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

BackgroundIn 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.ObjectiveAs histamine is a key mediator of allergic reactions, we investigated whether histamine is involved in airway remodeling.MethodsThe 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.ResultsHistamine 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.ConclusionsThese 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 implicationsThis mechanism could be important for prophylactic strategies aiming at airway remodeling and could be a new indication for antihistamine treatment.