Effects Of Dexamethasone On Acrolein-induced Mucus Hypersecretion Of Rat Airways

Purpose:1.To investigate the role of nuclear factor- K B in acrolein-induced MUC5AC expression in rat airways and the effects of dexamethasone on the nuclear factor-KB.2.To investigate the role of the protein kinase C signal transduction Pathway in acrolein-induced MUC5AC expression in rat airways and the effects of dexamethasone on the PKC.3.To investigate the role of TNF-α and IL — 8 in BALF of acrolein-induced MUC5AC expression in rat airways and the effects of dexamethasone on TNF— α and IL—8 release. Methods:1 .Rat models of mucus hypersecretion of airways were established by exposing to 3.0ppm acrolein fog 6 hours per day for 12 days.Animals were also injected intraperitoneally with dexamethasone (0.1mg.kg~-1.d~-1 or 0.5mg.kg~-1.d~-1) with or without exposing to acrolein fog.2. The mRNA of MUC5AC and the proteins of MUC5AC , nuclear factor-KB ,IκB— α and PKC of trachea and lung tissue of each animal were detected by RT-PCR and irnmunolhistochemistry.The results were processed semiquantitatively by image analysis.3. The release of TNF—α and IL—8 in BALF of each animal were detected by ELISA.Results:1. (DThe levels of MUC5AC mRNA and the expression of MUC5AC in both the trachea and the lung tissue in the acrolein group increased on day 6 and peaked on day 12,compared with those in control group (P<0.01) ; Acrolein up-regulated MUC5AC mRNA expression in both the trachea and the lung tissue decreased at day 6,and were lowest on day 9,after treated with dexamethasone.A significant difference in expression of MUC5AC of both trachea and lung tissue was found between acrolein group and the group treated with either low or high dose of dexamethasone ( PO.01 ) . (2)The levels of MUC5AC mRNA and the expression of MUC5AC protein in both the trachea and the lung tissue at the each time point were slightly lower in group treated with dexamethasone alone than that of control with no significance (P >0.05) . (3)For the effect of dexamethasone on both the expression of MUC5AC and the level of MUC5AC mRNA in rat airway,no significant difference was found between the low and the high dose (P > 0.05) .2. (DThe percentage of NF— k B positive nuclei-stained cell in both the trachea and the lung tissue in acrolein group increased on day 6,and peaked on day 12,compared with that in control group (P<0.01) ; Dexamethasone treatment decreased the percentage of the NF— k B positive nuclei-stained cell in both the trachea and the lung tissue,which induced by acrolein(PO.01) . (2)The expression of I— KB in both the trachea and the lung tissue in acrolein group significantly decreased on day 6,and dropped to the minimum on day 12,compared with that in control (PO.01) . The expression of I— K B in both the trachea and the lung tissue in groups treated with either low or high dose of dexamethasone increased on day 6,and reached the peak on day 9,compared with that in acrolein group . A significant difference was noted in the the expression of I— K B of in both the trachea and in the lung tissue between the acrolein group and dexamethasone treated groups(PO.05) . (3)Correlation analysis showed the percentage of the NF—k B positive nuclei-stained cell in both the trachea and the lung tissue in theacrolein -induced group were positively related to the level of MUC5AC mRNA of the trachea and the lung tissue respectively(r=0.79 and 0.71, PO.05), whereas the percentage of nuclear factor- K B positive nuclei-stained cell were negatively related to the expression of I— k B both in the trachea and the lung tissue, respectively(r=-0.88 and -0.83, P<0.01)°3. The expression of PKC in both trachea and lung tissue in the acrolein group markedly elevated on day 6,and reached the peak on day 12,compared with those in control group (P<0.01) . The expression of PKC at each time point were positively related to the expression of MUC5AC(r=0.86 and 0.78, PO.01 and 0.05).In contrast,the increased expression of PKC in both the trachea and the lung tissue were significantly reduced in groups treated with low or high dose of dexamethasone (PO.01) .4. The level of TNF— a and IL—8 in BALF in acrolein group started to elevate on day 6,and peaked on day 12,which were significantly different than that of control group (P<0.01) . Correlation analysis showed the level of TNF— a and IL—8 in BALF in acrolein group were positively related to the expression of MUC5AC in both the trachea and the lung tissue,respectively(r=0.73> 0.70 ^ 0.79 and 0.68, P< 0.05), whereas the levels of TNF— a and IL—8 in BALF in groups treated with low or high dose of Dexamethasone were decreased on day 6,and reduced to the minimum on day 9,which were significantly lower than that in acrolein group.Conclusion1. NF —KB activation involved in the acrolein-induced mucus hypersecretion in rat airway. Dexamethasone might decrease NF —KB activation through up-regulation of the expression of 1KB- a ,and therefore reduce the expression of MUC5AC in rat airways .2.PKC involved in the acrolein-induced mucus hypersecretion in rat airway. Dexamethasone might inhibit the expression of MUC5AC in rat airways through the reduction of PKC activity.3. TNF — a and IL — 8 involved in the acrolein-induced mucus hypersecretion in rat airway. Dexamethasone might inhibit the expression of MUC5AC in rat airways by reducing the release of TNF— a and IL—8 activity.4.For the effect of dexamethasone on the expression of MUC5AC in rat airway,no significant difference was found between the low and the high dose.