Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, debilitating respiratory disease whose pathogenesis is poorly understood. In IPF, the lung parenchyma undergoes extensive remodeling. We hypothesized that lymphangiogenesis is part of lung remodeling and sought to characterize pathways leading to lymphangiogenesis in IPF. We found that the diameter of lymphatic vessels in alveolar spaces in IPF lung tissue correlated with disease severity, suggesting that the alveolar microenvironment plays a role in the lymphangiogenic process. In bronchoalveolar lavage fluid (BALF) from subjects with IPF, we found short-fragment hyaluronic acid, which induced migration and proliferation of lymphatic endothelial cells (LECs), processes required for lymphatic vessel formation. To determine the origin of LECs in IPF, we isolated macrophages from the alveolar spaces; CD11b(+) macrophages from subjects with IPF, but not those from healthy volunteers, formed lymphatic-like vessels in vitro. Our findings demonstrate that in the alveolar microenvironment of IPF, soluble factors such as short-fragment hyaluronic acid and cells such as CD11b(+) macrophages contribute to lymphangiogenesis. These results improve our understanding of lymphangiogenesis and tissue remodeling in IPF and perhaps other fibrotic diseases as well.
El-Chemaly
Souheil
S
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Malide
Daniela
D
Zudaire
Enrique
E
Ikeda
Yoshihiko
Y
Weinberg
Benjamin A
BA
Pacheco-Rodriguez
Gustavo
G
Rosas
Ivan O
IO
Aparicio
Marta
M
Ren
Ping
P
MacDonald
Sandra D
SD
Wu
Hai-Ping
HP
Nathan
Steven D
SD
Cuttitta
Frank
F
McCoy
J Philip
JP
Gochuico
Bernadette R
BR
Moss
Joel
J
D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D039481:CD11b Antigen / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006262:Health; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D054990:Idiopathic Pulmonary Fibrosis / Q000150:complications* / Q000473:pathology*; D042583:Lymphangiogenesis / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000378:metabolism
D015415:Biomarkers; D039481:CD11b Antigen; C119248:LYVE1 protein, human; D033921:Vesicular Transport Proteins; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase