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-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.


CONCLUSIONS
This mechanism could be important for prophylactic strategies aiming at airway remodeling and could be a new indication for antihistamine treatment.
Kunzmann
Steffen
S
University Children's Hospital, Würzburg, Germany. kunzmann_s@kinderklinik.uni-wuerzburg.de
Schmidt-Weber
Carsten
C
Zingg
Jean-Marc
JM
Azzi
Angelo
A
Kramer
Boris W
BW
Blaser
Kurt
K
Akdis
Cezmi A
CA
Speer
Christian P
CP
D002460:Cell Line; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000502:physiology*; D006632:Histamine / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology
C526317:CCN2 protein, human; D016326:Extracellular Matrix Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor; D006632:Histamine