Decrease in airway mucous gene expression caused by treatment with anti-tumor necrosis factor alpha in a murine model of allergic asthma.
BACKGROUND
Mucous hypersecretion increases asthma morbidity and mortality. Tumor necrosis factor a (TNF-a) levels are elevated in bronchoalveolar fluid, sputum, and monocyte membranes in some patients with asthma. Anti-TNF-a decreased asthma exacerbations and improved forced expiratory volume in 1 second in these patients. Whether anti-TNF-a reduces mucous cell metaplasia or hyperplasia has not been evaluated.


OBJECTIVE
To investigate the role of anti-TNF-alpha in mucous hypersecretion.


METHODS
BALB/c mice sensitized intraperitoneally and challenged intratracheally with ovalbumin were treated with 250 microg of anti-TNF-alpha before ovalbumin sensitization and challenge or before only ovalbumin challenge. Control groups were sham treated. The tumor necrosis factor receptor (TNFR) mice (TNFR-/- and TNFR+/+) were identically sensitized and challenged. Seventy-two hours after the final challenge, the airway pressure time index (APTI), which measures airway hyperresponsiveness, was recorded. Mucous cell metaplasia was accessed by quantitative polymerase chain reaction for MUC-5AC (the epithelial cell mucous-inducing gene) and the percentage of periodic acid-Schiff (PAS) staining of bronchial epithelial cells. A human airway cell line (constitutively expressing MUC-5AC) was pretreated with a NF-kappaB inhibitor before TNF-alpha culture.


RESULTS
The mean (SE) fold change of MUC-5AC expression (compared with naive controls), the percentage of PAS-positive bronchiole epithelial cells, and the APTI decreased in BALB/c mice treated with anti-TNF-alpha before sensitization and challenge (4.9 [1.14], P = .007; 28.9% [6.8%], P < .001; and 545.8 [104.5] cm H2O/s, P < .001, respectively) and before challenge alone (9.3 [1.8], P = .03; 43.6% [10.7%], P = .009; and 896.8 [81.23] cm H2O/s, P = .06, respectively) compared with sham-treated mice (20.9 [3.9], 82.4% [1.8%], and 1,055 [30.6] cm H20/s, respectively). MUC-5AC expression decreased in ovalbumin sensitized or challenged TNFR-/- (2.41 [0.4]) compared with ovalbumin sensitized or challenged TNFR+/+ mice (18.4 [2.5], P < .001). TNF-alpha-induced MUC-5AC expression in human airway culture significantly decreased with pretreatment of a NF-kappaB inhibitor.


CONCLUSIONS
Anti-TNF-alpha treatment reduces airway mucous cell metaplasia in a mouse model of asthma, which may in part underlie its beneficial effect as asthma therapy.
Busse
Paula J
PJ
Division of Clinical Immunology, Mount Sinai School of Medicine, New York, New York 10029, USA. paula.busse@mssm.edu
Zhang
Teng Fei
TF
Schofield
Brian
B
Kilaru
Saikiran
S
Patil
Sangita
S
Li
Xiu-Min
XM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006651:Histocytochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000235:genetics; D010047:Ovalbumin / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology
D000911:Antibodies, Monoclonal; D055271:Mucin 5AC; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin