Carbon dioxide-induced decrease in extracellular pH enhances the production of extracellular matrix components by...

Area of Science:

• Dermatology
• Cell Biology
• Biochemistry

Background:

• Transcutaneous carbon dioxide (CO2) administration causes mild skin acidification, improving epidermal issues like inflammation.
• The impact of this mild acidity on dermal tissue, particularly extracellular matrix (ECM) production, remains largely unexplored.

Purpose of the Study:

• To investigate the effects and underlying mechanisms of mild acidity on ECM protein production in normal human dermal fibroblasts (NHDFs).
• To determine if CO2-induced acidification influences key signaling pathways involved in ECM synthesis.

Main Methods:

• Assessed CO2 skin permeability and intradermal pH reduction in reconstructed human skin equivalents (HSEs) using a CO2 formulation.
• Cultured NHDFs in a pH-adjusted medium (pH 6.5) to mimic acidic conditions.
• Utilized RNA interference (RNAi) to suppress CREB1 and specific G protein-coupled receptors (GPCRs), and chemical inhibitors for signaling pathways (cAMP/PKA, PLC/PKC).

Main Results:

• CO2 successfully permeated HSEs, lowering intradermal pH.
• Reduced extracellular pH activated CREB, upregulated TGF-β1 expression, and increased elastic and collagen fiber production, alongside elevated hyaluronan concentration in NHDFs.
• Suppression of CREB1 and GPCRs (GPR4, GPR65) attenuated TGF-β1 upregulation, while inhibiting cAMP/PKA and PLC/PKC pathways reduced CREB activation.

Conclusions:

• CO2-induced dermal acidification promotes ECM production in NHDFs.
• This effect is mediated by TGF-β1 upregulation, driven by GPCR signaling pathway activation and CREB.
• CO2 administration presents a potential therapeutic strategy for conditions like photoaging, intrinsic aging, and ECM deterioration.