Fei He1, Lina Gu2, Nan Cai3, Jun Ni4, Yong Liu5, Quan Zhang5, Chao Wu6. 1. Department of Emergency Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China. hefei1201@njglyy.com. 2. Department of Pulmonary and Critical Care Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China. 3. Department of Infectious Disease, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China. 4. Department of Clinical Laboratory, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China. 5. Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China. 6. Department of Infectious Disease, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, China. chaowu_62@sina.com.
Abstract
OBJECTIVE: Apoptosis plays a major role in the progression of acute respiratory distress syndrome (ARDS) that may involve the interaction of the high mobility group box 1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). However, the underlying mechanism remains unclear. Thus, we aimed to explore the mechanisms of HMGB1-RAGE axis-induced apoptosis in ARDS. METHODS: Blood samples from ARDS patients and healthy volunteers were collected to investigate the correlation between serum HMGB1 levels and the severity of ARDS in patients. Mouse models of ARDS induced by caecal ligation and perforation and A549 cell models established by stimulation with recombinant human HMGB1 (rHMGB1) were designed to explore lung inflammatory injury and apoptosis. RESULTS: Serum HMGB1 levels were significantly increased in ARDS patients compared to controls, and HMGB1 levels in the Severe group and Nonsurvival group were significantly higher than those in the Mild and Moderate group and Survival group. In vivo, compared to sham mice, ARDS mice showed significant lung inflammatory injury and apoptosis as well as upregulation of HMGB1 and RAGE and endoplasmic reticulum stress (ERs) protein expression. All injury was attenuated by treatment with an HMGB1 inhibitor GA, a RAGE blocker FPS-ZM1, and an ERs inhibitor 4-PBA. In vitro, A549 cells challenged with rHMGB1 exhibited significant increases in the levels of proteins in the RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway and in apoptosis, all of which were significantly inhibited by pre-treatment with lenti-shPERK and an anti-RAGE antibody. CONCLUSION: The HMGB1-RAGE axis induces apoptotic injury during ARDS, possibly through PERK/eIF2α/ATF4-mediated ERs.
OBJECTIVE: Apoptosis plays a major role in the progression of acute respiratory distress syndrome (ARDS) that may involve the interaction of the high mobility group box 1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). However, the underlying mechanism remains unclear. Thus, we aimed to explore the mechanisms of HMGB1-RAGE axis-induced apoptosis in ARDS. METHODS: Blood samples from ARDS patients and healthy volunteers were collected to investigate the correlation between serum HMGB1 levels and the severity of ARDS in patients. Mouse models of ARDS induced by caecal ligation and perforation and A549 cell models established by stimulation with recombinant human HMGB1 (rHMGB1) were designed to explore lung inflammatory injury and apoptosis. RESULTS: Serum HMGB1 levels were significantly increased in ARDS patients compared to controls, and HMGB1 levels in the Severe group and Nonsurvival group were significantly higher than those in the Mild and Moderate group and Survival group. In vivo, compared to sham mice, ARDS mice showed significant lung inflammatory injury and apoptosis as well as upregulation of HMGB1 and RAGE and endoplasmic reticulum stress (ERs) protein expression. All injury was attenuated by treatment with an HMGB1 inhibitor GA, a RAGE blocker FPS-ZM1, and an ERs inhibitor 4-PBA. In vitro, A549 cells challenged with rHMGB1 exhibited significant increases in the levels of proteins in the RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway and in apoptosis, all of which were significantly inhibited by pre-treatment with lenti-shPERK and an anti-RAGE antibody. CONCLUSION: The HMGB1-RAGE axis induces apoptotic injury during ARDS, possibly through PERK/eIF2α/ATF4-mediated ERs.
Authors: F Katsuoka; Y Kawakami; T Arai; H Imuta; M Fujiwara; H Kanma; K Yamashita Journal: Biochem Biophys Res Commun Date: 1997-09-18 Impact factor: 3.575
Authors: Robert Paine; Theodore J Standiford; Ronald E Dechert; Marc Moss; Gregory S Martin; Andrew L Rosenberg; Victor J Thannickal; Ellen L Burnham; Morton B Brown; Robert C Hyzy Journal: Crit Care Med Date: 2012-01 Impact factor: 7.598
Authors: Michael A Matthay; Rachel L Zemans; Guy A Zimmerman; Yaseen M Arabi; Jeremy R Beitler; Alain Mercat; Margaret Herridge; Adrienne G Randolph; Carolyn S Calfee Journal: Nat Rev Dis Primers Date: 2019-03-14 Impact factor: 52.329