p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog.
OBJECTIVE
To evaluate the role of p38 mitogen-activated protein kinase (MAPK) on mice airway inflammation, mucus production and the possible cross-talk between p38 MAPK and matrix metalloproteinase-9 (MMP-9) in mucin protein synthesis.


METHODS
Mice were exposed to 4.0 ppm of acrolein for 21 days with daily intraperitoneal injection of SB203580, a specific inhibitor of p38 MAPK. In control mice, sterile saline was administered instead. On days 7 and 21, mice were sacrificed to examine airway inflammation and mucus production by BALF cell counts, cytokine ELISA, and H&E and AB-PAS staining. The mRNA and protein levels of Muc5ac, p38 MAPK and MMP-9 in the lung were determined by RT-PCR, immunohistochemistry and Western blotting analysis. MMP-9 activity was measured by gelatin zymography.


RESULTS
Both the numbers of inflammatory cells and mucus-secreting goblet cells were significantly increased in the airways of mice exposed to acrolein as compared to the control mice. Acrolein-increased phosphorylation of p38 MAPK was significantly reduced by SB203580. The airway inflammation and goblet cell hyperplasia after acrolein challenge were also attenuated by SB203580 administration. Moreover, SB203580 treatment decreased the acrolein-induced increase of Muc5ac and MMP-9 expression and MMP-9 activity in airway epithelium.


CONCLUSIONS
The results indicate an important role of p38 MAPK in acrolein-induced airway inflammation and mucus hypersecretion in mice. The cooperation of p38 and MMP-9 may contribute to the mucin overproduction after inflammatory challenge.
Liu
Dai-Shun
DS
Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Sichuan, China.
Wang
Tao
T
Han
Su-Xia
SX
Dong
Jia-Jia
JJ
Liao
Zeng-Lin
ZL
He
Guang-Ming
GM
Chen
Lei
L
Chen
Ya-Juan
YJ
Xu
Dan
D
Hou
Yan
Y
Li
Yan-Ping
YP
Wen
Fu-Qiang
FQ
D000171:Acrolein / Q000009:adverse effects; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D055271:Mucin 5AC / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009093:Mucus / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage*; D020239:Receptor Cross-Talk; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology
D016207:Cytokines; D007093:Imidazoles; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D011725:Pyridines; D000171:Acrolein; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C093642:SB 203580