Exp Mol Med.  2005 Feb;37(1):27-35.

Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective tissue growth factor expression in the lung

• Lee YS
• Byun J
• Kim JA
• Lee JS
• Kim KL
• Suh YL
• Kim JM
• Jang HS
• Lee JY
• Shin IS
• Suh W
• Jeon ES
• Kim DK

Abstract

Pulmonary hypertension (PH) is characterized by structural and functional changes in the lung including proliferation of vascular smooth muscle cells (VSMCs) and excessive collagen synthesis. Although connective tissue growth factor (CTGF) is known to promote cell proliferation, migration, adhesion, and extracellular matrix production in various tissues, studies on the role of CTGF in pulmonary hypertension have been limited. Here, we examined CTGF expression in the lung tissues of male Sprague Dawley rats treated with monocrotaline (MCT, 60 microgram/kg), a pneumotoxic agent known to induce PH in animals. Establishment of PH was verified by the significantly increased right ventricular systolic pressure and right ventricle/left ventricle weight ratio in the MCT-treated rats. Histological examination of the lung revealed profound muscular hypertrophy in the media of pulmonary artery and arterioles in MCT-treated group. Lung parenchyma, vein, and bronchiole did not appear to be affected. RT-PCR analysis of the lung tissue at 5 weeks indicated significantly increased expression of CTGF in the MCT-treated group. In situ hybridization studies also confirmed abundant CTGF mRNA expression in VSMCs of the arteries and arterioles, clustered pneumocytes, and infiltrated macrophages. Interestingly, CTGF mRNA was not detected in VSMCs of vein or bronchiole. In saline-injected control, basal expression of CTGF was seen in bronchial epithelial cells, alveolar lining cells, and endothelial cells. Taken together, our results suggest that CTGF upregulation in arterial VSMC of the lung might be important in the pathogenesis of pulmonary hypertension. Antagonizing the role of CTGF could thus be one of the potential approaches for the treatment of PH.

Keyword

connective tissue growth factor; fibrosis; hypertrophy; monocrotaline; pulmonary hypertension

MeSH Terms

Animals
Blood Pressure/drug effects
Bronchi/cytology/drug effects/metabolism
Endothelial Cells/cytology/drug effects/metabolism
Epithelial Cells/cytology/drug effects/metabolism
Hypertension, Pulmonary/chemically induced/*metabolism
Immediate-Early Proteins/genetics/*metabolism
Intercellular Signaling Peptides and Proteins/genetics/*metabolism
Lung/cytology/drug effects/*metabolism
Male
Monocrotaline/*toxicity
Pulmonary Alveoli/cytology/drug effects/metabolism
Pulmonary Artery/cytology/drug effects/metabolism
Rats
Rats, Sprague-Dawley
Research Support, Non-U.S. Gov't
Reverse Transcriptase Polymerase Chain Reaction
Up-Regulation