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Carbon Monoxide Modulates –Smooth Muscle Actin and Small Proline Rich-1a Expression in Fibrosis

¹ Division of Pulmonary, Allergy and Critical Care Medicine; and ² Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Danielle Morse, M.D., Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115. E-mail: edmorse{at}partners.org

Carbon monoxide (CO) is a biologically active molecule produced in the body by the stress-inducible enzyme, heme oxygenase. We have previously shown that CO suppresses fibrosis in a murine bleomycin model. To investigate the mechanisms by which CO opposes fibrogenesis, we performed gene expression profiling of fibroblasts treated with transforming growth factor-β₁ and CO. The most highly differentially expressed categories of genes included those related to muscular system development and the small proline-rich family of proteins. We confirmed in vitro, and in an in vivo bleomycin model of lung fibrosis, that CO suppresses –smooth muscle actin expression and enhances small proline-rich protein-1a expression. We further show that these effects of CO depend upon signaling via the extracellular signal–regulated kinase pathway. Our results demonstrate novel transcriptional targets for CO and further elucidate the mechanism by which CO suppresses fibrosis.

Key Words: carbon monoxide • heme oxygenase-1 • lung fibrosis • small proline-rich protein • -smooth muscle actin

CLINICAL RELEVANCE Although carbon monoxide (CO) has been shown to confer protection in the setting of lung fibrosis, the mechanism by which it does this remains poorly understood. This study points to potential mechanisms by which CO may inhibit fibrogenesis and introduces a new candidate molecule that may be involved in the pathogenesis of fibrosis: small proline-rich protein-1.