Central Role of Fibroblast α3 Nicotinic Acetylcholine Receptor in Mediating Cutaneous Effects of Nicotine

• DOI: 10.1097/01.lab.0000053917.46614.12
• Publication Date: 2013-09-04T18:38:43Z
• Authors: Juan Arredondo; Leon L Hall; Assane Ndoye; Vu Thuong Nguyen; Alexander I Chern...; Dani Bercovich; Avi Orr-Urtreger; Arthur L Beaudet; Sergei A Grando
• Keywords: Mecamylamine; Nicotinic Antagonist

Smoking is associated with aberrant cutaneous tissue remodeling, such as precocious skin aging and impaired wound healing. The mechanism not fully understood. Dermal fibroblasts (DF) are the primary cellular component of dermis may provide a target for pathobiologic effects tobacco products. purpose this study was to characterize nicotine (Nic) on growth remodeling function DF. We hypothesized that Nic DF result from its binding specific nicotinic acetylcholine receptors (nAChRs) expressed by these cells downstream signaling alters normal cell functioning, leading changes in homeostasis. Using RT-PCR Western blotting, we found 24-hour exposure human 10 micro M causes 1.9- 28-fold increase mRNA protein levels cycle regulators p21, cyclin D1, Ki-67, PCNA 1.7- 2-fold apoptosis Bcl-2 caspase 3. also up-regulated expression dermal matrix proteins collagen type Ialpha1 elastin well metalloproteinase-1. Mecamylamine (Mec), antagonist nAChRs, abolished Nic-induced alterations, indicating they resulted pharmacologic stimulation nAChRs To establish relevance findings nicotinergic pathway, studied transfected anti-alpha3 antisense oligonucleotides murine alpha3 nAChR knockout mice. In both cases, lack alterations fibroblast were opposite those observed treated Nic, suggesting mostly mediated nAChR. addition alpha3, subunits detected alpha5, alpha7, beta2, beta4. altered relative amounts each subunits, reciprocal [(3)H]epibatidine-binding kinetics. Thus, some products extracellular turnover stem physiologic control unfolding genetically determined program structure nAChRs.