title: Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic airways.
abstract: BACKGROUND
  Many airway cells manifest signs of chronic activation in asthma. The mechanism of this chronic activation is unknown.
  
  
  OBJECTIVE
  We sought to study the activation of the mitogen-activated protein kinase (MAPK) signaling pathway in airway cells.
  
  
  METHODS
  Endobronchial biopsy specimens from patients with severe and mild asthma (n = 17 in each group) and healthy control subjects (n = 15) were analyzed for the phosphorylated MAPKs extracellular signal-regulated kinase (ERK) 1/2, p38, and Jun N-terminal kinase (JNK) and their downstream effectors by means of immunofluorescence staining. Airway epithelial activation of ERK1/2 and p38 was studied by using Western blotting. Epithelial function was studied by means of real-time PCR, ELISA, and the thymidine incorporation assay.
  
  
  RESULTS
  We detected strong phospho-ERK1/2 staining in airway epithelium and smooth muscle cells in biopsy specimens from asthmatic patients. Fluorescent areas per image, as well as mean fluorescence intensity, were significantly (P < .0001) different among the 3 study groups (patients with severe asthma, patients with mild asthma, and healthy control subjects). Patients with severe asthma also demonstrated strong phospho-p38 staining, mostly in epithelial cells, which was significantly different from that in patients with mild asthma (P = .0001) and healthy control subjects (P = .02). Phospho-JNK primarily stained airway smooth muscle cells. Healthy subjects showed the highest intensity of phospho-JNK staining compared with that seen in patients with severe (P = .004) and mild asthma (P = .003). Inhibition of ERK1/2 and p38 in primary airway epithelial cells blocked their proliferation and expression of select, but not all, chemokines.
  
  
  CONCLUSIONS
  Significant phosphorylation of ERK1/2 and p38 and their correlation with disease severity suggests that the foregoing signaling pathways play an important role in asthma. The ERK1/2 and p38 pathways regulate epithelial cell secretory function and proliferation.
authors.affiliation: Division of Allergy and Immunology, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Liang
authors.forename: Silvana
authors.initials: S
authors.lastname: Balzar
authors.forename: Sally
authors.initials: S
authors.lastname: Wenzel
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gorska
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: D000328:Adult; D001249:Asthma / Q000201:enzymology* / Q000473:pathology; D001980:Bronchi / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology
chemical_list: D018925:Chemokines; D047428:Protein Kinase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases