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Direct Effects of TNF‐α on Fibronectin Generation in Rats with Heart Failure
Author(s) -
Doursout MarieFrancoise,
Liang Yang Yan,
Chelly Brice,
Drake Robert E.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a232-d
Subject(s) - proinflammatory cytokine , ventricle , fibronectin , medicine , endocrinology , tumor necrosis factor alpha , heart failure , diastole , cytokine , ventricular pressure , chemistry , blood pressure , inflammation , biochemistry , extracellular matrix
Elevated left artrial pressures (LAPs) are common in patients with heart failure. We have demonstrated TNF‐α is the primary proinflammatory cytokine in fibrogenesis in our elevated LAP model. We investigated the direct effects of TNF‐α production in our rat model of elevated LAP‐induced pulmonary fibrosis. The modulatory influences of TNF‐α on fibronectin generation in 1) sham‐control, 2) rats subjected to elevated LAP, and 3) rats subjected to LAP in the presence of pentoxyfilline (PTX), a methylxanthine derivative of a phosphodiesterase inhibitor were assessed. A catheter was introduced into the left ventricle to record left ventricular end diastole pressure. A wire was introduced through the left ventricle to restrict left ventricular filling during cardiac diastole, causing an increase in LAP about 15–20 mm Hg above baseline. 18 rats were divided into 3 groups (n=6). Group 1 was sham‐control, Group 2 was subjected to elevated LAP, whereas Group 3 was subjected to elevated LAP in the presence of PTX (1mg/kg/hr for 4 days), infused through an osmotic minipump to down‐regulate proinflammatory TNF‐α production by alveolar macrophages. Amounts of TNF‐α and fibronectin in the presence and absence of PTX were measured in alveolar macrophages using an ELISA assay. Our data show in rats treated with PTX, lung fluid decreased significantly by 35% compared to non‐treated rats with elevated LAP (2.74 ± 0.32 vs 4. 21 ± 0.57 ml/kg respectively). PTX inhibits TNF‐α production by 90% and fibronectin by 50%. Our data suggest fibronectin generation leading to fibroblast expansion is directly correlated to elevated TNF‐α production in rats with elevated LAP. Research funded by NIH.