The Profiles Of Th2 Cytokines, Control Of Breathing And The Effect Of Zafirlukast (Accolate): A Cysteinyl-LT Receptor Antagonist, On The Immune Regulation Of Airway Inflammation, IgE Synthesis In Stable Bronchial Asthma Patients

Objective: 1 To clarify the cyiokine profiles in atopic stable asthma patients and the effects of the Th2-like pattern of cytokines (IL-4 ,IL-5) on airway inflammation, IgE production and airway obstruction. 2 To investigate the effect of Zafirlukast on the immune regulation of airway inflammation and the profiles of control of breathing in atopic stable asthma patients.Method: Patients with allergic asthma was enrolled in this randomized, double-blind, self-controlled, two-period, crossover trial. Control subjects were required to have a lifelong absence of any symptoms indicative of allergic disease. Each asthma patient demonstrated reversible airway obstruction by a 15% or greater increase in 1-s forced expiratory volume (FEV1) after inhaled 3 2-agonist or a positive response to methacholine challenge. All the enrolled patients with asthma received 6 weeks of treatment with Zafirlukast (Accolate) . The Spirometry, the mouth occlusion pressure (PO.l) at rest , the ventilatory and occlusion pressure (PO.l) responses to hyperoxic progressive hypercapnia expressed as the slopes of the linear regression equation ( A VE/ A PaCO2 and A PO.l/ A PaCO2, respectively) using the least square method and inspiratory impedance (PO.l/Vt/Ti) were assessed in control subjects and the asthma patients without taking drugs .In order to clarify the cytokine profiles in asthma and the effect of Zafirlukast (Accolate) on the airway inflammation, We have therefore examined the serum levels of ECP and IgE . the PHA-induced IL-4 , PHA-induced r-IFN and spontaneous IL-5 concentration in cultures of peripheral blood mononuclear cells (PBMC) in control group without treatment and in asthma patients before and after the treatment with Zafirlukast.Results: (1) Mouth occlusion pressure (PO.l) and inspiratory impedance(PO.l/Vt/Ti) were significantly increased in asthma group compared with the control subjects (PO.01). The ventilatory response to progressive hypercapnia (AVE/APaCO2) , which correlated positively with FEV1% ( r=0.34, p<0.01), was lower in the asthma patients compared with control subjects (p < 0.05), whereas the PO.l response to progressive hypercapnia (A PO.l/ A PaCO2) was not significantly different between the two groups . In asthma group, the PO.l response to CO2 did not correlate with any pulmonary function test or respiratory muscle function variable. (2) The serum levels of ECP and IgE ,the PHA-induced IL-4 and spontaneous IL-5 concentration in cultures of peripheral blood mononuclear cells (PBMC)were significantly increased in asthma group before treatment of Zafirlukast compared with that in normal controls , while the PHA-induced r-IFN in cultures of PBMC was lower compared with that in controls. Furthermore the PHA-induced IL-4 concentration in cultures of peripheral blood mononuclear cells (PBMC) was positively related to the serum level of IgE (rs=0.743,p<0.001) , while the spontaneous IL-5 concentration in cultures of peripheral blood mononuclear cells (PBMC) was positively related to the serum ECP concentration (rs=0.683, PO.001) and inversely related to the FEV1% (rs=-0.854,P<0.001) in the asthma patients without treatment by Zafirlukast. (3) Zafirlukast therapy was associated with significantly decreasing of IL-4 concentration in PBMC , serum IgE concentration and serum ECP concentration in the asthma patients. In addition, Zafirlukast therapy could also decrease the spontaneous IL-5 concentration in PBMC in asthma patients. Furthermore , A IL-4 correlated positively with A IgE . (rs=0.459,P<0.001), while A IL-5 correlated positively with the A ECP ( rs=0.601 , PO.001 ) and A FEV1% (rs=0.432,P=0.002)in asthma patients.Conclusions: (1) Measurement of PO.l and PO.l/Vt/Ti in our research revealed increased neuromuscular drive , inspiratory impedance and decreased respiratory efficiency in asthma patients. The decreased ventilatory response to progressive hypercapnia ( A VE/ A PaCO2) was due to the increased airway resistance in asthma patients, while the PO.l response to CO2 had no rela...