Discovery of intra-parenchymal adipose tissue as a component of tissue remodeling in pulmonary fibrosis

Introduction: Pulmonary fibrosis is characterized by severe tissue remodeling with accumulation of fibroblasts and extracellular matrix. Aberrant cell differentiation processes are observed, with ectopic deposits of smooth muscle cells and diffuse ossification. However, adipocytes, which are also mesenchymal cells, have never been reported in the lung parenchyma. Aims: Characterize parenchymal lung adipocytes in pulmonary fibrosis. Methods: Formalin Fixed Paraffin-Embedded surgical samples from fibrotic and non-fibrotic (lobectomy for cancer) lungs were reviewed for adipocyte deposits on hematoxylin-eosin staining. Immunostainings were performed to assess adipocyte phenotype using perilipin 1 (PLIN1, pan-adipocyte marker), fatty-acid-binding protein 4 (FABP4, lipid chaperone), perilipin 4 (PLIN4, white adipocytes) and uncoupling protein 1 (UCP1, brown adipocytes). Perihilar fat was used as a control tissue. Results: Samples from 43 IPF (11 biopsies, 32 explants), 13 fibrotic HP (fHP), 13 fibrotic NSIP (fNSIP), and 47 non-fibrotic lungs were analyzed. Adipocytes were found in only 1 (2%) non-fibrotic lung. Subpleural clusters of adipocytes with a white phenotype (PLIN4+ UCP1-) were detected in 86% of IPF samples [8/11 biopsies, 29/32 explants], less frequently in fHP (69%) and fNSIP (23%) (p<0.001 for all). Lung adipocytes were smaller, more circular than perihilar ones, and expressed FABP4 less frequently (p<0,05). Presence of adipocytes was not related to age, BMI, or severity of fibrosis (assessed by FVC or DLCO). Conclusions: This is the first report of intra-parenchymal adipocyte deposits in fibrotic lung tissue. This raises the question of their origin and potential role in fibrogenesis.