To establish a model of cigarette smoke exposure to asthmatic rats and glucocorticoid resistance induced by nicotine in alveolar epithelioid cells A549 and study the mechanism for the change of glucocorticoid sensitivity induced by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580.Sixty Wistar rats were randomly divided into 4 groups: normal group, asthmatic group, cigarette smoke exposure to asthmatic group and SB203580 group. The mRNA expressions of glucocorticoid receptor (GR), heat shock protein 90 (HSP90) and p38 MAPK were detected by real time-polymerase chain reaction (RT-PCR) while their protein expressions detected by Western blot in vivo. A549 cells were divided averagely into 4 groups: group A: normal; group B: 1 µmol/L dexamethasone (DEX); group C: 1 µmol/L DEX +1 µmol/L nicotine; group D: 1 µmol/L DEX +1 µmol/L nicotine+1 µmol/L SB203580. Immunofluorescence staining was used to study the in vitro colocalization of glucocorticoid receptor (GR) in A549 cells.The mRNA expression of GR was 0.671 ± 0.002 in cigarette smoke exposure to asthmatic group and 0.595 ± 0.061 in SB203580 group (P = 0.065). The protein expression of GR was 0.700 ± 0.033 in cigarette smoke exposure to asthmatic group and 0.628 ± 0.091 in SB203580 group (P = 0.148). The mRNA expression of HSP90 was 0.558 ± 0.009 in cigarette smoke exposure to asthmatic group and 0.377 ± 0.046 in SB203580 group (P = 0.000). The protein expression of HSP90 was 0.507 ± 0.030 in cigarette smoke exposure to asthmatic group and 0.402 ± 0.050 in SB203580 group (P = 0.005). The mRNA expression of p38 MAPK was 0.971 ± 0.012 in cigarette smoke exposure to asthmatic group and 0.278 ± 0.049 in SB203580 group (P = 0.000). The protein expression of p38 MAPK was 0.982 ± 0.038 in cigarette smoke exposure to asthmatic group and 0.338 ± 0.042 in SB203580 group (P = 0.000). The ratio of GR amount within A549 nucleus versus that in cytoplasm was 0.077 ± 0.047 in group C and 0.592 ± 0.249 in group D (P = 0.000).The mechanism of SB203580 enhancing the corticosteroid sensitivity may be improving nuclear translocation of GR to elevate corticosteroid sensitivity.