TY - JOUR
T1 - Recombinant Antithrombin Attenuates Acute Respiratory Distress Syndrome in Experimental Endotoxemia
AU - Okamoto, Haruka
AU - Muraki, Isamu
AU - Okada, Hideshi
AU - Tomita, Hiroyuki
AU - Suzuki, Kodai
AU - Takada, Chihiro
AU - Wakayama, Yugo
AU - Kuroda, Ayumi
AU - Fukuda, Hirotsugu
AU - Kawasaki, Yuki
AU - Nishio, Ayane
AU - Matsuo, Maho
AU - Tamaoki, Yuto
AU - Inagawa, Risa
AU - Takashima, Shigeo
AU - Taniguchi, Toshiaki
AU - Suzuki, Akio
AU - Suzuki, Keiko
AU - Miyazaki, Nagisa
AU - Kakino, Yoshinori
AU - Yasuda, Ryu
AU - Fukuta, Tetsuya
AU - Kitagawa, Yuichiro
AU - Miyake, Takahito
AU - Doi, Tomoaki
AU - Yoshida, Takahiro
AU - Yoshida, Shozo
AU - Ogura, Shinji
N1 - Publisher Copyright:
© 2021 American Society for Investigative Pathology
PY - 2021/9
Y1 - 2021/9
N2 - Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1β was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury.
AB - Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1β was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury.
UR - http://www.scopus.com/inward/record.url?scp=85113723390&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2021.05.015
DO - 10.1016/j.ajpath.2021.05.015
M3 - 学術論文
C2 - 34116023
AN - SCOPUS:85113723390
SN - 0002-9440
VL - 191
SP - 1526
EP - 1536
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 9
ER -