Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms

Abstract

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 shortfragment 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.endothelial cell ͉ hyaluronan ͉ idiopathic pulmonary fibrosis ͉ lymphangiogenesis ͉ macrophage

Increased Lymphatic Vessel Length Is Associated With the Fibroblast Reticulum and Disease Severity in Usual Interstitial Pneumonia and Nonspecific Interstitial Pneumonia

“…19 This study adds to the information previously described by El-Chemaly et al, 10 who reported that the area of LVs inversely correlate with disease severity in UIP. Our study included normal-tissue stereologic assessments, as well as samples from the most common forms of IIP, UIP, and NSIP.…”

“…Furthermore, the patients with UIP or NSIP in the present study were fully characterized clinically using pulmonary function testing and chest CT scans. LV volume density was also increased in patients with UIP compared with the normal control group, in keeping with the fi ndings presented by El-Chemaly et al 10 In our study, LV volume density, although increased in both UIP and NSIP, was not associated with any metrics of parenchymal component volume density or any metrics of clinical severity, whereas the El-Chemaly et al 10 study found a negative association between LV area and disease severity in UIP. One explanation for the discrepancy is that the samples used in the present study were less subject to sampling and orientation bias and were are not limited by the usual pitfalls of randomization and lack of data pertaining to vessel length.…”

“…In fact, macrophages that participate in the process of fi brosis also interact with aberrant LVs, possibly contributing to pathogenic lymphangiogenesis. 10,11 Furthermore, damage to subpleural and interlobular LVs may adversely infl uence the alveolar compartment clearance, thereby contributing to disease in IPF. 12 Although emerging data suggest that lymphangiogenesis accompanies and may contribute to disease pathogenesis in fi brotic lung diseases, such as diffuse alveolar damage, 13 its clinical relevance to other IIPs, nonspecifi c interstitial pneumonia (NSIP) in particular , remains to be elucidated.…”

The pathogenesis of pulmonary fibrosis: a moving target

“…It is well known that mediastinal lymphadenopathy is present in a significant amount of patients with IPF [104,105]. In the study of EL-CHEMALY et al [106], lymphatic vessels in IPF lungs were in close proximity to alveolar spaces, even in those areas with a well-preserved architecture. Moreover lymphatic vessels were present throughout the fibrotic tissue and in close proximity to the main bronchovascular tree.…”

Myeloid Cells and Lymphangiogenesis

“…Finally, in human idiopathic pulmonary fibrosis, alveolar lymphangiogenesis correlates with the disease severity. CD11b þ macrophages from bronchoalveolar lavage fluid from pulmonary fibrosis patients, but not from healthy subjects, are able to form tube like structures in vitro expressing the LEC markers LYVE-1 and podoplanin (El-Chemaly et al 2009). These results indicate that inflammation is a prerequisite for the potential transdifferentiation of myeloid cells into LECs.…”