TY - JOUR
T1 - Lung lymphatic thrombosis and dysfunction caused by cigarette smoke exposure precedes emphysema in mice
AU - Summers, Barbara D.
AU - Kim, Kihwan
AU - Clement, Cristina C.
AU - Khan, Zohaib
AU - Thangaswamy, Sangeetha
AU - McCright, Jacob
AU - Maisel, Katharina
AU - Zamora, Sofia
AU - Quintero, Stephanie
AU - Racanelli, Alexandra C.
AU - Redmond, David
AU - D’Armiento, Jeanine
AU - Yang, Jisheng
AU - Kuang, Amy
AU - Monticelli, Laurel
AU - Kahn, Mark L.
AU - Choi, Augustine M.K.
AU - Santambrogio, Laura
AU - Reed, Hasina Outtz
N1 - Funding Information:
Supported by the NHLBI K01HL145365 (to H.O.R), the Robert Wood Johnson Foundation's Harold Amos Medical Faculty Development Program (to H.O.R.), NIH AI146180 and NIH AI137198 (to L.S.), NIGMS MIRA 1R35GM142835-01 (to K.M.), and AHA Predoctoral Fellowship 834524 (to J.M.).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The lymphatic vasculature is critical for lung function, but defects in lymphatic function in the pathogenesis of lung disease is understudied. In mice, lymphatic dysfunction alone is sufficient to cause lung injury that resembles human emphysema. Whether lymphatic function is disrupted in cigarette smoke (CS)-induced emphysema is unknown. In this study, we investigated the effect of CS on lung lymphatic function. Analysis of human lung tissue revealed significant lung lymphatic thrombosis in patients with emphysema compared to control smokers that increased with disease severity. In a mouse model, CS exposure led to lung lymphatic thrombosis, decreased lymphatic drainage, and impaired leukocyte trafficking that all preceded the development of emphysema. Proteomic analysis demonstrated an increased abundance of coagulation factors in the lymph draining from the lungs of CS-exposed mice compared to control mice. In addition, in vitro assays demonstrated a direct effect of CS on lymphatic endothelial cell integrity. These data show that CS exposure results in lung lymphatic dysfunction and a shift in thoracic lymph towards a prothrombic state. Furthermore, our data suggest that lymphatic dysfunction is due to effects of CS on the lymphatic vasculature that precede emphysema. These studies demonstrate a novel component of CS-induced lung injury that occurs early in the pathogenesis of emphysema.
AB - The lymphatic vasculature is critical for lung function, but defects in lymphatic function in the pathogenesis of lung disease is understudied. In mice, lymphatic dysfunction alone is sufficient to cause lung injury that resembles human emphysema. Whether lymphatic function is disrupted in cigarette smoke (CS)-induced emphysema is unknown. In this study, we investigated the effect of CS on lung lymphatic function. Analysis of human lung tissue revealed significant lung lymphatic thrombosis in patients with emphysema compared to control smokers that increased with disease severity. In a mouse model, CS exposure led to lung lymphatic thrombosis, decreased lymphatic drainage, and impaired leukocyte trafficking that all preceded the development of emphysema. Proteomic analysis demonstrated an increased abundance of coagulation factors in the lymph draining from the lungs of CS-exposed mice compared to control mice. In addition, in vitro assays demonstrated a direct effect of CS on lymphatic endothelial cell integrity. These data show that CS exposure results in lung lymphatic dysfunction and a shift in thoracic lymph towards a prothrombic state. Furthermore, our data suggest that lymphatic dysfunction is due to effects of CS on the lymphatic vasculature that precede emphysema. These studies demonstrate a novel component of CS-induced lung injury that occurs early in the pathogenesis of emphysema.
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U2 - 10.1038/s41598-022-08617-y
DO - 10.1038/s41598-022-08617-y
M3 - Article
C2 - 35322079
AN - SCOPUS:85127030740
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 5012
ER -