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Reactive Nitrogen Species Augment Fibroblast-Mediated Collagen Gel Contraction, Mediator Production, and Chemotaxis

University of Nebraska Medical Center, Omaha, Nebraska; and University of Michigan Medical School, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., University of Nebraska Medical Center, 985885 Nebraska Medical Center, Omaha, NE 68198-5885. E-mail: srennard{at}unmc.edu

Reactive nitrogen species (RNS) such as peroxynitrite cause cellular injury and tissue inflammation. Excessive production of nitrotyrosine, which is a footprint of RNS, has been observed in the airways of patients with asthma and chronic obstructive pulmonary disease, disorders characterized by tissue remodeling. The aim of this study was to evaluate whether RNS can affect tissue remodeling through direct effects on fibroblasts, and to determine if these effects depend on production of transforming growth factor- (TGF-). To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess fibroblast-mediated contraction of floating gels and chemotaxis toward fibronectin. In addition, the ability of fibroblasts to release TGF-₁, fibronectin, and vascular endothelial growth factor (VEGF) was assessed by enzyme-linked immunosorbent assay. Authentic peroxynitrite significantly augmented gel contraction (P < 0.01) and chemotaxis (P < 0.01) compared with control in a concentration-dependent manner. Similarly, the peroxynitrite donor 3-morpholynosidenonimine hydrochloride (SIN-1) also augmented gel contraction (P < 0.01). RNS also significantly increased TGF-₁ (P < 0.01), fibronectin (P < 0.01), and VEGF (P < 0.01) release into the media in both 3D gel and monolayer culture. Anti–TGF- antibody reversed RNS-augmented gel contraction (P < 0.01) and mediator production (P < 0.01). Anti–TGF- antibody also partially, but significantly, reversed RNS-augmented chemotaxis toward fibronectin (P < 0.01). Finally, peroxynitrite enhanced expression of ₅₁ integrin, which is a receptor for fibronectin (P < 0.01), and neutralizing anti–TGF- antibody suppressed peroxynitrite-augmented ₅₁ expression (P < 0.01). These results suggest that RNS can affect the tissue repair process by modulating TGF-₁.

Key Words: peroxynitrite • transforming growth factor- • collagen gel contraction • chemotaxis • tissue repair

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