Decitabine and 5-azacitidine both alleviate LPS induced ARDS through anti-inflammatory/antioxidant activity and protection of glycocalyx and inhibition of MAPK pathways in mice.
Decitabine (5-aza-2'-deoxycytidine, DAC) and 5-azacitidine (Aza), an inhibitor of DNA methyltransferases, possess a wide range of anti-metabolic and anti-cancer activities. This study examined the effects of DAC and Aza on inflammatory and oxidative injuries, as well as on glycocalyx and MAPK signaling pathways, in a LPS-stimulated ARDS mouse model. Results of ELISA revealed that DAC and Aza significantly inhibited the production of TNF-α and IL-1β and prevented LPS-induced elevation of myeloperoxidase and malondialdehyde levels in serum. The W/D ratio of lung and histopathologic examination with hematoxylin and eosin staining showed that DAC and Aza pretreatment substantially improved lung tissue injury. DAC and Aza reduced the level of glycocalyx degradation products (e.g., heparan sulfate and haluronic acid) and protected glycocalyx integrity. Western blot assay demonstrated that DAC and Aza both significantly suppressed LPS-induced activation of the MAPK signaling pathways by blocking the phosphorylation of JNK, ERK and P38 in lung tissues. Bisulfite sequencing PCR and real time-PCR showed that DAC reversed the RASSF1A promoter hypermethylation and furthermore elevated the expression of RASSF1A, which is a tumor suppressor that regulates MAPK signaling pathway. These results suggested that DAC inhibited the MAPK signaling pathway in LPS-induced ARDS mice might via demethylation in RASSF1A promoter region and by restoring its expression. This study highlighted the close relationship between DNA methylation and the development and progression of ARDS.
Department of Respirator Medicine and Intensive Care Unit, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong Province, China.
Xiao
X
Huang
Department of Respirator Medicine and Intensive Care Unit, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong Province, China.
Guiqing
G
Kong
Department of Respirator Medicine and Intensive Care Unit, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong Province, China.
Yan
Y
Li
Department of Respirator Medicine and Intensive Care Unit, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong Province, China.
Weiwei
W
Zhu
Department of Respirator Medicine and Intensive Care Unit, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong Province, China.
Haixiao
H
Xu
Department of Cell Biology, Binzhou Medical University, Yantai, 264003, Shandong Province, China.
Xiaohua
X
Zhang
Department of Respirator Medicine and Intensive Care Unit, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong Province, China.
Jiankui
J
Li
Department of Respirator Medicine and Intensive Care Unit, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong Province, China.
Lipeng
L
Wang
Department of Health Statistics, Binzhou Medical University, Yantai, 264003, Shandong Province, China.
Zhongwen
Z
Zhang
Department of Cell Biology, Binzhou Medical University, Yantai, 264003, Shandong Province, China.
Yaru
Y
Wu
Department of Cell Biology, Binzhou Medical University, Yantai, 264003, Shandong Province, China. Electronic address: liuxiangyong81@gmail.com.
Xiangyong
X
Liu
Department of Respirator Medicine and Intensive Care Unit, Affiliated Hospital of Binzhou Medical University, Binzhou 256603, Shandong Province, China. Electronic address: hxicuwxz@163.com.
Xiaozhi
X
Wang
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D019175:DNA Methylation / Q000235:genetics; D000077209:Decitabine; D004195:Disease Models, Animal; D019276:Glycocalyx / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D011401:Promoter Regions, Genetic; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C496882:RASSF1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D001374:Azacitidine
ARDS; Aza; DAC; Glycocalyx; LPS; MAPK pathway