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Pulmonary and Activation-Regulated Chemokine Stimulates Collagen Production in Lung Fibroblasts

Departments of Medicine and of Microbiology and Immunology, University of Maryland School of Medicine; and Research Service, Veterans Affairs Maryland Health Care System, Baltimore, Maryland; Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina; and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania

Address correspondence to: Sergei P. Atamas, M.D., Ph.D., Baltimore VA Medical Center, Research Service (151), Room 3C-125, 10 North Greene Street, Baltimore, MD 21201. E-mail: satamas{at}umaryland.edu

Levels of pulmonary and activation-regulated chemokine (PARC) mRNA and protein are increased in the lungs of patients with pulmonary fibrosis. The purpose of this study was to establish whether PARC could be directly involved in development of pulmonary fibrosis by stimulating collagen production in lung fibroblasts. Exposure to PARC increased production of collagen mRNA and protein by 3- to 4-fold in normal adult lung and dermal fibroblast cells. Collagen mRNA transiently increased after 3–6 h of activation with PARC, with an increase in collagen protein detected after 24 h of activation. At the same time, PARC had less pronounced effect on fibroblast proliferation, not exceeding 50% increase over control nonstimulated cells. PARC intracellular signaling led to activation of ERK1/2, but not p38, in fibroblasts; pharmacologic inhibition of ERK, but not p38, also blocked PARC's effect on collagen production. Inhibition experiments with pertussis toxin suggested that PARC receptor is G protein–coupled. Thus, PARC is a member of the CC chemokine family that acts directly as a profibrotic factor.

Abbreviations: bronchoalveolar lavage, BAL • enzyme-linked immunosorbent assay, ELISA • extracellular signal-regulated kinase, ERK • interleukin, IL • monocyte chemotactic protein, MCP • macrophage inflammatory protein, MIP • pulmonary and activation-regulated chemokine, PARC • polymerase chain reaction, PCR • pertussis toxin, PT • recombinant human, rh • transforming growth factor-ß1, TGF-ß1

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