Increased fibronectin expression in lung in the setting of chronic alcohol abuse.
BACKGROUND
The incidence and severity of the acute respiratory distress syndrome (ARDS) is increased in individuals who abuse alcohol. One possible mechanism by which alcohol increases susceptibility to acute lung injury is through alterations in alveolar macrophage function and induction of tissue remodeling activity. Our objective was to determine whether alcohol abuse, independent of other comorbidities, alters fibronectin and metalloproteinase gene expression in alveolar macrophages and in epithelial lining fluid (ELF) of the lung.


METHODS
Otherwise healthy subjects with alcohol abuse (n=21) and smoking-matched controls (n=17) underwent bronchoalveolar lavage. Alveolar macrophage fibronectin and matrix metalloproteinase (MMP) mRNA expression were measured via reverse transcription-polymerase chain reaction. The supernatant from cultured alveolar macrophages and lung ELF were tested for their ability to induce fibronectin and MMP-9 gene transcription in cell-based assays.


RESULTS
Alveolar macrophages from subjects with alcohol abuse demonstrated increased fibronectin mRNA expression (p<0.001), and their ELF also elicited more fibronectin gene transcription in lung fibroblasts compared with controls (p<0.001). In contrast, alveolar macrophages from subjects with alcohol abuse had decreased MMP-9 and MMP-2 mRNA expression (p<0.03 and p<0.005, respectively). Similarly, the supernatant (p<0.001) and ELF (p<0.01) from these subjects induced less MMP-9 gene transcription in THP-1 cells.


CONCLUSIONS
Alcohol abuse is associated with increased fibronectin mRNA expression in alveolar macrophages and increased fibronectin-inducing activity in the ELF. This appears to be a specific effect as other tissue remodeling genes, such as MMPs, were not equally affected. These findings suggest activation of tissue remodeling that may contribute to the increased susceptibility for the ARDS observed in alcoholism.
Burnham
Ellen L
EL
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. Ellen.Burnham@uchsc.edu
Moss
Marc
M
Ritzenthaler
Jeffrey D
JD
Roman
Jesse
J
D000328:Adult; D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001999:Bronchoscopy; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis*; D006801:Humans; D007202:Indicators and Reagents; D008168:Lung / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D005353:Fibronectins; D007202:Indicators and Reagents; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases