Published online before print June 14, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061167

Accepted for publication April 25, 2007.

Article

Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18

Kerill Pochetuhen^*, Irina G. Luzina^*, Virginia Lockatell^*, Jung Choi^*, Nevins W. Todd^*, and Sergei P. Atamas^*@

From the Department of Medicine,* University of Maryland School of Medicine and Research Service, Baltimore VA Medical Center, Baltimore, Maryland

^@ To whom correspondence should be addressed. E-mail: satamas{at}umaryland.edu.

	Abstract

Elevated pulmonary levels of CCL18 have been associated with influx of T lymphocytes, collagen accumulation, and a decline in lung function in pulmonary fibrosis patients. We previously reported that overexpression of CCL18 in mouse lungs triggers selective infiltration of T lymphocytes and moderate lymphocyte-dependent collagen accumulation. We hypothesized that in combination with bleomycin injury, overexpression of CCL18 will worsen the severity of lung inflammation and fibrosis. Mice were infected with a replication-deficient adenovirus encoding CCL18 and then instilled with bleomycin; control mice were challenged with either CCL18 overexpression or bleomycin. Additive effects of CCL18 overexpression and bleomycin injury were observed on pulmonary inflammation, particularly on T-cell infiltration, and increased levels of tumor necrosis factor-, interferon-, matrix metalloproteinase (MMP)-2, and MMP-9. Despite the additive effect on inflammation, CCL18 overexpression unexpectedly attenuated the bleomycin-induced collagen accumulation. Pulmonary levels of active transforming growth factor-1 mirrored the changes in collagen levels. Depletion of T cells with antilymphocyte serum or pharmacological inhibition of MMPs with GM6001 abrogated accumulation of collagen and increases in the levels of tumor necrosis factor-, interferon-, and active transforming growth factor-1. Thus, CCL18-stimulated T-lymphocytic infiltration is by itself mildly profibrotic to a healthy lung, whereas it partially protects against lung fibrosis in an inflammatory profibrotic pulmonary milieu.