Galectin-3 Is Associated with Restrictive Lung Disease and Interstitial Lung Abnormalities.

RATIONALE Galectin-3 (Gal-3) has been implicated in the development of pulmonary fibrosis in experimental studies, and Gal-3 levels have been found to be elevated in small studies of human pulmonary fibrosis. OBJECTIVES We sought to study whether circulating Gal-3 concentrations are elevated early in the course of pulmonary fibrosis. METHODS We examined 2,596 Framingham Heart Study participants (mean age, 57 yr; 54% women; 14% current smokers) who underwent Gal-3 assessment using plasma samples and pulmonary function testing between 1995 and 1998. Of this sample, 1,148 underwent subsequent volumetric chest computed tomography. MEASUREMENTS AND MAIN RESULTS Higher Gal-3 concentrations were associated with lower lung volumes (1.4% decrease in percentage of predicted FEV1 per 1 SD increase in log Gal-3; 95% confidence interval [CI], 0.8-2.0%; P < 0.001; 1.2% decrease in percentage of predicted FVC; 95% CI, 0.6-1.8%; P < 0.001) and decreased diffusing capacity of the lung for carbon monoxide (2.1% decrease; 95% CI, 1.3-2.9%; P < 0.001). These associations remained significant after multivariable adjustment (P ≤ 0.008 for all). Compared with the lowest quartile, participants in the highest Gal-3 quartile were more than twice as likely to have interstitial lung abnormalities visualized by computed tomography (multivariable-adjusted odds ratio, 2.67; 95% CI, 1.49-4.76; P < 0.001). CONCLUSIONS Elevated Gal-3 concentrations are associated with interstitial lung abnormalities coupled with a restrictive pattern, including decreased lung volumes and altered gas exchange. These findings suggest a potential role for Gal-3 in early stages of pulmonary fibrosis.

[1]  D. Laskin,et al.  Regulation of ozone-induced lung inflammation and injury by the β-galactoside-binding lectin galectin-3. , 2015, Toxicology and applied pharmacology.

[2]  Sanjiv J. Shah,et al.  Elevated plasma galectin-3 is associated with near-term rehospitalization in heart failure: a pooled analysis of 3 clinical trials. , 2014, American heart journal.

[3]  D. Levy,et al.  Galectin 3 and incident atrial fibrillation in the community. , 2014, American heart journal.

[4]  I. Rosas,et al.  Genetics and early detection in idiopathic pulmonary fibrosis. , 2014, American journal of respiratory and critical care medicine.

[5]  Kevin J. O'Brien,et al.  Dysregulation of galectin-3. Implications for Hermansky-Pudlak syndrome pulmonary fibrosis. , 2014, American journal of respiratory cell and molecular biology.

[6]  Raúl San José Estépar,et al.  MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities , 2013 .

[7]  D. Levy,et al.  Elevated galectin-3 precedes the development of CKD. , 2013, Journal of the American Society of Nephrology : JASN.

[8]  Bertram Pitt,et al.  Genetic and Pharmacological Inhibition of Galectin-3 Prevents Cardiac Remodeling by Interfering With Myocardial Fibrogenesis , 2013, Circulation. Heart failure.

[9]  Ken Garber.  Galecto Biotech , 2013, Nature Biotechnology.

[10]  D. Lynch,et al.  High-resolution CT scan findings in familial interstitial pneumonia do not conform to those of idiopathic interstitial pneumonia. , 2012, Chest.

[11]  D. Levy,et al.  Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. , 2012, Journal of the American College of Cardiology.

[12]  B. Celli,et al.  The expanding role of biomarkers in the assessment of smoking-related parenchymal lung diseases. , 2012, Chest.

[13]  G. Washko,et al.  Interstitial lung abnormalities and reduced exercise capacity. , 2012, American journal of respiratory and critical care medicine.

[14]  Jack Gauldie,et al.  Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. , 2012, American journal of respiratory and critical care medicine.

[15]  P. Winyard,et al.  Modified Citrus Pectin Reduces Galectin-3 Expression and Disease Severity in Experimental Acute Kidney Injury , 2011, PloS one.

[16]  B. Sastre,et al.  Gene Expression Profiling in Lungs of Chronic Asthmatic Mice Treated with Galectin-3: Downregulation of Inflammatory and Regulatory Genes , 2011, Mediators of inflammation.

[17]  Takeshi Johkoh,et al.  American Thoracic Society Documents An Official ATS / ERS / JRS / ALAT Statement : Idiopathic Pulmonary Fibrosis : Evidence-based Guidelines for Diagnosis and Management , 2011 .

[18]  Katherine P Andriole,et al.  Lung volumes and emphysema in smokers with interstitial lung abnormalities. , 2011, The New England journal of medicine.

[19]  A. Wu,et al.  Multi-center determination of galectin-3 assay performance characteristics: Anatomy of a novel assay for use in heart failure. , 2010, Clinical biochemistry.

[20]  H. Hillege,et al.  Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study , 2010, Clinical Research in Cardiology.

[21]  R. Strieter,et al.  New mechanisms of pulmonary fibrosis. , 2009, Chest.

[22]  Carl-Fredrik Westin,et al.  Lung Extraction, Lobe Segmentation and Hierarchical Region Assessment for Quantitative Analysis on High Resolution Computed Tomography Images , 2009, MICCAI.

[23]  N. Henderson,et al.  The regulation of inflammation by galectin‐3 , 2009, Immunological reviews.

[24]  K. Brown,et al.  Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. , 2009, Chest.

[25]  K. Dhaliwal,et al.  Galectin-3 reduces the severity of pneumococcal pneumonia by augmenting neutrophil function. , 2008, The American journal of pathology.

[26]  J. Iredale,et al.  Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. , 2008, The American journal of pathology.

[27]  J. Park,et al.  Expression and immunohistochemical localization of galectin‐3 in various mouse tissues , 2007, Cell biology international.

[28]  Fu-Tong Liu,et al.  Role of galectin-3 in human pulmonary fibrosis. , 2007, Allergology international : official journal of the Japanese Society of Allergology.

[29]  Stephan Gebel,et al.  The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[30]  J. Iredale,et al.  Galectin-3 regulates myofibroblast activation and hepatic fibrosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Nishimura,et al.  Prognostic value of circulating KL‐6 in idiopathic pulmonary fibrosis , 2006, Respirology.

[32]  Yigal M. Pinto,et al.  Galectin-3 Marks Activated Macrophages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction , 2004, Circulation.

[33]  V. del Pozo,et al.  Gene therapy with galectin-3 inhibits bronchial obstruction and inflammation in antigen-challenged rats through interleukin-5 gene downregulation. , 2002, American journal of respiratory and critical care medicine.

[34]  M. Bergeron,et al.  Role of Galectin-3 as an Adhesion Molecule for Neutrophil Extravasation During Streptococcal Pneumonia1 , 2002, The Journal of Immunology.

[35]  W James Gauderman,et al.  Sample size requirements for matched case‐control studies of gene–environment interaction , 2002, Statistics in medicine.

[36]  J L Hankinson,et al.  Spirometric reference values from a sample of the general U.S. population. , 1999, American journal of respiratory and critical care medicine.

[37]  M. Kasper,et al.  IMMUNOCYTOCHEMICAL EVIDENCE FOR A MODULATION OF GALECTIN 3 (Mac‐2), A CARBOHYDRATE BINDING PROTEIN, IN PULMONARY FIBROSIS , 1996, The Journal of pathology.

[38]  T. Standiford,et al.  Neutrophilic alveolitis in idiopathic pulmonary fibrosis. The role of interleukin-8. , 1992, The American review of respiratory disease.

[39]  W. Kannel,et al.  An investigation of coronary heart disease in families. The Framingham offspring study. , 1979, American journal of epidemiology.