Airway Inflammation And Mucus Hypersecretion Is Regulated Through P38 MAPK/MMP-9 Pathway

[Objectives] To clarify the effect of p38 MAPK on airway inflammation and mucus hypersecretion and the possible cross-talk between p38 MAPK and MMP-9 in mucin gene transcription.[Methods] In order to establish airway mucus hypersecretion, mice were exposed to 4.0 ppm of acrolein for 21 days, meanwhile, SB203580 was intraperitonealy injected into the experimental animals every day, whereas saline inhalation for sham exposure group. On Days 7 and 21, animals were sacrificed. Airway inflammation and mucus overproduction were evaluated by HE, AB-PAS, IHC, Western blot, and RT-PCR.[Main Results] Both inflammatory cells and Mucus-secreting goblet cells were strikingly increased in exposed mice inhaled with acrolein for 21 days, which was significantly reduced after administration of SB203580. In acrolein group and acrolein+SB203580 group, AB/PAS-positive staining areas were calculated as 15.54±0.93%, 9.82±0.56% respectively, with significant difference (P<0.01). Increased expression of MUC5AC, MMP-9 protein (MUC5AC, 0.153±0.017; MMP-9, 0.236±0.038) and mRNA (MUC5AC, 1.180±0.054; MMP-9, 1.270±0.048) in mice exposed to acrolein were attenuated with the administration of SB203580 at day 21 (P<0.01). Western blot analysis showed that phospho-p38 MAPK (1.004±0.039) as well as p38 MAPK (1.016±0.06) protein was dramatically activated in mice exposed to acrolein compared with control, which was a markedly suppressed with p38 MAPK inhibitor SB203580. The expression of phospho-p38 MAPK protein was positive correlation with total cells in BALF, AB/PAS-positive staining areas, and MUC5AC and MMP-9 mRNA as well.[Conclusions] Those findings indicate that acrolein may induce murine airway inflammation and mucus overproduction; p38 MAPK and MMP-9 regulate MUC5AC mucin transcription, p38 MAPK/MMP-9 pathway might be therefore a novel molecular mechanism and therapeutic target for mucus hypersecretion.