Increased lymphatic vessel length is associated with the fibroblast reticulum and disease severity in usual interstitial pneumonia and nonspecific interstitial pneumonia.
BACKGROUND
Lymphangiogenesis responds to tissue injury as a key component of normal wound healing. The development of fibrosis in the idiopathic interstitial pneumonias may result from abnormal wound healing in response to injury. We hypothesize that increased lymphatic vessel (LV) length, a marker of lymphangiogenesis, is associated with parenchymal components of the fibroblast reticulum (organizing collagen, fibrotic collagen, and fibroblast foci), and its extent correlates with disease severity.


METHODS
We assessed stereologically the parenchymal structure of fibrotic lungs and its associated lymphatic network, which was highlighted immunohistochemically in age-matched samples of usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) with FVC &lt; 80%, COPD with a Global Initiative for Obstructive Lung Disease stage 0, and normal control lungs.


RESULTS
LV length density, as opposed to vessel volume density, was found to be associated with organizing and fibrotic collagen density (P &lt; .0001). Length density of LVs and the volume density of organizing and fibrotic collagen were significantly associated with severity of both % FVC (P &lt; .001) and diffusing capacity of the lung for carbon monoxide (P &lt; .001).


CONCLUSIONS
Severity of disease in UIP and NSIP is associated with increased LV length and is strongly associated with components of the fibroblast reticulum, namely organizing and fibrotic collagen, which supports a pathogenic role of LVs in these two diseases. Furthermore, the absence of definable differences between UIP and NSIP suggests that LVs are a unifying mechanism for the development of fibrosis in these fibrotic lung diseases.
Division of Pulmonary Science and Critical Care Medicine, University of Colorado Denver, Aurora, CO. Electronic address: Abigail.Lara@UCDenver.edu.
Abigail R
AR
Lara
Division of Pulmonary Science and Critical Care Medicine, University of Colorado Denver, Aurora, CO; Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO.
Gregory P
GP
Cosgrove
Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO.
William J
WJ
Janssen
Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO.
Tristan J
TJ
Huie
Division of Pulmonary Science and Critical Care Medicine, University of Colorado Denver, Aurora, CO.
Ellen L
EL
Burnham
Division of Pulmonary Science and Critical Care Medicine, University of Colorado Denver, Aurora, CO.
David E
DE
Heinz
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO; Department of Biostatistics and Bioinformatics, National Jewish Health, Denver, CO.
Douglas
D
Curran-Everett
Department of Radiology, University of Colorado Denver, Aurora, CO.
Hakan
H
Sahin
Division of Pulmonary Science and Critical Care Medicine, University of Colorado Denver, Aurora, CO.
Marvin I
MI
Schwarz
Department of Pathology, University of Colorado Denver, Aurora, CO.
Carlyne D
CD
Cool
Department of Pathology, National Jewish Health, Denver, CO.
Steve D
SD
Groshong
Division of Pulmonary Science and Critical Care Medicine, University of Colorado Denver, Aurora, CO.
Mark W
MW
Geraci
Division of Pulmonary Science and Critical Care Medicine, University of Colorado Denver, Aurora, CO.
Rubin M
RM
Tuder
Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California-Davis, Davis, CA.
Dallas M
DM
Hyde
Division of Immunology, National Jewish Health, Denver, CO.
Peter M
PM
Henson
D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D003094:Collagen / Q000378:metabolism / Q000648:ultrastructure*; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000145:classification* / Q000378:metabolism / Q000473:pathology*; D042583:Lymphangiogenesis / Q000502:physiology; D042601:Lymphatic Vessels / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011859:Radiography; D012720:Severity of Illness Index; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D042582:Vascular Endothelial Growth Factor C / Q000097:blood; D042643:Vascular Endothelial Growth Factor D / Q000097:blood
D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D003094:Collagen