (R,R)-formoterol (R,R-FMT). METHODS: The changes of lung resistance (RL), dynamic lung compliance (Cdyn), and the accumulation of inflammatory cells in bronchoalveolar lavage fluids (BALF) induced by ovalbumin aerosol in sensitized guinea pigs and mice were investigated in vivo. RESULTS: Mean value increase of RL and mean value reduction of Cdyn from 1 to 30 min after antigen challenge were up to 101 %+/-34 % and 42 %+/-7 %, respectively. rac-FMT 0.5, 1.0, and 2.0 mg/kg, and R,R-FMT 0.25, 0.5, and 1.0 mg/kg ig, induced dose-related inhibition of the bronchoconstrictive responses to aerosolised ovalbumin. ID50 (95% confidence limits, 95 % CL) value of rac-FMT on RL maximal increase and Cdyn maximal reduction at 5 min were 0.64 (0.54-0.76) and 1.02 (0.88-1.18) mg/kg, respectively. For R,R-FMT they were 0.46 (0.40-0.53) and 0.52 (0.45-0.61) mg/kg, respectively. ID50 (95 % CL) value of rac-FMT on RL mean increase and Cdyn mean reduction from 1 to 30 min were 0.96 (0.86-1.07) and 1.59 (1.32-1.92) mg/kg, respectively. For R,R-FMT they were 0.52 (0.45-0.59) and 0.43 (0.37-0.51) mg/kg, respectively. Ovalbumin-aerosol challenge induced an increase of inflammatory cells in BALF in sensitized mice. rac-FMT and RR-FMT caused a dose-dependent and almost complete inhibition at 2.0 mg/kg. ID50 (95 % CL) of rac-FMT on the number of total inflammatory cells and eosinophil in BALF were 1.48 (1.22-1.81) and 0.80 (0.62-1.04) mg/kg, respectively. ID50 (95 % CL) of RR-FMT were 0.80 (0.57-1.13) and 0.60 (0.43-0.83) mg/kg, respectively. CONCLUSION: R,R-FMT protected lung against increase of RL and reduction of Cdyn induced by bronchial challenge of ovalbumin in the asthma model of guinea pigs, and inhibited airway inflammation in the sensitized mice. Efficacy of R,R-FMT was approximately 2-fold than that of rac-FMT.

Effects of cyclosporin A by aerosol on airway hyperresponsiveness and inflammation in guinea pigs.

AIM: To study cyclosporin A (CsA) by aerosol for anti-asthmatic effects in guinea pigs. METHODS: PC200 changes of lung resistance (RL) in the antigen-challenged sensitized guinea pig induced by acetylcholine (ACh) or histamine, and eosinophils changes in bronchoalveolar lavage fluid (BALF) and pulmonary histologic section induced by antigen in vivo in sensitized guinea pigs were investigated. RESULTS: Pretreatment with CsA 10 g/L and 20 g/L by aerosol but not with CsA 5 g/L, dexamethasone (DXM) 0.5 mg/kg by ip increased PC200 value and prevented ACh or histamine-induced airway hyperresponsiveness. However, CsA 5 g/L also prevented histamine-induced airway hyperresponsiveness. CsA 10 g/L, 20 g/L and DXM 0.5 mg/kg reduced markedly eosinophil accumulation in BALF. The lymphocyte accumulation induced by antigen was not changed significantly by CsA and DXM tested. DXM 0.5 mg/kg increased number of neutrophil in the BALF. There was a statistical significance comparison with CsA groups. In the pulmonary histological studies, CsA 20 g/L and DXM 0.5 mg/kg also inhibited eosinophil infiltration in the epithelium and subepithelial connective tissue of bronchi and bronchioles. CONCLUSION: Anti-inflammation and anti-hyperresponsiveness of CsA by aerosol in animal model offered an experimental evidence for airway inhalation of CsA in the treatment of asthma.