CCN1 secretion and cleavage regulate the lung epithelial cell functions after cigarette smoke
Hyung-Geun Moon1, Sang-Heon Kim2, Jinming Gao3
1Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
Summary
Cigarette smoking causes emphysema through CCN1 cleavage. Cleaved CCN1 (cCCN1) promotes lung tissue damage by increasing MMPs and decreasing VEGF, contributing to epithelial cell death.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Biochemistry
Background:
- The exact mechanisms driving cigarette smoking (CS)-associated emphysema are not fully understood, hindering the development of effective treatments.
- Existing research has not fully elucidated the role of protein modifications in emphysema pathogenesis.
Purpose of the Study:
- To investigate a novel mechanism involving CCN1 cleavage in the development of epithelial cell death and tissue loss in CS-associated emphysema.
- To explore the differential functions of full-length CCN1 (flCCN1) and cleaved CCN1 (cCCN1) in response to cigarette smoke.
Main Methods:
- In vitro and in vivo experiments exposing cells and mice to cigarette smoke extract (CSE).
- Analysis of CCN1 secretion via exosomes and its conversion to cCCN1 by plasmin.
- Assessment of cytokine (IL-8, VEGF) and matrix metalloproteinase (MMP) production.
- Investigation of integrin-α7 as a receptor for cCCN1.
Main Results:
- Prolonged CS exposure led to CCN1 cleavage, generating cCCN1.
- Exosome-shuttled flCCN1 promoted IL-8 and VEGF release, potentially aiding anti-inflammatory and homeostatic responses.
- cCCN1 abolished flCCN1's beneficial functions and promoted MMP-1 production, favoring emphysema development.
- cCCN1, via integrin-α7, induced MMP-1 production, contributing to epithelial damage.
- Elevated cCCN1 levels were observed in mice with CS-induced emphysema.
Conclusions:
- CCN1 cleavage into cCCN1 is a key event in CS-associated emphysema pathogenesis.
- cCCN1 promotes epithelial cell damage and tissue loss by increasing MMPs and decreasing VEGF.
- Integrin-α7 acts as a receptor mediating cCCN1's detrimental effects on lung epithelial cells.
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