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-beta 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-beta1 on proliferation of lung fibroblast cells IMR-90 was studied by [(3)H]-thymidine proliferation assay. The regulation of CTGF by histamine and TGF-beta1 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-beta1 enhanced proliferation of lung fibroblast cells IMR-90. Both induced CTGF mRNA and protein expression with different time kinetics. Whereas TGF-beta1 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-beta1 stimulated the CTGF promoter and the TGF-beta-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-alpha. 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.
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-beta 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-beta1 on proliferation of lung fibroblast cells IMR-90 was studied by [(3)H]-thymidine proliferation assay. The regulation of CTGF by histamine and TGF-beta1 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-beta1 enhanced proliferation of lung fibroblast cells IMR-90. Both induced CTGF mRNA and protein expression with different time kinetics. Whereas TGF-beta1 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-beta1 stimulated the CTGF promoter and the TGF-beta-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-alpha. 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.
Authors: Bridgette L Jones; Gregory Kearns; Kathleen A Neville; Catherine M T Sherwin; Michael M G Spigarelli; J Steven Leeder Journal: J Clin Pharmacol Date: 2013-05-16 Impact factor: 3.126
Authors: Byeong Gon Kim; Pureun Haneul Lee; Shin Hwa Lee; Young En Kim; Mee Yong Shin; Yena Kang; Seong Hwan Bae; Min Jung Kim; Taiyoun Rhim; Choon Sik Park; An Soo Jang Journal: Allergy Asthma Immunol Res Date: 2016-05 Impact factor: 5.764
Authors: Markus Fehrholz; Kirsten Glaser; Christian P Speer; Silvia Seidenspinner; Barbara Ottensmeier; Steffen Kunzmann Journal: Respir Res Date: 2017-03-23