Manipulation of allergen-induced airway remodeling by treatment with anti-TGF-beta antibody: effect on the Smad signaling pathway.

Abstract

Airway inflammation and remodeling are important pathophysiologic features of chronic asthma. Previously, we have developed a mouse model of prolonged allergen challenge which exhibits many characteristics of chronic asthma such as goblet cell hyperplasia and subepithelial collagen deposition, in association with an increase in lung expression of the profibrotic mediator, TGF-beta. The aim of this study was to determine the effects of blockade of TGF-beta on the development of airway inflammation and remodeling using our murine model of prolonged allergen challenge. Importantly anti-TGF-beta Ab was administered therapeutically, with dosing starting after the onset of established eosinophilic airway inflammation. Therapeutic treatment of mice with anti-TGF-beta Ab significantly reduced peribronchiolar extracellular matrix deposition, airway smooth muscle cell proliferation, and mucus production in the lung without affecting established airway inflammation and Th2 cytokine production. Thus, our data suggest that it might be possible to uncouple airway inflammation and remodeling during prolonged allergen challenge. In addition, anti-TGF-beta Ab treatment was shown to regulate active TGF-beta signaling in situ with a reduction in the expression of phospho-Smad 2 and the concomitant up-regulation of Smad 7 in lung sections. Therefore, this is the first report to suggest that anti-TGF-beta Ab treatment prevents the progression of airway remodeling following allergen challenge even when given in a therapeutic mode. Moreover, the molecular mechanism behind this effect may involve regulation of active TGF-beta signaling.

• Authors: Sarah J McMillan, Georgina Xanthou, Clare M Lloyd
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 174 Issue 9 Pg. 5774-80 (May 01 2005) ISSN: 0022-1767 [Print] United States
• PMID: 15843580 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• DNA-Binding Proteins
• Growth Inhibitors
• Immune Sera
• Inflammation Mediators
• Smad Proteins
• Trans-Activators
• Transforming Growth Factor beta
• Ovalbumin

Topics

• Allergens (administration & dosage)
• Animals
• Bronchoalveolar Lavage Fluid (immunology)
• Cell Proliferation
• DNA-Binding Proteins (physiology)
• Down-Regulation (immunology)
• Extracellular Matrix (immunology, metabolism, pathology)
• Female
• Growth Inhibitors (administration & dosage)
• Immune Sera (administration & dosage)
• Inflammation (immunology, pathology, prevention & control)
• Inflammation Mediators (administration & dosage, metabolism)
• Lung (immunology, pathology, physiopathology)
• Mice
• Mice, Inbred BALB C
• Mucus (immunology, metabolism)
• Muscle, Smooth (cytology, immunology)
• Ovalbumin (administration & dosage, immunology)
• Signal Transduction (immunology)
• Smad Proteins
• Trans-Activators (physiology)
• Transforming Growth Factor beta (antagonists & inhibitors, immunology, physiology)