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.
Division of Clinical Immunology, Mount Sinai School of Medicine, New York, New York 10029, USA. paula.busse@mssm.edu
Paula J
PJ
Busse
Teng Fei
TF
Zhang
Brian
B
Schofield
Saikiran
S
Kilaru
Sangita
S
Patil
Xiu-Min
XM
Li
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