Connective tissue growth factor expression is regulated by histamine in lung fibroblasts: Potential role of histamine in airway remodeling

Background: In the inflamed lung of allergic asthma, an aberrant injury-repair response is accompanied by structural changes in the airway, known as airway remodeling. TGF-β and its downstream mediator connective tissue growth factor (CTGF) are playing a key role in these processes, resulting in irreversible airway remodelling. Objective: As histamine is a key mediator of allergic reactions, we investigated whether histamine is involved in airway remodeling. Methods: The effect of histamine and TGF-β1 on proliferation of lung fibroblast cells IMR-90 was studied by [³H]-thymidine proliferation assay. The regulation of CTGF by histamine and TGF-β1 in lung fibroblasts was analyzed by RT-PCR, real-time PCR, Western blot analysis, and promoter analysis and characterized by specific histamine-receptor antagonists. Results: Histamine and TGF-β1 enhanced proliferation of lung fibroblast cells IMR-90. Both induced CTGF mRNA and protein expression with different time kinetics. Whereas TGF-β1 induced maximal CTGF expression after 12 hours (347% ± 23%), histamine-induced maximal CTGF expression was lower and delayed (maximum expression of 204% ± 11% after 48 hours). Histamine and TGF-β1 stimulated the CTGF promoter and the TGF-β-response element in the CTGF promoter. The histamine-induced CTGF expression was mediated through the histamine receptor (HR1) and could be completely abolished by TNF-α. Conclusions: These findings demonstrate that histamine plays a potential role in the induction of airway remodeling mediated by the induction of lung fibroblasts proliferation and CTGF expression. Clinical implications: This mechanism could be important for prophylactic strategies aiming at airway remodeling and could be a new indication for antihistamine treatment.