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

Abstract

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: Steffen Kunzmann, Carsten Schmidt-Weber, Jean-Marc Zingg, Angelo Azzi, Boris W Kramer, Kurt Blaser, Cezmi A Akdis, Christian P Speer
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 119 Issue 6 Pg. 1398-407 (Jun 2007) ISSN: 0091-6749 [Print] United States
• PMID: 17412405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCN2 protein, human
• Extracellular Matrix Proteins
• Immediate-Early Proteins
• Intercellular Signaling Peptides and Proteins
• Connective Tissue Growth Factor
• Histamine

Topics

• Cell Line
• Cell Proliferation
• Connective Tissue Growth Factor
• Extracellular Matrix Proteins (metabolism)
• Fibroblasts (metabolism, pathology)
• Fibrosis
• Gene Expression Regulation (physiology)
• Histamine (physiology)
• Humans
• Immediate-Early Proteins (biosynthesis, genetics, metabolism)
• Intercellular Signaling Peptides and Proteins (biosynthesis, genetics, metabolism)
• Lung (cytology, metabolism, pathology)