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Ccn2/Ctgf Overexpression Induced by Cigarette Smoke during Cutaneous Wound Healing is Strain Dependent

¹ Department of Histology and Embryology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
² Department of Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Correspondence: Dr. Andréa Monte Alto Costa, State University of Rio de Janeiro, Department of Histology and Embryology, Rua Professor Manuel de Abreu, 444, 3° andar, 20550-170, Rio de Janeiro, RJ, Brazil; e-mail:amacosta{at}uerj.br.

Cigarette smoke has been associated with poor healing in several studies, but the precise mechanisms involving this impairment are still not elucidated. The aim of this work was to investigate cigarette smoke exposure effects on initial phases of cutaneous healing in mice, focusing mainly on gene expression of two molecules involved in wound repair (Ccn2/Ctgf and Tgfb1) and to study if these effects are strain dependent. Mice were exposed to the smoke of nine cigarettes per day, three times per day, for ten days. In the eleventh day an excisional wound was made. The control group was sham-exposed. The cigarette smoke exposure protocol was performed until euthanasia, seven days after wounding. Wound contraction was evaluated. Sections were stained with hematoxylin-eosin, Sirius red, and toluidine blue, and also immunostained for alpha-smooth muscle actin. Gene expression of Ccn2/Ctgf and Tgfb1 was evaluated by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). Smoke-exposed animals presented delay in wound contraction; fibroblastic, inflammatory, and mast cell recruitment; re-epithelialization; myofibroblastic differentiation; and Ccn2/Ctgf and Tgfb1 gene expression. Those alterations were strain dependent. This work confirmed the deleterious effects of cigarette smoke exposure on mouse cutaneous healing depending on mouse strain and links these effects to an overexpression of Ccn2/Ctgf.

Key Words: Ccn2/Ctgf • cigarette smoke • connective tissue • Tgfb1 • wound healing

Abbreviations: -SMA, alpha-smooth muscle actin • BSA, bovine serum albumin • cDNA, complementary DNA • CTGF, connective tissue growth factor • CYR61, cysteine-rich, angiogenic inducer 61 • GAPDH, glyceraldehyde-3-phosphate dehydrogenase • MMP, matrix metalloproteinase • NO, nitric oxide • NOV, nephroblastoma overexpressed • PBS, phosphate buffered saline • PMN, polymorphonuclear • TGF-β1, transforming growth factor-β1 • TIMP, tissue inhibitors of metalloproteinases • WISP, WNT1 inducible signaling pathway

Toxicologic Pathology, Vol. 37, No. 2, 175-182 (2009)
DOI: 10.1177/0192623308328134


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