title: Chronic exposure to TNF-alpha increases airway mucus gene expression in vivo.
abstract: BACKGROUND
  Hypersecretion of mucus plays an important role in the pathogenesis and severity of asthma. The primary proteins in mucus are mucin glycoproteins; MUC-5AC is the primary airway mucin gene. The calcium chloride-activated channel gene hCLCA1 (gob-5 in the mouse) has been suggested to increase MUC-5AC gene expression, and both are increased in asthmatic patients and murine models. TNF-alpha increases the expression of these genes in vitro but has not been investigated in vivo.
  
  
  OBJECTIVE
  We sought to determine whether TNF-alpha increases gene expression of gob-5 and MUC-5AC and induces mucus cell metaplasia in vivo.
  
  
  METHODS
  Naive BALB/c mice received 50 ng of recombinant murine TNF-alpha (rmTNF-alpha) intratracheally daily for 1, 2, or 3 weeks; another group received the same dose of intratracheal rmTNF-alpha daily for 3 weeks and then alternate-day treatment for 3 additional weeks (total of 6 weeks). AKR mice received 50 ng of rmTNF-alpha intratracheally for 3 or 6 weeks daily. Naive nontreated mice were used as control animals. Airway gene products for gob-5 and MUC-5AC were determined by means of real-time PCR. Lung tissue sections were stained with periodic acid-Schiff/Alcian blue to assess mucus cell metaplasia.
  
  
  RESULTS
  rmTNF-alpha significantly increased gene expression of airway gob-5 and MUC-5AC after 2 weeks in the BALB/c mice. There was noticeable mucus staining in all mice treated for at least 3 weeks with TNF-alpha and in 80% of the mice receiving 2 weeks of treatment. After 3 weeks of treatment, the AKR mice also showed increased gob-5 expression.
  
  
  CONCLUSIONS
  This study demonstrates for the first time that TNF-alpha alone in vivo is sufficient to increase airway mucus gene expression in 2 murine strains.
authors.affiliation: Division of Clinical Immunology, Mount Sinai School of Medicine, New York, NY 10029, USA. paula.busse@mssm.edu
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Busse
authors.forename: Teng Fei
authors.initials: TF
authors.lastname: Zhang
authors.forename: Kamal
authors.initials: K
authors.lastname: Srivastava
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Lin
authors.forename: Brian
authors.initials: B
authors.lastname: Schofield
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
authors.forename: Xiu-Min
authors.initials: XM
authors.lastname: Li
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000209:etiology; D018118:Chloride Channels / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics*; D009088:Mucoproteins / Q000235:genetics*; D009093:Mucus / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D016207:Cytokines; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D009088:Mucoproteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha