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Articles in PresS, published online ahead of print August 9, 2002
J Appl Physiol, 10.1152/jap.00083.2002
Submitted on February 1, 2002
Accepted on August 5, 2002
1 Research Institute for Disease of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2 Department of Medicine, National Jewish Medical and Research Center, Denver, CO, USA
3 Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA
4 Pulmonary Biology, Children's Hospital Medical Center of Cincinnati, Cincinnati, OH, USA
5 Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: karen.fagan{at}uchsc.edu.
Tumor necrosis factor (TNF)-
transgenic mice have previously been found to have characteristics consistent with emphysema and severe pulmonary hypertension. Lungs demonstrated alveolar enlargement as well as interstitial thickening due to chronic inflammation and perivascular fibrosis. In the present report, we sought to determine potential mechanisms leading to development of pulmonary hypertension in TNF- transgenic mice. To determine if sustained vasoconstriction was an important component of this pulmonary hypertension, nitric oxide was administered and hemodynamics measured. 25 ppm NO failed to normalize right ventricular pressure in transgene positive mice suggesting that the pulmonary hypertension was not due to sustained vasoconstriction. Structural analysis of the pulmonary arteries found adventitial thickening and a trend toward medial hypertrophy in pulmonary arteries of transgene positive mice suggesting that vascular remodeling had occurred. Echocardiographic measurement of the percent fractional shortening of the left ventricle as a measurement of ventricular function in vivo revealed left ventricular dysfunction was not contributing to pulmonary hypertension. We examined expression of genes known to be important in regulation of vascular tone and structure. Messenger RNA expression of vascular endothelial growth factor (VEGF) and its receptor flk-1 were reduced compared to transgene-negative littermates at all ages. Endothelial (ecNOS) and inducible (iNOS) nitric oxide synthase mRNA levels were similar in both groups. Endothelin-1 mRNA was also decreased in TNF- transgenic mice. Interestingly, female transgenic mice had decreased survival rate compared to male transgenic mice We conclude that chronic overexpression of TNF- is associated with decreased VEGF and flk-1 gene expression, pulmonary vascular remodeling, and severe pulmonary hypertension although the precise mechanism is unknown.
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